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Risk factors, sequellae and intervention studies for the treatment of diabetes mellitus in Native American populations
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Risk factors, sequellae and intervention studies for the treatment of diabetes mellitus in Native American populations
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Content
Risk Factors, Sequellae and Intervention Studies
for the Treatment of Diabetes Mellitus
in Native American Populations
Copyright 2001
by
Susan Smith Gilliland
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
in Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(EPIDEMIOLOGY)
May 2001
Susan Smith Gilliland
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UMI Number: 3027720
Copyright 2001 by
Gilliland, Susan Smith
All rights reserved.
___ ®
UMI
UMI Microform 3027720
Copyright 2001 by Bell & Howell Information and Learning Company.
All rights reserved. This microform edition is protected against
unauthorized copying under Title 17, United States Code.
Bell & Howell Information and Learning Company
300 North Zeeb Road
P.O. Box 1346
Ann Arbor, Ml 48106-1346
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UNIVERSITY OF SOUTHERN CALIFORNIA
THE GRADUATE SCHOOL
UNIVERSITY PARK
LOS ANGELES. CALIFORNIA 90007
This dissertation, written by
Susan SrrOfh L it land
under the direction o f h&lC. Dissertation
Committee, and approved by all its members,
has been presented to and accepted by The
Graduate School, in partial fulfillment of re
quirements for the degree of
DOCTOR OF PHILOSOPHY
‘ er^n /
....L r r r ~ C : .
Dean of Graduate Studies
Date 2001.
DISSERTATION COMMITTEE.
( A ^ k u i......
7 // ‘ 7
J .....
u
Chairperson
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Susan Smith G illiland Stanley P. Azen, PhD
Janette S. Carter, MD
Risk Factors, Sequellae, and Intervention Studies
For the Treatment of Diabetes Meilitus in Native American Populations
Diabetes meilitus was essentially unknown among Native Americans in 1900. Since
the 1950's, type 2 diabetes has increased dramatically and today Native Americans
have the highest prevalence of type 2 diabetes in the world. In addition, Native
American children, once thought to be at low risk for type 2 diabetes, are now being
diagnosed with type 2 diabetes at increasing frequency. The rate of diabetes-related
complications such as kidney failure, blindness, amputations and infections are
disproportionately higher among Native Americans than the general US population.
The increase in mortality associated with type 2 diabetes over last 40 years provides
further evidence for the consequences of ignoring the urgent need to prevent or delay
the complications of diabetes. The high and increasing prevalence, especially among
the young, combined with the high risk for complications and high mortality rates
portend an even greater burden among Native Americans if control of risk factors for
complications is not improved. Based on these alarming trends, there is an urgent
need for the development and dissemination of effective prevention interventions
that are culturally appropriate and clinically comprehensive.
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In 1993 a NIH-funded study, the Native American Diabetes Project, was conducted
to evaluate a community-based intervention program in Native American
populations. The results from the study are encouraging. The study shows that a
culturally competent lifestyle intervention is effective in improving glycemic control
among Native American people with diabetes. This beneficial outcome has the
potential to substantially reduce microvascular complications and mortality. The
effectiveness of the Native American Diabetes Project intervention may reflect the
use of: 1) intervention materials that were developed with input from Native
American community members and were pertinent to Native communities, and 2)
social learning theory as an approach to how people learn. The well-accepted
culturally appropriate lifestyle intervention offers hope in reducing the
disproportionate burden of type 2 diabetes in minority populations.
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ii
ACKNOWLEDGEMENTS
1 am indebted to Drs. Janette Carter and Stanley Azen whose competent research and
career advice was invaluable. Not only did Drs. Carter and Azen guide me to this
research project they directed me to a new career path. Their generosity with their
time and patience are deeply appreciated. Drs. Gauderman, Jacque, and Stram
served on my committee and they deserve special thanks for their efforts.
I wish to thank the Department of Preventive Medicine at the University of Southern
California for the superb training opportunities I have had. Several members of the
Department of Biostatistics were instrumental in the successful completion of this
research effort. Mary Trujillo and Patty Huezo provided excellent administrative
support.
Last, but not least,, this work could not have been accomplished without the loving
support of Frank, my husband. His understanding, patience and excellent editorial
comments are greatly appreciated.
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iii
TABLE OF CONTENTS
1.0 INTRODUCTION....................................................................... 1
2.0 REVIEW OF THE LITERATURE: Orientation to Type 2 Diabetes Meilitus....6
2.1 Introduction ...........................................................................................6
2.2 Type 2 Diabetes Meilitus.......................................................................7
2.3 Pathophysiology of Type 2 Diabetes Meilitus.................................... 9
2.4 Definitions of Type 2 Diabetes Meilitus...................... 12
3.0 REVIEW OF THE LITERATURE: Descriptive Epidemiology and
Complications of Type 2 Diabetes......................................................... 22
3.1 Descriptive Epidemiology of Type 2 Diabetes Meilitus........................ 23
3.2 Complications of Diabetes......................... 26
3.2.1 Nephropathy......................................................... 27
3.2.2 Visual Disorders.................................................... 30
3.2.3 Neuropathy.................................................................. 33
3.2.4 Macrovascular Complications .................. 36
3.2.5 Infections................ 38
4.0 REVIEW OF THE LITERATURE: Risk Factors for the Onset and
Complications of Type 2 Diabetes Meilitus .................................................... 44
4.1 Risk Factors for the Onset of Type 2 Diabetes Meilitus........................ 44
4.2 Demographic Risk Factors ......... 45
4.2.1 Gender..................... 45
4.2.2 Age................................................. 45
4.2.3 Ethnicity.................................................................................. 46
4.3 Behavioral and Lifestyle Factors........................................... 46
4.3.1 Obesity......................................................................... 46
4.3.2 Physical Inactivity................................................................... 48
4.3.3 D iet................................... 50
4.3.4 Westernization ................................... 51
4.4 Genetic Factors............................................ 53
4.5 Physiologic Risk Factors ...................... 56
4.5.1 Impaired Glucose Tolerance......................................... 56
4.5.2 Insulin Resistance.............................................................. 57
4.5.3 Gestational Diabetes.............................................................. 59
4.6 Physiologic Risk Factors for the Complications of Type 2 Diabetes .... 60
4.6.1 Hyperglycemia ................................ 61
4.6.2 Hypertension.................. 62
4.6.3 Dyslipidemia................................................... 65
4.6.4 Obesity ............. 66
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iv
4.6.5 Joint Effects of Hyperglycemia, Hypertension, Dyslipidemia
and Obesity in Native Americans................... 67
5.0 REVIEW OF THE LITERATURE: Interventions to Prevent or Delay
Complications................. 76
5.1 Interventions to Prevent or Delay Complications................ 76
5.2 Clinical Interventions ,.................................... 77
5.2.1 Diabetes Control and Complications Trial........................... ..78
5.2.2 United Kingdom Prospective Diabetes Study ........... 79
5.3 Lifestyle Interventions ...... 81
5.3.1 The Steno Type 2 Randomized Trial .............................. 87
5.4 Motivation for Intervention among Native American Populations 88
6.0 The Native American Diabetes Project: Results of a Lifestyle Intervention for
Native American Adults with Diabetes in New Mexico........................................ .92
6.1 Introduction................................................ 94
6.2 Methods......................................... 95
6.2.1 Study Design............................................................................95
6.2.2 Chart Audit...................................................... 96
6.2.3 Intervention Outcome Measures............................................ 97
6.2.4 Intervention................................................................. 97
6.2.5 Statistical Analysis.................................. 99
6.3 Results................................................................................................... 100
6.3.1 Description of Study Participants...........................................100
6.3.2 Change in Outcomes........................ 104
6.4 Discussion.............................................................................. 108
7.0 Grant Proposal............................................................................................. ....117
7.1 Specific Aims....................................................................................... 118
7.2 Background and Significance.................................. 121
7.2.1 Magnitude of Type 2 Diabetes among Native American
Populations................................................................................ 121
7.2.2 Diabetes Complications and Native American Populations... 122
7.2.2.1 Nephropathy ....... 122
7.2.2.2 Retinopathy.............................................................123
7.2.2.3 Neuropathy ............... 123
7.2.2.4 Diabetes-related Mortality................................. 124
7.2.2.5 Infections....................... 124
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V
7.2.3 Risk Factors for the Complications of Type 2 Diabetes among
Native American Populations............................................ 125
7.2.3.1 Hyperglycemia............................... 125
123.2 Hypertension .. 127
7.23,3 Dyslipidemia and Obesity ...............................128
7.2.4 Models for Intervention.........................................................129
7.3 Preliminary Studies.................. ..131
7.3.1 Native American Diabetes Project: Physical Activity among
Native Americans, with diabetes.............. 131
7.3.2 Native American Diabetes Project: Higher HbAlc Levels
among Younger Native American People with Diabetes................132
7.3.3 Native American Diabetes Project: A Lifestyle Intervention. 132
7.3.4 Development of a Self-Management Intervention..................135
7.4 Research Design and Methods........................................................... ..136
7.4.1 Overview of the Study Design...............................................136
7.4.2 Description of the Study ....... 138
7.4.2.1 Target Population and Research Setting.....................138
7.4.2.2 Sources of Subjects.................................. .139
7.4.23 Recruitment.................................................................139
7.4.2.4 Intervention Description.................. 142
7.4.3 Data Acquisition...................................... 145
7.4.3.1 Interview Administered Questionnaire.......................145
7.43.2 Clinical Measures to Assess Complications Associated
with Diabetes......................................................................147
7.4.33 Medical Record Review.............................................149
7.4.3.4 Data Editing................................................................150
7.4.3.5 Quality Control.......................................... 151
7.4.4 Statistical Analyses.................................................................152
7.4.4.1 Overall Analysis........................................................ 152
7.4.4.2 Sample Size and Power ..................................153
7.4.5 Timeline..................................................................................154
7.5 Potential Limitations..............................................................................155
7.6 Human Subjects.............................. 156
7.7 Vertebrate Animals................................................................................158
8.0 Summary, Conclusions and Recommendations.............................................. 165
8.1 Summary ................................................... .165
8.2 Conclusions............................................................................ 166
8.3 Recommendations.................... 167
Bibliography..................... 169
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LIST OF TABLES
vi
Table 6.1 Selected pre-intervention demographic and clinical characteristics of
evaluable NADP participants.............................................. 103
Table 6.2 Post-intervention change in adjusted mean diastolic blood pressure,
cholesterol, triglyceride levels for family and friends (FF) and one-on-one (00)
intervention aims and usual care control arm (UC) and combined intervention
arms................................................................ 107
Table 7.1 Prevalence of diabetes in North America Native populations................139
Table 7.2 Titles for lifestyle intervention, Native American Diabetes Project,
and the proposed self-management intervention, Enhancing self-management
activities........................................................ ..143
Table 7.3 Data acquisition from in-person interview...............................................148
Table 7.4 Data acquisition from medical record review..........................................150
Table 7.5 Sample size needed to detect 0.7% difference in HbAlc between
intervention and control arm, alpha=0.05,1-Besta=0.8, 0.9 ......................... ..153
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vii
LIST OF FIGURES
Figure 2.1 The 2-Stage Model Of Type 2 Diabetes...................... 11
Figure 6.1 Intervention Profile Of The Native American Diabetes Project 101
Figure 6.2 Post-Intervention Change In Adjusted Mean Hbalc For Family
And Friends (FF) And One-On-One (00) Intervention Arms And Usual
Care Control Arm................................................................................................ 105
Figure 6.3 Change In Adjusted Mean Weight Over The Intervention Period
For The Intervention Arms, Family And Friends (FF) And One-On-One
And Usual Care (UC) And Combined Intervention Arms................................ 106
Figure 7.1 Opportunities For Intervention To Prevent/Delay The
Complications Associated With Type 2 Diabetes......................................... 130
Figure 7.2 Post-Intervention Change in Adjusted Mean HbAlc for Family
and Friends, One on One versus Control versus Combined Intervention
Arms.................................................................................................................... 135
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1.0 INTRODUCTION
l
Diabetes meilitus was virtually unknown among Native Americans in 1900.1
However, beginning in the 1950’ s the prevalence of type 2 diabetes has risen
dramatically in Native communities and today there is an epidemic of type 2 diabetes
among many Native American p o p u latio n s3 The Pima tribe of Arizona has the
highest prevalence of type 2 diabetes in the US and the world today, reaching 70% in
the 55-64 year age group 4-6 Among New Mexico Native American tribes the
prevalence of type 2 diabetes is about 30% in those age 35+ y e a r s . ^ Initially diabetes
was thought to be a benign disease among Native Americans, but it is now clear that
the rate of diabetes related complications such as kidney failure, blindness,
amputations and infections are disproportionately higher among Native Americans
than the general US population.^ ■
Today we know the complications of diabetes can be prevented or delayed with
appropriate treatment and modification of l i f e s t y l e . ^ 10 Two important trials, the
Diabetes Control and Complications Trial and the United Kingdom Prospective
Diabetes Study, have demonstrated that tight control of blood glucose levels and
hypertension can reduce rates of microvascular complications including
nephropathy, retinopathy, and neuropathy in both type 1 and type 2 diabetes. 10
Another important clinical trial, the Steno Study, showed that an intensified lifestyle
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2
and clinical intervention in people with type 2 diabetes who had microalbuminuria
slowed the progression to nephropathy, retinopathy and neuropathy. *1
Despite the high prevalence of type 2 diabetes and its complications among Native
Americans, a limited number of diabetes lifestyle interventions have been designed
specifically to reduce morbidity and mortality among Native American populations
with diabetes. *2,13 Native American Diabetes Project (NADP) was developed
to fulfill this unmet need. The NADP was a community intervention to reduce the
risk factors associated with the complications of type 2 diabetes. The NADP was
initiated in 1993 and data were collected from 1994-1997. The primary objective of
the intervention was to determine the effects of a culturally appropriate, participatory
lifestyle intervention on risk factors for diabetes complications in eight Pueblo
communities in New Mexico. People with diabetes participated in one of two
intervention groups held in five sessions over twelve months and included 1)
meetings of family and friends or 2) one-on-one appointment For comparison
purposes, a control group received their usual medical care. The primary outcomes
were change in glycemic level (HbAlc) and weight.
This dissertation presents the results of the NADP focusing on our primary
outcomes, change in HbAlc and weight. We provide the context for the intervention
through a review of the pathophysiology of type 2 diabetes meilitus (Chapter 2) and
a presentation of the descriptive epidemiology (Chapter 3) and risk factors for type 2
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3
diabetes and its complications (Chapter 4). We then review clinical and lifestyle
secondary interventions to prevent the complications of diabetes (Chapter 5). Type 2
diabetes in Native American populations, the background to the Native American
Diabetes Project and the results from the analysis of the NADP lifestyle intervention
are presented (Chapter 6). Based on the findings from NADP we propose the next
step in this program of research in the form of a grant application with the specific
aim to evaluate a comprehensive lifestyle and self-management intervention for
diabetes in the Pima and Tohono O'Odham tribes (Chapter 7). Finally, we provide a
conclusion and overall summary regarding diabetes in Native American populations
and the place of culturally appropriate lifestyle interventions in secondary prevention
efforts (Chapter 8).
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4
References for Chapter 1
1. Gohdes D. Diabetes in North American Indians and Alaska Natives. In: Group
NDD, ed. Diabetes in America. Second ed. Bethesda: National Institutes of Health;
1995:683-701.
2. Gohdes D, Bennett PH. Diabetes in American Indians and Alaska Natives.
Diabetes Care. 1993;16:214-5.
3. Howard BY, Lee ET, Cowan LD, et al. Rising tide of cardiovascular disease in
American Indians. The Strong Heart Study. Circulation. 1999;99:2389-95.
4. Charles MA, Eschwege E, Bennett PH. [Non-insulin-dependent diabetes in
populations at risk: the Pima Indians]. Diabetes & Metabolism. 1997;23:6-9.
5.Dabelea D, Hanson RL, Bennett PH, Roumain J, Knowler WC, Pettitt DJ.
Increasing prevalence of Type II diabetes in American Indian children. Diabetologia.
1998;41:904-10.
6. Knowler WC, Saad MF, Pettitt DJ, Nelson RG, Bennett PH. Determinants of
diabetes meilitus in the Pima Indians. Diabetes Care. 1993;16:216-27.
7. Carter J, Horowitz R, Wilson R, Sava S, Sinnock P, Gohdes D. Tribal differences
in diabetes: Prevalence among American Indians in New Mexico. Pub Health Rep.
1989;104:665-669.
8. Carter JS, Pugh JA, Monterrosa A. Non-insulin-dependent diabetes meilitus in
minorities in the United States [see comments], Ann Intern Med. 1996;125:221-32.
9. DCCT. The effect of intensive treatment of diabetes on the development and
progression of long-term complications in insulin-dependent diabetes meilitus.
NEJM. 1993;329:977-86.
10. UKPDS. Intensive blood-glucose control with sulphonylureas or insulin
compared with conventional treatment and risk of complications in patients with type
2 diabetes. Lancet. 1998;352:837-853.
11. Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial
intervention in patients with type 2 diabetes meilitus and microalbuminuria: the
Steno type 2 randomised study [see comments]. Lancet. 1999;353:617-22.
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12. Leonard B, Leonard C, Wilson R. Zuni Diabetes Project. Public Health Rep.
1986;101:282-88.
13. Dawson L. Taking Diabetes Education to Home and Hearth. Diabetes Spectrum.
1993;6:346-349.
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6
2.0 REVIEW OF THE LITERATURE
Orientation to Type 2 Diabetes Mellitiis
Summary of Key Points
• Diabetes was first described in the first century AD
• Type 2 diabetes meilitus is a broad underlying disorder thought to include the
insulin resistance syndrome
• Pathogenesis o f type 2 diabetes meilitus is not fully understood but three factors
are likely involved in the development:
• Genetic factors that predispose an individual to diabetes
• Defects in pancreatic beta-cell functioning
• Insulin resistance
2.1 Introduction
Diabetes was first described in the first century AD by Arataeus who gave diabetes
its name. 1 Arataeus observed that people who had diabetes had an excessive volume
of urine. Over the centuries others described the sweet taste of the urine among
people with diabetes and added meilitus to it's name. * Nonetheless, it was not until
1921, nearly 2000 years later, that Frederick Banting of Canada discovered insulin,
and diabetes was no longer considered a universally fatal disease. *
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Insulin treatment was not the ’ cure' for diabetes that people had hoped. While
insulin restored the patient's health and increased survival, complications, which
were once thought to be rare as people did not live long enough to develop them,
emerged. Gradually it was discovered that people with diabetes suffered from severe
complications that affected their eyes, kidneys, and nervous system.
The distinction between the major types of diabetes, type 1 and type 2 diabetes, was
an important advance. Clinicians had long appreciated the differences between the
two types of diabetes, but did not understand the pathogenetic mechanisms of the
diseases. In 1936, Himsworth demonstrated that the two types of diabetes meilitus
had considerable biochemical differences; type 1 diabetes was associated with
insulin lack but preserved insulin sensitivity whereas, type 2 diabetes was associated
with insulin resistance. 1
2.2 Type 2 Diabetes Meilitus
Type 2 diabetes meilitus is a descriptive term used to describe a broad underlying
disorder that in most cases is thought to include the metabolic syndrome, called the
insulin resistance syndrome, syndrome X, or chronic metabolic s y n d r o m e .^ The
insulin resistance syndrome is a non-random association that is often related to a
common e l e m e n t . ^ In the insulin resistance syndrome, central location of fat,
impaired glucose tolerance, hyperinsulinemia, dyslipidemia, and hypertension are
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8
clustered with insulin r e s i s t a n c e . 3? 4 Obesity is not an essential elem ent of the
insulin resistance syndrome, but is often p r e s e n t . ^
Type 2 diabetes is often asymptomatic for many .years, and.can be present at any age,
although it most commonly appears in adults. Diabetes is often 'discovered* when
people present to their health care provider with one or more of the complications
associated with diabetes, or the diabetes is discovered incidentally with an abnormal
blood or urine test as a part of a routine physical examination.
Type 2 diabetes meilitus accounts for approximately 90% of all cases of diabetes in
residents of western countries. ^ Persons with type 2 diabetes meilitus are not
dependent on exogenous insulin, as are people with type 1 diabetes meilitus, yet they
may need exogenously delivered insulin in order to control their hyperglycemia. The
diagnosis of type 2 diabetes meilitus is generally made among adults; however, this
is not always the case. Today, among Native American populations, the onset of type
2 diabetes is occurring in children ten years old and younger A 2
There are three accepted methods used to diagnose type 2 diabetes meilitus^; 1)
symptoms of diabetes plus a "casual" plasma glucose concentration >200mg/dL,
where "casual" is defined as any time of day without regard to time since last meal
and the classic symptoms of diabetes include polyuria, polydipsia, and unexplained
weight loss, or 2) a fasting plasma glucose of >126 nag/dL, or 3) a 2-hour
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9
postprandial glucose >200 mg/dL during an oral glucose tolerance test (OGTT).
The OGTT should be performed as described by World Health Organization using a
glucose load of 75 grams. Any of these three criteria for diagnosis are acceptable, as
long as each is confirmed on a subsequent day by any one of the three methods.
2.3 Pathophysiology of Type 2 Diabetes Meilitus
The pathogenesis of type 2 diabetes is not fully understood, but there are at least
three factors that are important in the development. The main form of type 2 diabetes
is associated with 1) genetic or ethnic factors that predispose an individual to
diabetes; 2) defects in pancreatic beta-cell functioning and; 3) insulin resistance in
insulin sensitive tissues (muscle, liver and fat).2> 9 , 1 0 T y p e 2 diabetes appears to be
a result of an interaction between the genetic susceptibility of an individual and
exposure to environmental and lifestyle factors. Currently it is unknown, and
controversial, whether the defects in the beta-cells are secondary to insulin resistance
or concurrent with insulin resistance or if beta-cell failure precedes the development
of insulin resistance. 1 1 Insulin resistance is the subnormal response to a given
concentration of insulin and plays a central role in the pathogenesis of type 2
diabetes.9> 10, 12,13 The mechanisms responsible for insulin resistance are not
clear, but several ideas have been proposed including decreased activation of the
enzymes, glucokinase and glycogen synthase, and decreased levels of cell-membrane
glucose transporters and increased levels of circulating fatty acids.2 Insulin
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10
resistance is more severe among people with central body adiposity and in people
with low levels of physical a c t i v i t y . 2 . 14-17
Figure 2.1 portrays a two-stage model that includes hyperinsulinemia and insulin-
resistance and has been proposed for the pathogenesis of the major form of type 2
diabetes. * The first step in the process is development of insulin resistance that
leads to an increase in insulin secretion, hyperinsulinemia, with the plasma glucose
levels remaining normal. It is generally believed that the process of hyperinsulinemia
is compensating for the process of insulin resistance, however, it may be that the
inverse is true, that hyperinsulinemia causes insulin resistance. The increase in
insulin resistance may be due to the individual's genetic susceptibility and
environmental and lifestyle factors. ** Genetic factors are thought to include
polymorphisms in the insulin gene, the insulin receptor gene, the adenine deaminase
gene and other genes, glucose transporters, Native American admixture, and the
genes involved in obesity and fat patterning. Recently researchers found genetic
variation in the gene encoding calpain-10 (CAPN10) was associated with type 2
d i a b e t e s . * 9 This suggests that pathways yet to be identified may be important.
The environmental and lifestyle factors that are thought to be important include
obesity, weight gain, diet (increased calorie and fat and decreased fiber intake),
physical inactivity, westernization, psychosocial factors, intrauterine environment
and other unknown factors.
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1 1
The increase in insulin resistance results in postprandial hypergyclemia, despite
hyperinsulinemia, and the person progresses from a state of normoglycemia to a state
of impaired glucose tolerance (IGT). Impaired glucose tolerance is defined as an
abnormal glycemic response to an oral glucose load that is at a level between normal
blood glucose response and a diabetes response, 11 The second step involves a
decline in insulin production along with a deficit in the beta cell functioning, which
leads to hyperglycemia in the fasting state and overt type 2 diabetes.
Figure 2.1 The 2-stage model of type 2 diabetes (Adapted from the
International Textbook of D ia b e t e s ^ O )
Normoglycemia— > i Impaired Glucose Tolerance — ->
Genetic susceptibility
\^N A admixture
Insulin resistance -->
I
hyperglycemia~>
glucose toxicity?
^B-celHunc iction->
Environmental factors,
’ N
obesity genetic? ;
physical activity
►
B-cell defect? i
diet? aging?
others?
~>Type 2
diabetes
Fasting
hyperglycemia
Z
Insulin
deficiency
a
Hepatic .
glucose T
output
Alternatively, another model has been proposed for the etiology of type 2 diabetes.
The latent beta-cell defect model assumes that the beta cells have been injured early
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12
in life, before the development of insulin resistance. 1 1 It is thought that an injury
can occur during a viral infection, an exposure to a chemical toxin or from an
inherited genetic defect leading to a reduction in functional beta cells, which are then
further reduced by the same genetic and lifestyle factors proposed in the two-step
model. 11 Moreover, it has been hypothesized that people who carry certain alleles at
HLA and non-HLA ioci can have injury to the beta cells that leads to autoimmunity
toward the beta cells just as in type 1 diabetes, and this injury leads to a reduction in
beta cell mass and function that contributes to an abnormal glycemic response. 1 *
2.4 Definitions of Type 2 Diabetes
The following tables provide descriptions of commonly used terms related to
diabetes and it's treatment.
Albuminuria The presence of protein in. the urine, usually a sign of
kidney disease.
Beta Cell A type of cell in the pancreas in areas called the islets of
Langerhans. Beta cells make and release insulin, a
hormone that controls the level of glucose in the blood.
Blood Glucose The main sugar that the body makes from the three
elements of food (proteins, fats, and carbohydrates) but
mostly from carbohydrates. Glucose is the major source of
energy for living cells and is carried to each cell through
the bloodstream. However, the cells cannot use glucose
without the help of insulin.
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13
Blood Glucose
Meter
A machine that helps test how much glucose is in the
blood. A specially coated strip containing a fresh sample
of blood is inserted into the machine, which calculates the
correct level of glucose in the blood sample and shows the
result in a digital display.
Blood Glucose
Monitoring
A way of testing how much glucose is in the blood. A
drop of blood, usually taken from the fingertip, is placed
on the end of a specially coated strip, called a testing strip.
The strip is inserted into a small machine, called a meter,
which "reads" the strip and shows the level of blood
glucose in a digital window display. Blood testing is more
accurate than urine testing in monitoring blood glucose
levels because it shows what the current level of glucose
is, rather than what the level was an hour or so previously,
and with greater precision.
Chronic
Metabolic
Syndrome
See insulin resistance syndrome.
Creatinine A chemical found in the blood and passed in the urine. A
creatinine clearance test of the amount of creatinine in
blood or in blood and urine shows if the kidneys are
working properly or if they are diseased.
Dialysis A method for removing waste such as urea from the blood
when the kidneys can no longer do the job. The two types
of dialysis are: hemodialysis and peritoneal dialysis. In
hemodialysis, the patient's blood is passed through a tube
into a machine that filters out waste products. The
cleansed blood is then returned to the body.
In peritoneal dialysis, a special solution is run through a
tube into the peritoneum, a thin tissue that lines the cavity
of the abdomen. The body's waste products are removed
through the tube. There are three types of peritoneal
dialysis. Continuous ambulatory peritoneal dialysis
(CAPD), the most common type, needs no machine and
can be done at home. Continuous cyclic peritoneal
dialysis (CCPD) uses a machine and is usually performed
at night when the person is sleeping. Intermittent
peritoneal dialysis (IPD) uses the same type of machine as
CCPD, but is usually done in the hospital because
treatment takes longer. Hemodialysis and peritoneal
dialysis may be used to treat people with diabetes who
have kidney failure.
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14
Dyslipidemia High cholesterol and triglyceride levels associated with
increased risk of atherosclerosis, narrowing and blocking
of blood vessels due to cholesterol build-up.
End-Stage Menal
Disease
Damage to the kidneys so great that either dialysis or a
kidney transplant is needed.
Fasting Blood
Glucose Test
A method for finding out how much glucose is in the
blood. The test can show if a person has diabetes. A blood
sample is taken in a lab or doctor's office. The test is
usually done in the morning before the person has eaten.
The normal range for blood glucose is from 70 to 110
mg/d!, depending on the type of blood being tested. If the
level is equal to or over 126 mg/dl, it usually means the
person has diabetes.
Focal Laser
treatment
Laser surgery to the retina of the eye.
Funduscopy A test to look at the back area of the eye to see if there is
any damage to the vessels that bring blood to the retina.
Gestational
Diabetes
Diabetes that develops only during pregnancy.
Glaucoma An eye disease associated with increased pressure within
the eye. Glaucoma can damage the optic nerve and cause
impaired vision and blindness.
Glomerular
Filtration Mate
Measure of the kidneys' ability to filter and remove waste
products.
Glomeruli Network of tiny blood vessels in the kidneys where the
blood is filtered and waste products are removed.
Glucagon A hormone that raises the level of glucose in the blood.
The alpha cells of the pancreas (in areas called the islets.
of Langerhans) make glucagon when the body needs to
put more sugar into the blood.
Glucose A simple sugar found in the blood. It is the body's main
source of energy; also known as dextrose.
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15
Glucose
Tolerance Test
A test to see if a person has diabetes. The test is given in a
lab or doctor's office in the morning before the person has
eaten. A sample of blood is taken from the person. Then
the person drinks a liquid that has glucose in it. After two
hours, a second blood sample is drawn. The object is to
see how well the body handles the glucose in the blood
over time.
Glycated
Hemoglobin
(HbAlc)
The substance of red blood cells that carries oxygen to the
cells and sometimes joins with glucose (sugar). Because
the glucose stays attached for the life of the cell (about 4
months), HbAlc can be used to measure what the person's
average blood glucose level was for that period of time.
Glycemie
Response
The effect of different foods on blood glucose levels over
a period of time. Researchers have discovered that some
kinds of foods may raise blood glucose levels more
quickly than other foods containing the same amount of
carbohydrates.
Glycogen A substance made up of sugars. It is stored in the liver and
muscles and releases glucose into the blood when needed
by cells. Glycogen is the chief source of stored fuel in the
body.
Glycogenesis (or
glucogenesis)
The process by which glycogen is formed from glucose.
Glycosuria Having glucose in the urine. Occurs when glucose levels
are higher than normal in the blood.
HDL Cholesterol High-density lipoproteins are fats made by the liver that
collect excess cholesterol from the blood and blood
vessels and transport it back to the liver, the "good"
cholesterol.
Human Insulin Man-made insulins that are similar to insulin produced by
your own body. Human insulin has been available since
October 1982.
Hyperglycemia Too high a level of glucose in the blood; a sign that
diabetes is out of control. Many things can cause
hyperglycemia. It occurs when the body does not have
enough insulin or cannot use the insulin it does have to
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16
turn glucose into energy. Signs of hyperglycemia are a
great thirst, a dry mouth, and a need to urinate often.
Hyperinsulinism Too high a level of insulin in the blood. This term most
often refers to a condition in which the body produces too
much insulin. Researchers believe that this condition may
play a role in the development of type 2 diabetes and in
hypertension.
Hyperlipidemia High levels of cholesterol and other fats in the blood.
Hypoglycemia Too low a level of glucose in the blood. This occurs when
a person with diabetes has injected too much insulin,
eaten too little food, or has exercised without extra food.
A person with hypoglycemia may feel nervous, shaky,
weak, or sweaty, and have a headache, blurred vision, and
hunger. Taking small amounts of sugar, sweet juice, or
food with sugar will usually help the person feel better
within 10-15 minutes.
Impaired Glucose
Tolerance (IGT)
IGT occurs when the body cannot use some of the insulin
that it makes, and blood glucose levels are high, but not in
the range of having diabetes.
Insulin A hormone that helps the body use glucose for energy.
The beta cells of the pancreas (in areas called the islets of
Langerhans) make the insulin. When the body cannot
make enough insulin on its own, a person with diabetes
must inject insulin made from other sources, i.e., beef,
pork, human insulin (recombinant DNA origin), or human
insulin (pork-derived, semisynthetic).
Insulin
Resistance
Insulin resistance is the subnormal response to a given
concentration of insulin and the body cannot efficiently
use the insulin that it produces.
Insulin
Resistance
Syndrome
Term describing a combination of health conditions that
place a person at high risk for heart disease. These
conditions are type 2 diabetes, high blood pressure, high
insulin levels, and high levels of fat in the blood. Also
called syndrome X, or chronic metabolic syndrome.
Insulin Sensitivity The normal response to a given concentration of insulin
and the body can efficiently use insulin that it produces.
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17
Islets of
Langerhaas
Special groups of cells in the pancreas. They make and
secrete hormones that help the body break down and use
food. Named after Paul Langerhans, the German scientist
who discovered them in 1869, these cells sit in clusters in
the pancreas. There are five types of cells in an islet: beta
cells, which make insulin; alpha cells, which make
glucagon; delta cells, which make somatostaton; and PP
cells and D1 cells, about which little is known.
LDL cholesterol Low-density lipoproteins that have a very high
concentration of cholesterol and are responsible for the
build-up in the walls of the arteries that leads to
atherosclerosis, the "bad" cholesterol.
Macrovascular
Disease
A disease of the large blood vessels that sometimes occurs
when a person has had diabetes for a long time. Fat and
blood clots build up in the large blood vessels and stick to
the vessel walls. Three kinds of macrovascular disease are
coronary disease, cerebrovascular disease, and peripheral
vascular disease.
Macular edema Accumulation of fluid and swelling in the macular area of
the retina.
Microvasctilar
Disease
Disease of the smallest blood vessels that sometimes
occurs when a person has had diabetes for a long time.
The walls of the vessels become abnormally thick but
weak, and therefore they bleed, leak protein, and slow the
flow of blood through the body. Then some cells, for
example, the ones in the center of the eye, may not get
enough blood and may be damaged.
Nephropathy Kidney or renal failure.
Neuropathy Disease of the nerves.
Nonproliferative
Retinopathy
Retinopathy associated with diabetes marked by pinpoint
leaks in blood vessels to the retina and changes to the
blood vessels.
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18
Pancreas An organ behind the lower part of the stomach that is
about the size of a hand. It makes insulin so that the body
can use glucose for energy. It also makes enzymes that
help the body digest food. Spread all over the pancreas are
areas called the islets of Langerhans. The cells in these
areas each have a special purpose. The alpha cells make
glucagon, which raises the level of glucose in the blood;
the beta cells make insulin; the delta cells make
somatostatin. There are also the PP cells and the D1 cells,
about which little is known.
Polydipsia A great thirst that lasts for long periods of time and is
often a sign of diabetes.
Polyphagia Great hunger often accompanied by weight loss and a sign
of diabetes.
Polyuria Having to urinate often; a common sign of diabetes.
Postprandial
Blood Glucose
Blood taken 1-2 hours after eating to see the amount of
glucose in the blood.
Proliferative
Retinopathy
A severe form of diabetic retinopathy that includes the
growth of fragile, new blood vessels on the retina of the
eye.
Proteinuria Protein appearing in the urine in amounts large enough to
be measured by a dipstick test (300 mg/day or more) and
is an indication of advancing kidney disease.
Retinopathy Disease of the retina of the eye.
Self-Monitoring
of Blood Glucose
A way a person can test how much glucose is in the blood.
Sensorimotor
Neuropathy
Damage to the nerves of the feet and hands particularly
caused by long-term exposure to high levels of blood
glucose.
Syndrome X See insulin resistance syndrome.
Triglycerides Pats that are carried in the blood but mostly stored in fat
tissue.
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19
Type 1 Diabetes A chronic condition in which the pancreas makes little or
no insulin because the beta cells have been destroyed. The
body is then not able to use the glucose (blood sugar) for
energy. Type 1 diabetes usually comes on abruptly,
although the damage to the beta cells may begin much
earlier. The signs of Type 1 diabetes are a great thirst,
hunger, a need to urinate often, and loss of weight. To
treat the disease, the person must inject insulin, follow a
diet plan, exercise daily, and test blood glucose several
times a day. Type 1 diabetes usually occurs in children
and adults who are under age 30. This type of diabetes
used to be known as "insulin-dependent", "juvenile
diabetes," "juvenile-onset diabetes," and "ketosis-prone
diabetes."
Type 2 Diabetes The most common form of diabetes mellitus; about 90 to
95 percent of people who have diabetes have type 2
diabetes. Unlike Type 1 diabetes, in which the pancreas
makes no insulin, people with type 2 diabetes produce
some insulin, sometimes large amounts. However, either
their bodies do not produce enough insulin or their body
cells are resistant to the action of insulin (see Insulin
Resistance). People with type 2 diabetes can often control
their condition by losing weight through diet and exercise.
If not, they may need to combine insulin or oral
medications with diet and exercise. Generally, type 2
diabetes occurs in people who are over age 40. Most of
the people who have this type of diabetes are overweight.
Type 2 diabetes mellitus used to be called "non-insulin-
dependent", "adult-onset diabetes," "maturity-onset
diabetes," "ketosis-resistant diabetes," and "stable
diabetes."
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20
References for Chapter 2
1. Pyke D. Preamble: the History of Diabetes. In.: Alberti K, Zimmet P, DeFronzo R,
Keen H, eds. International Textbook o f Diabetes Mellitus. Second ed. Chichester:
John Wiley and Sons; 1997:1 -6.
2. WHO. Prevention of Diabetes Mellitus. Geneva: World Health Organization;
1994.
3. Ferrannini E. Insulin resistance, iron, and the liver. Lancet. 2000;355:2181-2.
4. de Courten M, Bennet P, Tuomilehto J, Zimmet P. Epidemiology ofNIDDM in
Non-Europids. In: Alberti K, Zimmet P, DeFronzo R, Keen H, eds. International
Textbook o f Diabetes. Chichester: John Wiley and Sons; 1997:143-170.
5. Kenny S, Aubert R, Geiss L. Prevalence and Incidence of Non-Insulin Dependent
Diabetes. In: Group NDD, ed. Diabetes in America. Second ed. Washington DC:
NIH; 1995:47-68.
6. Dabelea D, Hanson RL, Bennett PH, Roumain J, Knowler WC, Pettitt DJ.
Increasing prevalence of Type II diabetes in American Indian children. Diabetologia.
1998;41:904-10.
7. Dean H, TK Y, Flett B, Wood-Steiman P. Screening for type-2 diabetes in
aboriginal children in northern Canada. Lancet. 1998;352:1523-1524.
8. Harris M, Zimmet P. Classification of Diabetes Mellitus and Other Categories of
Glucose Intolerance. In: Alberti K, Zimmet P, DeFronzo R, Keen H, eds.
International Textbook o f Diabetes Mellitus. Second ed. Chichester: John Wiley and
Sons; 1997:9-23.
9. Knowler WC, Saad MF, Pettitt DJ, Nelson RG, Bennett PH. Determinants of
diabetes mellitus in the Pima Indians. Diabetes Care. 1993;16:216-27.
10. Bogardus C, LilSioja S, Bennett PH. Pathogenesis ofNIDDM in Pima Indians.
Diabetes Care. 1991;14:685-90.
11. Rewers M, Hamman R. Risk Factors for Non-Insulin-Dependent Diabetes. In:
Group NDD, ed. Diabetes in America. Second ed. Bethesda: National Institutes of
Health; 1995:179-220.
12. Lillioja S, Mott DM, Spraul M, et al. Insulin resistance and insulin secretory
dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective
studies of Pima Indians. N Engl J Med. 1993;329:1988-92.
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21
13. Moller D, Flier J. Insulin resistance-mechansims, syndromes, and implications. N
Engl J Med. 1991;325:938-948.
14. Trevisan R, Vedovato M, Tiengo A. The epidemiology of diabetes mellitus.
Nephrol Dial Transplant. 1998;13:2-5.
15. Knowler WC, Narayan KM, Hanson RL, et al. Preventing non-insulin-dependent
diabetes. Diabetes. 1995;44:483-8.
16. Nelson RG, Everhart JE, Knowler WC, Bennett PH. Incidence, prevalence and
risk factors for non-insulin-dependent diabetes mellitus. Prim Care. 1988;15:227-50.
17. Knowler WC, Pettitt DJ, Bennett PH, Williams RC. Diabetes mellitus in the
Pima Indians: genetic and evolutionary considerations. Am JPhys Anthropol.
1983;62:107-14.
18. Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Charles MA, Bennett PH. A two-
step model for development of non-insulin-dependent diabetes. Am J Med.
1991;90:229-35.
19. Horikawa Y, Oda N, Cox N, et al. Genetic variation in the gene encoding
calpain-10 is associated with type 2 diabetes mellitus. Nature. 2000;26:163-75.
20. Alberti K, Zimmet P, DeFronzo R, Keen H. International Textbook of Diabetes
Mellitus. Second ed. Chichester: John Wiley a n d Sons; 1997.
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22
3 J ME VIEW OF THE LITERATURE
Descriptive Epidemiology and Complications of Type 2 Diabetes
Summary of Key Points
» 625,000 new cases o f diabetes diagnosed annually in the U S.
0 Prevalence generally higher among those aged 65 years old (10.4%) compared
with those aged 18-44 years old (1.3%), although this varies by ethnicity.
0 50-fold variation o f type 2 diabetes among certain ethnic groups with the highest
prevalence among Native American populations.
0 Diabetes associated with many pathophysiologic changes that occur in a multiple
organ systems and results in increased morbidity and mortality.
0 Microvascular disease -nephropathy which progresses to end stage renal
disease (ERSD), visual disorders including retinopathy, cataracts, and glaucoma
that can advance to blindness, and neuropathies which can lead to pain, loss o f
sensation and lower extremity amputations.
0 Macrovascular diseases - ischemic heart disease, hypertension, stroke and
lower extremity amputations.
0 Infections - periodontal disease, pneumonia, and sepsis.
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3.1 Descriptive Epidemiology of Type 2 Diabetes Mellitus
23
Diabetes mellitus can be found in almost all populations in the world, but the
incidence and prevalence varies dramatically by region and ethnic groups. Diabetes
mellitus refers to a group of disorders that are characterized by high blood glucose
levels. The National Diabetes Data Group and the World Health Organization
(WHO) Expert Committee on Diabetes Mellitus recognize several major forms of
diabetes and this review will focus exclusively on type 2 diabetes mellitus.
Type 2 diabetes accounts for nearly 90% of all cases of diabetes found among
residents of Western countries J There are about 100 million persons worldwide
with type 2 diabetes mellitus and it thought that this number will increase to 230
million by the year 2010.2
Based on the National Health Interview Study conducted in the US, about 7.8 million
people had diagnosed diabetes mellitus in 1993 and 90-95%, or approximately 7.2
million, had type 2 diabetes. * It is estimated for every diagnosed case of type 2
diabetes, there is another undiagnosed case, and the actual number of people in the
US with type 2 diabetes may be closer to 15 million. 1 People with type 2 diabetes
can remain undiagnosed for some time after developing the disease as screening for
diabetes is not routinely performed and because the signs and symptoms of diabetes
are generally not clinically apparent or debilitating until about 20 or more years after
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24
the onset of the disease. Although the complications do not occur for years after
the condition develops, the occurrence of symptomatic complications are frequently
the reason people seek medical care and the diagnosis of type 2 diabetes is made
during the clinical evaluation.
The incidence rate of type 2 diabetes is about 2.4/1,000 per year and has been
constant over the last 20 years for all groups combined in the US. * In 1990-1992
about 625,000 new cases of type 2 diabetes were diagnosed annually in the US. Type
2 diabetes is a chronic disease with a long asymptomatic stage and good incidence
data is not readily available because it is very difficult to know the when the onset of
disease occurs. Because of the problems defining incidence, prevalence of diabetes is
often used as the measure of disease occurrence. It is estimated that 3.1% of the US
population has type 2 diabetes, although the prevalence varies widely by age, from
1.3% for those aged 18-44 years to 10.4% for those age 65 years and older. 1 The
prevalence of type 2 diabetes is about the same for men and women but varies
substantially among ethnic groups. In the US, type 2 diabetes is more common
among African-Americans, certain Latino and Asian groups, and Native American
populations compared with non-Hispanic whites. 1 Diabetes is more prevalent
among African-Americans at all ages compared with non-Hispanic whites. *
Prevalence of type 2 diabetes, estimated from the Hispanic National Health And
Nutrition Examination Survey 1982-1984, was higher among Mexican-American,
Puerto Ricans, and Cuban Americans in the 45-74 years age range as compared with
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25
non-Hispanic whites of the same age. 1 The prevalence of type 2 diabetes in Native
populations is high, with some tribes having the highest prevalence in the world. *
In 1986, it was estimated that diabetes-related deaths accounted for 17.2% of all
deaths among persons aged 25 years and older in the US and the overall age-adjusted
morality was approximately twice that of persons who did not have d i a b e t e s . 3
Diabetes-related mortality varies by age, sex and ethnicity. Diabetes-related
mortality increases with age. Age-specific death rates for people with diabetes in
1986 were 1% for those age 25-44 years, 2.8% for those age 45-64 years, 5.8% for
those age 65-74 years, and 13.7% for those age 75+ years? Among middle-aged
populations with type 2 diabetes the life expectancy was reduced by 5-10 years. 3
Reduction in life expectancy is greater for women with diabetes than men. 3
Diabetes ranks higher as the cause of death in racial and ethnic minority groups than
for non-Hispanic whites. 3 Rates of diabetes mortality are disproportionately high and
rising among ethnic minorities in the United States including African-American,
some Latino, Asian and Native American p o p u l a t i o n s .3
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3.2 Complications of Diabetes
26
Diabetes is a chronic, progressive disease and is associated with, many
pathophysiologic changes that occur in a number of organs that can result in
increased morbidity and m o rtality Diabetes implies a relatively poor prognosis for
the individual with diabetes. However, today we know that the complications
associated with diabetes are not inevitable and can be prevented or delayed with
secondary and tertiary prevention strategies. 5 • .
Bennett and Knowler have defined several stages in the process of diabetes
c o m p l i c a t i o n s . ^ They suggest that initially when diabetes is established, a person can
have diabetes with hyperglycemia and may not have any complications present. But
as diabetes progresses, the person may develop microvascular and macrovascular
complications that can occur without overt disability or symptoms. Finally, as the
disease progresses, people suffer from disabilities associated with the diabetes-
related complications that can lead to functional impairment and premature death.
The progressive changes can result in microvascular diseases such as nephropathy
which can progress to end stage renal disease (ERSD), visual disorders including
retinopathy, cataracts, and glaucoma that can advance to blindness, and neuropathies
which can lead to pain, loss of sensation and lower extremity amputations.
Complications also include macrovascular diseases such as ischemic heart disease,
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27
hypertension, stroke and lower extremity amputations. And finally, complications
include infections, including periodontal disease, pneumonia, sepsis, and gallbladder
disease. Many people with diabetes progress through these stages and suffer the
complications and premature death. Yet progression through the stages of diabetes
complications is not compulsory. Therefore it is essential to intervene at any of the
stages in order to prevent or delay the progression to a later stage.
3.2.1 Nephropathy
Nephropathy is a common cause of morbidity and mortality in persons with diabetes.
Nephropathy of diabetes refers to elevated urinary albumin or protein excretion in
the absence of other renal disease. ^ Normally functioning kidneys produce urine that
is free of protein. Diabetes nephropathy is due primarily to advanced glomerulopathy
or glomerulosclerosis, which is the renal expression of diabetes-related
microangiopathy. 7
Albumin is the primary component of urinary protein in persons with diabetes-
related nephropathy. Quantification of urinary protein is used to describe the severity
of nephropathy associated with diabetes. Albumin excretion can be determined in
several ways including timed urine collections (24-hour, overnight, or shorter
periods) or measuring the urinary-to-creatinine ratio in spot urine. ^
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28
Nephropathy associated with diabetes can be divided into four stages: 1)
subciinical or incipient, 2) clinical or overt, 3) advanced, and 4) end-stage renal
disease (ESRD)A ? Subciinical nephropathy is defined by a persistent increase in
the albumin excretion rate, called microalbuminuria, of 30-300 mg/24 hoursA 7
Microalbuminuria may be accompanied by hypertension and in increase in the
glomerular filtration rate, called hyperfiltrationA ? Clinical nephropathy is defined
by the presence of persistent proteinuria of >300 mg/24 hours. The presence of
microalbuminuria is associated with an increase in the mortality rate overall and
from cardiovascular deaths7 Clinical nephropathy is usually accompanied by
hypertension. Advanced nephropathy is associated with a significant drop in the
glomerular filtration rate and the kidneys no longer function effectively to remove
metabolic by-products A ? Persons with nephropathy are often placed on protein
restrictive diets in order to slow the decline of the glomerular filtration rate. 7 End-
stage renal disease requires renal dialysis or renal transplantationA ? However,
nearly 50% of persons die within 2 years of beginning dialysis. ^ Once proteinuria
occurs, progression to end stage renal disease is likely7
Nephropathy associated with type 2 diabetes appears to be increasing over time. ?
About 20-30% of people with type 2 diabetes have nephropathy7 People with
diabetes are 17 times more likely to develop nephropathy compared with people
without diabetes. ^ The prevalence of nephropathy is higher in those who have had
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29
diabetes for longer duration, but this varies by ethnicity? Among the Pima, the
cumulative incidence of end-stage renal disease ten years after the diagnosis of
proteinuria was 40%, and 15 years after the diagnosis, was 61%. This is higher than
the cumulative incidence rate of end-stage renal disease among US non-Hispanic
whites, of 11% and 17%, ten and 15 years after the onset of proteinuria,
respectively. ^ This may be related to the younger age of onset of diabetes and the
ethnic susceptibility in the Pima p o p u l a t i o n . ^ Persons with diabetes contribute more
than any other group to renal dialysis and kidney transplants.? Diabetes accounts for
about 35% of all cases of end-stage renal disease and is the leading known cause of
end-stage renal disease in the US A ? Among Native Americans, diabetes accounts
for 55% of all end-stage renal disease 7
Hypertension also plays a role in nephropathy and if left untreated, hypertension can
hasten the progression of renal disease7 Lowering blood pressure to <130/85, is the
goal in adults with hypertension.? Treatment with anti-hypertensive medications,
called ACE inhibitors, have been shown to delay the progression of nephropathy and
are recommend for adults who have hypertension and microalbuminuria or
proteinuria present.
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3,2.2 Visual Disorders
30
Complications of diabetes include several visual disorders such as retinopathy,
cataracts and glaucoma that may lead to blindness. ^ 1 Damage to the small blood
vessels in the retina can occur, called retinopathy. Diabetes-related retinopathy
includes 5 basic pathophysiologic changes: 1) formation of retinal capillary
microaneurysms, 2) excessive vascular permeability, 3) vascular occlusion, 4)
proliferation of new blood vessels and fibrous tissue on the retinal surface and optic
disc, and 5) contraction of the fibrovascular proliferation and the vitreous. 12
Microaneuiysms can be a benign process with no visual impairment, unless it is
accompanied by excessive vascular permeability, which can then result in retinal
edema and hard exudate formation, macular edema and visual impairment. 12
Macular edema has been considered to be more important in people with type 2
diabetes. 12 Vascular occlusion can progress to involvement of the terminal arterioles
and capillaries become occluded with increasing visual impairment. 12 The final and
most severe stage is retinal vasoproliferation that results in vitreous hemorrhage and
loss of vision. 12 In addition, the new vessels are often accompanied by fibrous
proliferations that can distort or detach the retina and also lead to visual loss. *2
Seven-field stereo photography is the most sensitive method to detect retinopathy A
11 Proper fundus photographs require rigorous methods to take and interpret the
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31
photographs A 1 1 If fundus photography is not available or no skilled readers of
the photographs are available then fundus examination by direct opthalmoscopy of
the dilated pupil can. be usedA 1 1 In some cases, clinical examination is better to
detect retina! thickening which is associated with macular edema. 12
It is estimated that about 15-28% of people with type 2 diabetes have retinopathy at
the time of diabetes diagnosis which is likely due to the extended period of time the
person has had diabetes but remained undiagnosed and uncontrolled A 12 The
prevalence of retinopathy increases with duration of diabetes so that after about 20
years of the disease, more than 60% of patients with type 2 diabetes will have some
degree of retinopathy and at some time in their lives 10% will develop proliferative
retinopathyA 12,13
Retinopathy of diabetes is the leading cause of new cases of adult (20-74 years)
blindness in the US. 1 1 Among people who are legally blind, 8% have diabetes as the
cause of their blindness. 11 The prevalence of blindness increases with age until
about 65-74 years, at which time the prevalence declines. 1 1 Prevalence of diabetes-
related blindness is higher in females than males. * 1 The highest prevalence of
blindness due to diabetes is among the non-white population. A 14 The incidence of
new-onset diabetes-related blindness is highest among those age 45-64 years and is
higher in females than males.
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32
Visual disorders have been reported in many Native American populations. The
prevalence of retinopathy among the Oklahoma and Pima adults with diabetes
ranged from 18-49.3%. ^ ^ Among the Sioux tribe in South Dakota the
prevalence of retinopathy among adults with diabetes was 45.3% J ? The risk factors
associated with the severity of retinopathy included mean fasting glucose, HbAlc
level, systolic blood pressure, urinary albumin-to-ereatinine ratio, renal dialysis, and
duration of diabetes. Incidence of proliferative retinopathy among the Minnesota
Chippewa tribe was found to be 12/1000 diabetes person years from 1 9 8 6 -1 9 8 8J ?
Cataracts and glaucoma are more common in people with diabetes and can also lead
to blindness. 1 * Prevalence of cataracts is about 50% higher, and the risk of glaucoma
is about 70% higher in people with diabetes than in people without diabetes. ^ A
slit-lamp examination of the lens can be used to assess presence of cataracts.4 ,11
Measurement of intraocular pressure, the optic nerve and visual field testing are
needed to determine if glaucoma is present A * * There are very few published
studies of the prevalence and incidence of cataracts among Native American
populations. An incidence study done in 1985 among the Pima population found the
rate of cataract surgery for people with diabetes was more than two times the rate of
cataract surgery for people without diabetes. ^
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The Diabetes Control and Complications Trial clearly established that intensive
diabetes management to obtain near-normal glucose levels could prevent and delay
the progression of diabetic retinopathy for the patient with type 1 d i a b e t e s . ^
Secondary and tertiary prevention methods include clinical pan-retinal laser
photocoagulation for advanced proliferative retinopathy and focal laser
photocoagulation for macular edema to prevent visual loss A 1 * Surgical treatments
exist for the visual disorders associated with cataracts and medications can be used to
treat glaucoma A 11
3,2.3 Neuropathy
Diabetes-related neuropathy may be the most common of all the complications.^
Neuropathy can be either subciinical or clinically evident and can occur in both the
peripheral and autonomic nervous systems. In the peripheral systems neuropathies
include 1) polyneuropathy that includes a distal sensorimotor neuropathy and
proximal motor neuropathy, 2) focal neuropathy that includes cranial neuropathy,
and 3) multifocal neuropathy.4 Neuropathies cause pain, paraesthia, hyperesthsia,
dysesthia, m uscle weakness, atrophy and loss of sensation of the extremities. 20
Hyperglycemia is thought to play a primary role in the effect on nerve structure or
function. A variety of pathways have been elucidated including increased activity in
the polyol pathway, altered myo-inositol metabolism and non-enzymic glycation
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34
which may interact with nerve growth factor activity, blood viscosity, circulating
platelets and. rate of synthesis and transport of intra-axonal protein.4
To determine if a person has neuropathy, a neurological exam is required to evaluate
sensorimotor activities of the extremities. There are a number of complex
neurophysiofogical methods to assess sensory and motor function. However, clinical
examinations use the monofilament method. 21 The goal of the examination is to
ascertain whether protective sensation has been lost. A IG-g (5.07) Semmes-
Weinstein monofilament is used to determine if a patient can feel the touch of the
monofilament. 21
The epidemiology of neuropathies associated with diabetes is the least well
established of ail the complications due to inconsistencies in study design, and
difficulties with assessment. ^ A consensus conference in 1988 made
recommendations for the standardization of neuropathy endpoints and some
improvements in study methods and measurements have o c c u r r e d J 2 Jn a summary
of studies among people with type 2 diabetes, the prevalence of neuropathy ranged
from 17.2% to 2 5 .8%. 13 The prevalence of neuropathy increases with age, duration
of diabetes, as well as increasing glucose i n t o l e r a n c e 2 0 In a study in Colorado,
prevalence of distal sensorimotor neuropathy among people with type 2 diabetes was
27% among the Hispanic population and 30% among non-Hispanic white
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p o p u l a t i o n .22 While there are few incidence studies of neuropathy, a study from
1993 reported that 10.6% of persons with type 2 diabetes had developed some level
of neuropathy after 5 years of diabetes duration. 23
Neuropathy is associated with pain that can be debilitating and as of yet, there is no
good treatment for the pain once it develops. Neuropathy is also the most important
factor leading to amputation among people with diabetes. 24 Because neuropathy is
associated with lack of sensation, people with diabetes are at very high risk of
developing foot ulcers. Foot ulcers affect about 15% of all people with diabetes and
are a major cause of morbidity and mortality.25 Among people with diabetes, foot
ulcers frequently lead to lower extremity amputations.
Amputations among people with diabetes are a serious concern. In a s t u d y of 733
people with either type 1 or type 2 diabetes who were 10-79 years old, 25 of the
people h a d an amputation at the end of the follow-up 7 years later.26 People who
had an amputation h a d a longer duration of diabetes and a history of nephropathy,
retinopathy, abnormal neurophysiological findings and hypertension compared with
the people who did not have an a m p u t a t i o n . 2 6 The 3-year survival a f t e r amputation
is less than 50%, so people with a neuropathy require intensive treatment in order to
prevent or delay a m p u t a t i o n s ^
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Lower extremity amputations are an important problem for Native American
populations as well. ^ A cross-sectional study of non-traumatic lower extremity
amputations from 1982 to 1987 in four Indian Health Service areas was
conducted. 27 Compared with participants without diabetes, people with diabetes had
increased risks in each age group, with a 158-fold increased risk among those aged
15-44 y e a r s . 2 7 The average annual age-adjusted incidence rates of all lower
extremity amputations among people with diabetes were 240.8/10,000 and
203.1/10,000 for the Tucson and Phoenix areas, respectively, compared to the overall
US rates of 73.1/10,000.27 Rates varied by tribal group. The rates for the Navajo and
Oklahoma areas, which have lower prevalence of diabetes, were 74.0/10,000 and
87.3/10,000, respectively. 27
3.2.4 Macrovascular Complications
The development of atherosclerosis is accelerated among people with diabetes. ^
Thus, methods to prevent it must be developed. Atherosclerosis is the most common
complication of diabetes among Europid populations and accounts for 75% of the
mortality.^ Coronary and cerebrovascular diseases are two to three times more
common among people with diabetes.^ The causes of the accelerated development of
atherosclerosis are not well understood. 2 8 However, risk factors for the
development of atherosclerosis are known and are also risk factors for diabetes and
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often are seen t o g e t h e r 28 Smoking, hypertension and dyslipidemia increase the
risk of coronary artery disease in people with diabetes .4 Hyperglycemia may also be
a risk factor for the development of atherosclerosis by inducing modifications of
lipoproteins and stimulating insulin s e c r e t io n . ^ Hyperinsulinemia is associated with
coronaiy artery disease, but the exact mechanism of the high levels of insulin and its
effect on coronary disease is not u n d e r s t o o d . ^ Obesity, particularly centrally located
obesity, is also a risk factor for atherosclerosis.^
In a study of persons with type 2 diabetes, the most important risk factors for
macrovascular complications among men were age and hypertension, but among
women, the most important factors were age and duration of diabetes. 29 in the
United Kingdom Prospective Diabetes Study, modifiable and non-modifiable risk
factors for stroke among 3776 people with new onset type 2 diabetes, aged 25 to 65
years, were studied for approximately eight years.2® Of the participants, 99 (2.6%)
had a stroke. Significant risk factors for stroke in this study were hypertension and
male sex. 20
Mortality rates due to stroke vary by ethnicity.21, 22 Mortality is higher among the
African-American population compared with non-Hispanic white population.2 H 22
However, there is very little published data on the rates of stroke for Native
American populations.22,34
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Diabetes is a major risk factor for cardiovascular disease in all tribal groups,
although rates vary among tribes.^, 35-39 Among the Pima population, who have a
low incidence of coronary heart disease but high rates of diabetes, diabetes is a major
predictor of fatal coronary heart disease.40 Between 1975 and 1984,394 deaths
occurred among 4,828 Pima persons aged 5+ years, and 199 occurred in the 1,093
persons with diabetes. Twenty-eight of the deaths were attributable to coronary heart
disease and all occurred among the 689 persons with diabetes who were aged 454-
years. No coronary heart disease deaths occurred among the 419 people without
diabetes aged 45+ years. The rate of fatal coronary heart disease among the people
with diabetes was higher in men than among women, increased with increasing age
and duration of diabetes. A higher incidence of fatal coronary heart disease was
associated with proteinuria, renal insufficiency, medial arterial calcification, diabetic
retinopathy, insulin therapy, and an abnormal electrocardiogram. The low incidence
of fatal coronary heart disease among the Pima aged 50-79 years, was less than 50%
of that found in the Framingham study, may be due to protective genetic factors,
favorable lipid profile, and the rarity of heavy smoking. 40
3.2.5 Infections
In the early 1900's many people with diabetes died of overwhelming i n f e c t i o n . 4 1
Improved treatment dramatically altered this situation, yet people with poorly
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controlled diabetes remain at high risk of developing i n f e c t i o n s .4, 41 Chronic
hyperglycemia impairs the defense mechanisms and is associated with increased
morbidity and mortality among people with diabetes 4 People with diabetes are
particularly prone to mycobacterial and anaerobic and fungal infections, including
tuberculosis, skin fungal infections, bacterial urinary infections and anaerobic
infections of deep tissues which can be serious and even life threatening.^ 41
Among Native Americans infections are a serious concern. ^ In 1987, mortality due
to tuberculosis among all Native American populations was 5.8 times higher than the
rate for the US general population. 1 8 Among the Sioux tribes, people with diabetes
were 4.4 times as likely to develop tuberculosis compared with persons without
diabetes. 18
In summary, type 2 diabetes is an important public health concern worldwide as well
as in the US. Type 2 diabetes is a chronic, progressive disease that is associated with
many pathophysiologic changes that occur in multiple organ systems and can result
in serious complications and premature mortality.
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References for Chapter 3
1 . Kenny S, Aubert R, Geiss L. Prevalence and Incidence of Non-Insulin Dependent
Diabetes. In: Group NDD, ed. Diabetes in America. Second ed. Washington DC:
NIH; 1995:47-68.
2. McKinlay J, Marceau L. US Public Health and the 21st Centuiy: Diabetes
Mellitus. Lancet. 2000;356:757-761.
3. Geiss L, Herman W, Smith P. Mortality in Non-insulin Dependent Diabetes. In:
Group NDD, ed. Diabetes in America. Second ed. Washington DC: NIH; 1995.
4. WHO. Prevention of Diabetes Mellitus. Geneva: World Health Organization;
1994.
5. Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial intervention
in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2
randomised study [see comments]. Lancet. 1999;353:617-22.
6. Bennett PH, Knowler WC. Early detection and intervention in diabetes mellitus: is
it effective? Journal o f Chronic Diseases. 1984;37:653-66.
7. Nelson R, Knowler W, Pettitt D, Bennett P. Kidney Disease in Diabetes. In:
Group NDD, ed. Diabetes in America. Second ed. Bethesda: National Institues of
Health; 1995.
8. Nelson RG, Knowler WC, McCance DR, et al. Determinants of end-stage renal
disease in Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus and
proteinuria. Diabetologia. 1993;36:1087-93.
9. Newman JM, Marfin AA, Eggers PW, Helgerson SD. End state renal disease
among Native Americans, 1983-86. Am J Public Health. 1990;80:318-9.
10. Bilous R, Marshall S. Clinical Aspects of Nephropathy. In: Alberti K, Zimmet P,
DeFronzo R, Keen H, eds. International Textbook o f Diabetes Mellitus. Chichester:
John Wiley and Sons; 1997:1363-1411.
11. Klein R, Klein B. Vision Disorders in Diabetes. In: Group NDD, ed. Diabetes in
America. Second ed. Bethesda: National Institutes of Health; 1995.
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41
12. Davis M, Kern T, Rand L. Diabetic Retinopathy. In: Alberti K, Zimmet P,
DeFronzo R, Keen H, eds. International Textbook o f Diabetes Mellitus. Chichester:
John Wiley and Sons; 1997:1413-1446.
13. Hamman R. Epidemiology of Micro vascular Complications. In: Alberti D,
Zimmet P, DeFronzo R, Keen H, eds. International Textbook o f Diabetes. Second
ed. Chichester: John Wiley and Sons; 1997:1293-1319.
14. Carter IS, Pugh JA, Monterrosa A. Non-insulin-dependent diabetes mellitus in
minorities in the United States [see comments]. Ann Intern Med. 1996;125:221-32.
15. West K, Edreich L, Stober J. A detailed study of risk factors for retinopathy and
nephropathy in diabetes. Diabetes. 1980;29:501-08.
16. Nelson RG, Wolfe JA, Horton MB, Pettitt DJ, Bennett PH, Knowler WC.
Proliferative retinopathy in NIDDM. Incidence and risk factors in Pima Indians.
Diabetes. 1989;38:435-40.
17. Berinstein DM, Stahn RM, Welty TK, Leonardson GR, Herlihy JJ. The
prevalence of diabetic retinopathy and associated risk factors among Sioux Indians.
Diabetes Care. 1997;20:757-9.
18. Gohdes D. Diabetes in North American Indians and Alaska Natives. In: Group
NDD, ed. Diabetes in America. Second ed. Bethesda: National Institutes of Health;
1995:683-701.
19. DCCT. The effect of intensive treatment of diabetes on the development and
progression of long-term complications in insulin-dependent diabetes mellitus.
NEJM. 1993;329:977-86.
20. Eastman R. Neuropathy in Diabetes. In: Group NDD, ed. Diabetes in America.
Second ed. Bethesda: National Institutes of Health; 1995,
21. ADA. Standards of Medical Care for Patients With Diabetes Mellitus. Diabetes
Care. 1998;21:1514-1522.
22. Franklin G. Sensory neuropathy in non-insulin-dependent diabetes mellitus: the
San Luis Valley Diabetes Study. AJE. 1990;131:633-643.
23. Lehtinen J, Niskanen L, Hyvonen K, Siitonen O, Uusitupa M. Nerve function
and its determinants in patients with newly-diagnosed type 2 (non-insulin-dependent)
diabetes mellitus and in control subjects - a 5 year follow-up. Diabetologia.
1993;36:68-72.
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42
24. Reiber G, Boyko E, Smith D. Lower extremity foot ulcers and amputations in
diabetes. In: Group NDD, ed. Diabetes in America. Second ed. Bethesda: National
Institutes of Heatih; 1995.
25. Palumbo P, Melton LI. Peripfaeriai Vascular Disease and Diabetes. In: Group
NDD, ed. Diabetes in America. Second ed. Bethesda: National Institutes of Health;
1995.
26. Hamalainen H, Ronnemaa T, Halonen JP, Toikka T. Factors predicting lower
extremity amputations in patients with type 1 or type 2 diabetes mellitus: a
population-based 7-year follow-up study. J Intern Med. 1999;246:97-103.
27. Valway SE, Linkins RW, Gohdes DM. Epidemiology of lower-extremity
amputations in the Indian Health Service, 1982-1987. Diabetes Care. 1993;16:349-
53.
28. Lopes-Virella M. Biochemica Aspects of Macrovascular Disease. In: Alberti K,
Zimmet P, DeFronzo R, Keen H, eds. International Textbook o f Diabetes Mellitus.
Chichester: John Wiley and Sons; 1997:1631-1642.
29. Wandell PE. Risk factors for microvascular and macrovascular complications in
men and women with type 2 diabetes. ScandJPrim Health Care. 1999;17:116-21.
30. Daws TM, Millns H, Stratton M , Holman RR, Turner RC. Risk factors for
stroke in type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study
(UKPDS) 29 [see comments]. Arch Intern Med. 1999:159:1097-103.
31. Wingard D, Barrett-Connor E. Heart Disease and Diabetes. In: Group NDD, ed.
Diabetes in America. Second ed. Bethesda: National Institues of Health; 1995.
32. Cowie D, Harris M. Physical and metabolic characteristics of persons with
diabetes. In: Group NDD, ed. Diabetes in America. Second ed. Bethesda: National
Institutes of Health; 1995.
33. Kattapong VJ, Becker TM. Ethnic differences in mortality from cerebrovascular
disease among New Mexico's Hispanics, Native Americans, and non-Hispanic
whites, 1958 through 1987. Ethnicity & Disease. 1993;3:75-82.
34. Yurgalevitch SM, Kriska AM, Welty TK, Go O, Robbins DC, Howard BV.
Physical activity and lipids and lipoproteins in American Indians ages 45-74.
Medicine & Science in Sports & Exercise. 1998;30:543-9.
35. Howard BV, Lee ET, Cowan LD, et al. Rising tide of cardiovascular disease in
American Indians. The Strong Heart Study. Circulation. 1999;99:2389-95.
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36. Howard BY, Lee ET, Cowan LD, et a l. Coronary heart disease prevalence and its
relation to risk factors in American Indians. The Strong Heart Study. Am J
Epidemiol 1995;142:254-68.
37. Howard BV. Risk factors for cardiovascular disease in individuals with diabetes.
The Strong Heart Study. Acta Diet beta!. 1996;33:180-4.
38. Howard BV, Lee ET, Yeh JL, et al. Hypertension in adult American Indians. The
Strong Heart Study. Hypertension. 1996;28:256-64.
39. Howard BV, Cowan LD, Go O, Welty TK, Robbins DC, Lee ET. Adverse effects
of diabetes on multiple cardiovascular disease risk factors in women. The Strong
Heart Study. Diabetes Care. 1998;21:1258-65.
40. Nelson RG, Sievers ML, Knowler WC, et al. Low incidence of fatal coronary
heart disease in Pima Indians despite high prevalence of non-insulin-dependent
diabetes. Circulation. 1990;81:987-95.
41. Pozzilli P, Signore A, Lesliie R. In: Infections laD, ed. International Textbook of
Diabetes Mellitus. Chichester: John Wiley and Sons; 1997:1231-1241.
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4.0 REVIEW OF THE LITERATURE
Risk Factors for the Onset and Complications of Type 2 Diabetes
Summary of Key Points
® Risk factors for tin onset of type 2 diabetes include:
« Family history o f diabetes, belonging to a certain ethnic group, obesity,
diet, physical inactivity, Westernization, glucose intolerance, insulin
resistance, gestational diabetes and in utero exposure to diabetes.
» Risk factors for diabetes-related complications include:
• Hyperglycemia, hypertension, and dyslipidemia.
4.1 Risk Factors for the Onset of Type 2 Diabetes Mellitus
Risk factors for type 2 diabetes have been extensively investigated, although risk
factors vary widely among populations. A number of consensus risk factors have
been identified including genetic, demographic, and lifestyle components. Although
the focus of this review is about the complications of diabetes, risk factors for the
onset will be presented, as they are often the same as risk factors for' complications.
In the next section, the risk factors for diabetes will be briefly reviewed as a
foundation for the discussion of determinants for complications.
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4.2 Demographic Risk Factors
45
4.2.1 Gender
In the general US population, there is little evidence that type 2 diabetes varies by
gender. 1 However, unlike the US general population, diabetes risk does vary by
gender among Native American populations. Although the data have been
inconsistent, Native American women have a slightly higher prevalence of diabetes
(13.2%) as compared to Native American men (11.0%).2
4.2.2 Age
The prevalence of type 2 diabetes is low among those under 30 years of age and
increases rapidly with age in the US. 1 While there are a shortage of incident studies
of type 2 diabetes, the US National Health Interview Study found that incidence of
diabetes increases up to age 65-73 years and then d e c l i n e s . 3
Age-specific incidence of diabetes also varies by ethnicity. In contrast to the US
general population, Native American populations have the highest risk of diabetes
among those under 40 years of age and risk decreases thereafter. * Pima Indians aged
25-29 years, had a similar prevalence as the non-Hispanic white population aged 60-
64 years. * This likely due to a cohort effect among the Native American population
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46
due to the increased risk among the later birth cohort at younger ages. However,
age-specific incidence also varies by degree of Native American heritage and degree
of obesity. ^
4.2.3 Ethnicity
There are huge variations in, prevalence of type 2 diabetes by ethnicity. Among
traditional societies such as the Mapuche Indians of Chile or the Bantu in Tanzania,
diabetes is virtually non-existent, <1% have diabetes compared with more than 50%
of the adult population of Pima Indians in Arizona and Nauruan populations in the
South Pacific A 5 The 50-fold ethnic variation in prevalence may be explained, at
least in part, by differences in obesity and lifestyle f a c t o r s . 6
4.3 Behavioral and Lifestyle Factors
4.3.1 Obesity
Obesity has been found to be a major risk factor for people with diabetes in both
cross-sectional and longitudinal studies A 7-10 Obesity is positively associated with
increased rates of type 2 diabetes in both men and women of many p o p u l a t i o n s . 10
Incident data provides evidence that the degree of overweight, weight change,
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duration of obesity and distribution of body fat are all important risk factors for the
onset of diabetes. 10-13
The relationship between obesity and type 2 diabetes is not well understood as not all
obese people develop diabetes nor do only obese people develop diabetes. Moreover,
understanding the temporal relationship is further complicated because many people
with type 2 diabetes lose weight from diabetes, or because they are encouraged to
lose weight by their health care provider. 6 Several hypotheses have been proposed
for the mechanisms involved. 1) Obesity may be on the causal pathway of a
particular type of type 2 diabetes, or 2) obesity and type 2 diabetes may have a
similar genetic predisposition that leads independently both to obesity and type 2
diabetes, or 3) there is a genetic polymorphism that predisposes an individual to
obesity and type 2 diabetes, but different genetic and/or environmental factors
complete the sufficient causes for obesity and type 2 diabetes. 1
Obesity is widespread in many Native American communities and has been
increasing over the last one to two generations. 14-17 Native American males and
females of all ages have a high prevalence of obesity. 1? Broussard et al found the
prevalence of obesity in Native Americans to be higher for women then men, (16.5%
and 13.6% respectively) and higher than the US rates of obesity of 9.1% and 8.2%
respectively. 1 8 The population-based Navajo Health and Nutrition Survey conducted
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in 1991-92 reported that two thirds or more ofNative American women in all age
groups were overweight.^
Obesity among Nati ve American children is higher than the US rates for all races
combined. ^ The high rates of obesity are a recent occurrence. 16 in a study among
Pima children, Knowler et al, found that children were much heavier for their height
when compared to Pima children studied 30 years prior, suggesting that obesity
among Pima children has increased over time. ^ Because obesity is an even stronger
risk factor for diabetes if it is of long duration, the increase in obesity among
children suggests that Native American children are at very high risk for the onset of
type 2 diabetes. 13, 20 This increase in obesity may be contributing to the increasing
prevalence of type 2 diabetes in the young. 13,21
4.3.2 Physical Inactivity
Physical inactivity is a predictor of diabetes. 1 0 > 22 Some studies have found an
association between a lower prevalence of type 2 diabetes and impaired glucose
tolerance with higher levels of physical activity. 1 > 22,23 xhere are two to four fold
differences in the prevalence of type 2 diabetes between the least physically active
and the most physically active.24
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It has been shown that regular physical activity prevents insulin resistance,
although the exact mechanism of the apparent protective effect is unknown. 1
However, in a study designed to evaluate the independent and joint effects of diet
and exercise on insulin resistance, it was shown that diet alone and diet and exercise
interventions significantly decreased insulin resistance but, the exercise intervention
did not significantly change insulin resistance. 25
Among many Native American populations, physical activity has declined as
motorized transportation, television and less active occupations have become more
p r e v a l e n t . 26-28 jn a study of Pima people aged 37-59 years, Kriska et al found that
physical inactivity during the teenage years was associated with the onset of diabetes
after adjusting for differences in age, sex and obesity.29
Physical inactivity is also a risk factor for obesity and is likely on the pathway to
developing diabetes especially in those with a genetic predisposition to diabetes or
impaired glucose tolerance. ^ In a randomized clinical trial of 110,660 men and
women in China, diet and exercise interventions were used in persons with impaired
glucose tolerance.30 After six years of follow-up, the researchers concluded that the
intervention did delay the development of type 2 diabetes. The cumulative incidence
of diabetes was 67.7% (95% Cl, 59.8-75.2) in the control group, compared with
43.8% (95% Cl, 35.5-52.3) in the diet group, 41.1% (95% Cl, 33.4-49.4) in the
exercise group, and 46.0% (95% Cl, 37.3-54.7) in the diet-plus-exercise group (p <
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0,05).30 Therefore, diet and/or exercise interventions can lead to a significant
decrease in the incidence of diabetes over time among those with impaired glucose
tolerance and consequently reduce the incidence of complications from diabetes and
the excess mortality attributable to these complications.^ However, in order to
have the results last beyond the end of the trial, participants must make long-lasting
lifestyle changes. 31
4.3.3 Diet
Dietary factors have been suspected of being associated with the onset of type 2
diabetes for a long time. In the 6th century Hindu physicians attributed diabetes to an
overindulgence of rich foods. 6 But it unlikely that diabetes is due to any single
nutrient. Valid measurement of long-term dietary intake is difficult to obtain as the
methods used to collect and measure diet are subject to measurement e r r o r .6
However, there is some evidence that increased energy intake results in an increased
frequency of type 2 diabetes, but there is little evidence that any specific nutrient is
responsible. ^ 32 studies among the Nauruan population in the South Pacific
who have very high prevalence of obesity and type 2 diabetes, found that the
Nauruan population energy intake was about 15-35% more than was needed to
maintain a healthy body weight. 3 3
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Dietary behaviors of many Native American populations have changed
dramatically over the years. Technology has brought profound changes in food
production, processing, storage and distribution to Native people and led to major
changes in dietary p r e f e r e n c e s . ^ The changes in dietary behavior have resulted in
increased energy intake, including energy-dense foods high in fat, sugars and low in
complex carbohydrates.-^^ These dietary changes have been associated with the onset
of both obesity and type 2 diabetes.35
Teufel et al conducted a study to determine the dietary intake of a sample of 28
Native American women, 14 obese, and 14 non-obese, residing in Arizona. 36
Dietary intake was determined through 24-hour dietary recalls over seven
consecutive days. They found that the diets were composed of nonalcoholic
beverages, such as soda pop, potatoes, beans, white wheat flour, and canned goods,
and that traditional foods were not eaten on a regular basis and that obese women
consumed more energy intake through consumption of nonalcoholic and alcoholic
beverages as compared with the non-obese w o m e n . 36
4.3.4 Westernization
It appears that increasing 'Westernization' of lifestyle is a promoter of obesity and
d i a b e t e s . ^ 6 Adoption of the western lifestyle is characterized by changes in
physical activity, diet, and o b e s i t y A 34
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Among the Pima and Nauruan populations, the prevalence of diabetes has
increased rapidly over the past 50 years. Because this increase has occurred so
rapidly it is unlikely to be due to genetic changes, but may be due to the increasingly
'Westernization' of lifestyle in combination with the genetic predisposition to
developing diabetes. ^ It may be that among ethnic groups that have a genetic
predisposition to type 2 diabetes, adoption of a western lifestyle 'unmasks' the
diabetes. 34 a western lifestyle is likely to be at least partially responsible for the
high rates of diabetes among Native Americans. 37 Studies suggest that
populations with a more traditional lifestyle, characterized by a diet low in animal fat
and higher in complex carbohydrates and Increased energy expenditure, may protect
against the development of type 2 diabetes. 3 8
To assess the possible impact of the lifestyle and environmental factors on the
prevalence of obesity and type 2 diabetes a study was done on members of the Pima
population o f M e x i c o . 3 8 The Mexico Pima and Arizona Pima share ancestry but
were separated about 700-1,000 years ago. The Mexico Pima live a traditional
lifestyle with a diet low in animal fat and high in complex carbohydrates, and more
physical activity. Researchers measured both groups and found Mexico Pima
weighed less (64.2 +/-13.9 vs. 90.2 +/- 21.1 kg, p < 0.0001; means +/- SD) and had
lower body mass indexes (24.9 +/- 4.0 vs. 33.4 +/- 7.5 kg/m2, p < 0.0001) and lower
total cholesterol levels (146 +/- 30 vs. 174 +/- 31 mg/dl, p < 0.0001) and less
diabetes than Arizona P i m a . 3 8 Of the Mexico Pima, only 11% of women and 6% of
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men had type 2 diabetes, compared to 37% and 54% in female and male Arizona
Pima, respectively. These findings suggest that while the Mexico and Arizona Pima
share a genetic predisposition to obesity and type 2 diabetes, the role of the
environment is important in the onset of diabetes. It may be that a traditional lifestyle
protects against the development of obesity and type 2 diabetes.
4.4 Genetic Factors
The incidence and prevalence of type 2 diabetes in first-degree relatives of people
with diabetes is higher than the general population and lends support to the idea that
type 2 diabetes shows familial aggregation.^ 24,39 pers0ns who have at least one
parent with diabetes have a higher incidence of diabetes than those who do not have
a parent with diabetes.1 Among the Pima population, diabetes prevalence is highest
among the children of parents who themselves have diabetes.^ Adjusted for age and
obesity, incidence of diabetes was 2.3 times as high in children with one diabetic
parent, and 3.9 times as high among children with two diabetic parents compared
with those with two parents without diabetes.
Twin studies show that the familial aggregation is likely the result of genetic
factors.^ Studies of monozygotic twins found the concordance rate for twins ranged
from 34-100%, which is at least twice that of dizygotic twins. However, the
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concordance rates are also consistent with a shared environment and lends support
to environmental and lifestyle factors also being involved. ^
A genetic hypothesis, the 'thrifty gene' hypothesis, was first proposed by Neel in
1962 to explain the persistence of obesity and type 2 diabetes genotypes.^® Neel
hypothesized that populations that formerly had vacillating periods of feast and
famine had developed a 'thrifty' genotype that allowed for fat and calorie storage in
times of feasting and these storage deposits were then used during times of famine.
While there is no direct evidence to support this hypothesis, it has been suggested
that the increase in diabetes among the Pima does follow an increase in a steady food
supply and is suggestive that the Pima population can store energy efficiently that
may lead to obesity, insulin resistance, and diabetes.41
A number of candidate genes have been identified as being involved in glucose
homeostasis, although it is challenging to study the genetics of type 2 diabetes due to
the complex, multifactorial nature of the disease. The insulin gene and the insulin
receptor gene have been the focus of a large number of studies and the results have
been inconsistent. 1 Among the Pima, the insulin gene polymorphism likely plays no
role in the onset of type 2 diabetes, but the class 3 allele may influence the severity
of the d i s e a s e .42 Glucose transporters, GLUT1 and GLUT4, have also been studied
extensively with limited evidence. 1 Reports of linkage of the glucokinase gene with
maturity onset diabetes in the young (MODY) stimulated an examination of the ri sk
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55
of iaie onset type 2 diabetes J More than 17 different polymorphisms have been
located in the glucose kinase gene. * However, these polymorphisms are unlikely to
be associated with type 2 diabetes in Native Americans. 1 Currently there is an active
investigation looking for genes among the Pima of Arizona, but as yet, no causal
genes have been identified at chromosome 7 or at chromosome 2 0 . 4 3 Among Native
American populations, obesity is tied closely to diabetes, and likely has a genetic
component as well. Research among the Pima suggests some evidence for a linkage
at chromosome I l q 2 1 - q 2 2 . 4 4
Racial admixture is also an important risk factor for the development of type 2
diabetes. In a study among the Pima, Knowler et al found that fall-blooded Pima had
two times the prevalence of type 2 diabetes as compared to Pima of half Pima
a n c e s t r y .4 1 ? 45 jn the southwestern US, the Hispanic population shares genes with
Native American population and consequently Hispanics in the southwest have
higher rates of diabetes than non-Hispanic whites A 46
There is also evidence that diabetes can be maternally transmitted due to non-genetic
factors. In a Pima study, the long-term effect of maternal glucose intolerance was
examined in 552 children aged 5-24 y e a r s . 4 7 Fasting hyperglycemia and impaired
glucose intolerance were found at younger ages in the children of women who had
abnormal glucose tolerance during pregnancy and the children were more o b e s e . 4 7
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56
A ImM (18.2 mg/dl) increase in the 2-hour glucose tolerance test during
pregnancy was associated with a higher prevalence of diabetes in the child exposed
to maternal diabetes (odds ratio =162). Gestational diabetes and in utero exposure to
maternal diabetes has long-term effects on the children's glucose metabolism
including insulin resistance, more obesity, and increased incidence of diabetes, and
therefore, gestational diabetes adds to the cycle of increasing risk of diabetes in
subsequent generations.^
4.5 Physiologic Risk Factors
Much of our understanding about the epidemic of type 2 diabetes in Native
Americans conies from studies done among the Pima population of A rizona. 34
However, the interaction between the genetic predisposition and environmental and
lifestyle factors is prevalent in many indigenous Native populations. There are three
main physiologic risk factors for the onset of type2 diabetes: 1) impaired glucose
tolerance 2) insulin resistance and 3) gestational diabetes.
4.5.1 Impaired Glucose Tolerance
Impaired glucose tolerance (IGT) is the glycemic response to the oral glucose
tolerance test (using the standard 75 gram dose) that is intermediate between normal
blood glucose and diabetes. * About 30-40% of patients with impaired glucose
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57
tolerance will develop diabetes48 In Colorado, Hispanics who had impaired
glucose tolerance had nine times the risk of developing diabetes as compared with
Hispanics without impaired glucose tolerance, whereas among non-Hispanic whites,
having impaired glucose tolerance increased the risk of developing diabetes to 23
t i m e s . 49 Age is strong risk factor for impaired glucose tolerance. Among the Pima
and Nauruan population obesity and 2-hour post-load insulin concentration were
important predictors of impaired glucose tolerance.^
Among Native American populations the prevalence of impaired glucose tolerance is
even greater than the prevalence of type 2 diabetes making impaired glucose
tolerance an epidemic as well as d i a b e t e s . 6 Increased risk for the development of
diabetes in persons with impaired glucose tolerance is related to higher glucose
levels, family history of diabetes, greater degree of obesity, hyperinsulinemia and
more insulin resistance. Therefore, Native American populations with impaired
glucose tolerance are at extremely high risk of developing type 2 diabetes. ^
4,5.2 Insulin Resistance
Himsworth first reported that defects in the insulin sensitivity of tissues in people
with diabetes were possible. 51 Since then many researchers have described the
pathogenesis and consequences of "insulin resistance." Insulin resistance is defined
as the subnormal response or decreased sensitivity to a given concentration of
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58
insulin, whether it is endogenously or exogenously d e l i v e r e d A 52 i n s u l i n
resistance can be measured in several ways, including the euglycemic insulin clamp
which is considered the gold standard, the minimal model, and the fasting insulin
level. The mechanism of insulin resistance is not fully understood, but genetics are
likely involved. The primary genetic component is characterized by reduced
efficiency of translocation of the GLUT4 in muscle cells, although there may be a
separate defect in glycogen synthesis.
It is generally thought that insulin resistance is involved in the pathogenesis of type 2
diabetes. * Insulin resistance is associated with several abnormalities including
obesity, especially obesity that is centrally located, and also impaired glucose
tolerance, hypertension and dyslipidemia.^ Weight gain appears to be the primaiy
mechanism for insulin resistance. 53
Insulin resistance is a characteristic of populations at high risk of developing type 2
diabetes.^ Studies among the Pima indicate that insulin resistance is an early
metabolic alteration and predisposes individuals to develop impaired glucose
tolerance and is highly predictive of the development of type 2 d i a b e t e s . 5 4 , 55
Insulin resistance is associated with hyperinsulinemia. Plasma insulin levels are a
strong predictor for the risk of type 2 diabetes, independent of obesity or waist
circumference and the risk i s very strong for individuals with a family history of
diabetes.^ In a study of Mexican Americans who had insulin resistance and
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59
hyperinsulinemia, participants had a 14-fold increased risk of developing type 2
diabetes as compared to non-Hispanic whites. 56
45.3 Gestational Diabetes
It is unclear if diabetes is acquired during pregnancy or is uncovered during
pregnancy due to the physiologic changes of pregnancy and increased testing for
diabetes. * Glucose intolerance that is first detected during pregnancy with a
subsequent return of post-partum glucose levels to normal, is associated with a high
risk of developing type 2 diabetes.6 About 30-35% of women with a history of
gestational diabetes progress to type 2 diabetes within 5-10 years.6 Risk factors that
increase the likelihood of progression from gestational diabetes to overt type 2
diabetes are pre-pregnancy obesity, low endogenous insulin secretion and the need
for exogenous insulin during pregnancy, recurrent history of gestational diabetes and
higher post-partum glucose levels.
Among Native American populations, gestational diabetes is a risk factor for type 2
diabetes in both the mother and her child. Gestational diabetes that is detected in the
third-trimester was found to be highly predictive of subsequent type 2 diabetes in the
mothers and have long-term effects on obesity and rates of diabetes in the children
who were exposed in u t e r o . 57-59 Almost 50% of Pima children age 20-24 years
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60
developed type 2 diabetes if their mothers had diabetes at the time of their
pregnancy. ^ 5
Conversely, breast-feeding is associated with a protective effect of development of
both obesity and diabetes in children. 60 Pettitt et al found that Pima Indians who
were exclusively breastfed during the first two months of their life had significantly
lower body weights and rates of diabetes, a 60% reduction compared to those who
were exclusively bottle-fed, 60 While few data exist on breast feeding practices
among Native American women, it likely that breast feeding is on the decline as
people become more Westernized and enter the work force. Therefore, it may be that
the rise in diabetes prevalence is related, at least in part, to the decrease in
breastfeeding.
4,6 Physiologic Risk Factors for the Complications of Type 2 Diabetes
Despite the great strides made in the treatment and understanding of diabetes,
complications associated with diabetes are still a major cause of morbidity and
mortality. 61 The primary risk factors for diabetes-related complications are
hyperglycemia, hypertension, and dyslipidemia. 62-64
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4.6.1 Hyperglycemia
61
The primary causal factor for the development of most diabetes-related
complications is prolonged exposure to hyperglycemia.^, 66 T h e pathological and
clinical consequences of hyperglycemia reflect a continuum of tissue changes, from
acute and reversible abnormalities to chronic and irreversible a b n o r m a l i t ie s . 6 6 The
mechanism of how hyperglycemia causes damage to the tissues remains unknown.67
Hyperglycemia is a major risk factor for nephropathy. 6 8 Hyperglycemia is
associated with an increase in the glomerular filtration rate, hyperfiltration, which
occurs in people with diabetes without proteinuria as well as those with overt
nephropathy.68 it has been proposed that hyperfiltration is associated with changes
in the glomerular membrane as well as an increase in renal prostaglandin production
which could lead to the development of renal disease. 68 Among Pima Indians with
diabetes, those persons who had a 2-hour post-load plasma glucose level > 450
mg/dL at diagnosis, had about three times the incidence of proteinuria after 15 years
of diabetes duration.69 However, studies have shown that among people with type 1
and type 2 diabetes, intensive management of glucose levels significantly reduces the
risk of development of microalbuminuria and overt nephropathy. 65, 70, 71
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62
Hyperglycemia is also strongly related to the risk of visual disorders, especially
r e t i n o p a t h y . 6 5 In the Diabetes Control and Complications Trial it was shown that
persons with no retinopathy at baseline, who had intensive insulin treatment had a
60% reduction in progression of retinopathy compared with persons who received
conventional therapy. 65 For those who had retinopathy at baseline, the intensive
treatment was associated with a 54% reduction in progression, a 47% reduction in
incidence of proliferative disease and a 54% reduction in laser treatment compared
with those who received conventional t h e r a p y .65 Moreover, any decrease in HbAlc
level, even if HbAlc level was not into the normal range was associated with a
decrease in risk of retinopathy. 65
Hyperglycemia is associated with lower-extremity amputations 72 in a study of 4399
subjects the incidence of lower-extremity amputations was estimated among the
Pima population of Arizona.^ During the study, lower-extremity amputations were
performed on 84 patients, 95% of whom had type 2 diabetes. Two-hour post-load
hyperglycemia were significant risk factors for lower-extremity amputations.^
4.6,2 Hypertension
Hypertension further complicates diabetes as i t often associated with d i a b e t e s 7 3 The
prevalence of hypertension in people with diabetes is about twice that of people
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63
without diabetes in. the same p o p u l a t i o n . 7 4 Hypertension is more common in men
than women until age 50, when it becomes more frequent in women than men.74 in
the US, both diabetes and hypertension occur more frequently among minority
populations, especially among the African-American population as compared with
non-Hispanic white population.73-75 Hypertension is also more common among
lower socioeconomic groups.73-75
Among people with type 2 diabetes, hypertension is often part of the insul in
resistance syndrome and about one-third of patients with type 2 diabetes have
hypertension at the time of their diagnosis.*’ 75 Hypertension is a major contributor
to the morbidity and mortality of type 2 diabetes. It is estimated that 30-75% of the
complications of diabetes can be attributed to hypertension. 75 Hypertension and
diabetes are strong independent risk factors for nephropathy, retinopathy and
cardiovascular disease. 6 fr 68 in a study of the Pima population in Arizona, Sievers
et al studied the effect of hypertension on mortality among 5284 Pima people, 1698
of whom had type 2 diabetes at baseline or developed it during follow-up. After 12.2
years of follow-up, 470 people without diabetes and 488 people with diabetes, died.
Among the people with diabetes, 85 died of diabetes-related nephropathy, 45 of the
deaths were due to cardiovascular disease. Among the people with diabetes,
hypertension strongly predicted deaths from diabetic nephropathy, but it had little
effect on deaths from cardiovascular disease. It may be that among the Pima
population, there is a relatively greater effect of hypertension on the progression of
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64
diabetes-related nephropathy that may be related to the younger age at onset of
type 2 diabetes, less smoking, good lipid profiles and, possibly, an increased
susceptibility to renal disease.^
Among the Native American population prevalence of hypertension and diabetes
varies significantly by t r i b e . 7 7 In a study of 4549 people, aged 45 to 7 4 years, from
13 tribal groups from South Dakota/North Dakota, southeastern Oklahoma, and
Arizona, the prevalence of hypertension ranged from 27% to 56%.78 Among the
participants from Arizona more than 60% had diabetes as compared with about 40%
of the participants from Oklahoma and the D a k o t a s . 7 7 Among these tribes, diabetes
and hypertension were independent predictors of cardiovascular d i s e a s e .7 9 Although
cardiovascular disease used to be rare among Native American tribes, the increasing
rates may be related to the high prevalence of diabetes and h y p e r t e n s i o n . 7 9
Hypertension is also a risk factor for visual disorders, especially retinopathy. 80-82
Studies among the Pima population have found that the higher the systolic blood
pressure the higher the incidence of retinopathy. 83 Control of hypertension has been
demonstrated to reduce the rate of progression of diabetic nephropathy and to reduce
cerebrovascular disease, including stroke, and cardiovascular disease. 84
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4.6.3 P v s lip id e m ia
65
The most common pattern of dyslipidemia in people with type 2 diabetes is elevated
triglyceride levels and decreased HDL cholesterol levels while the LDL cholesterol
is usually not significantly different from persons without diabetes. * Diabetes
increases the risk for atherosclerotic vascular disease and this risk is greatest among
those with dyslipidemia, as well those with hypertension, obesity, and those who
smoke. * In the Multiple Risk Factor Intervention Trial (MRFIT) the risk of .
cardiovascular mortality was significantly higher for people with diabetes at every
level of serum cholesterol as compared with people without diabetes. 85
Initial treatment of dyslipidemia in people with type 2 diabetes is initially aimed at
good glycemic control as tight glycemic control is associated with a decrease in
serum triglycerides and a slight rise in H D L . 8 6 , 87 However, good glycemic control
is not often achieved and cannot correct the lipid profile so additional therapies are
n e e d e d . 86, 87 However, studies on the effects of treatment on preventing
macrovascular disease are based on extrapolation from studies conducted in people
without diabetes. 86 The Diabetes Atherosclerosis Intervention Study is an
international, multi-center, clinical trial that was designed to answer whether
correcting dylipidemias among people with type 2 diabetes will reduce the risk of
coronary atherosclerosis, and to date those data are not published. 88
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4.6.4 Obesity
66
Obesity and diabetes are closely affiliated and are independently associated with
adverse metabolic consequences such as hyperglycemia and dyslipidemia.^ Central
obesity and type 2 diabetes are risk factors for macrovascular abnormalities,
including decreased fibrinolysis, elevated levels of plasminogen activator inhibitor
factor, high blood viscosity, increased erythrocyte aggregability, and endothelial
dysfunction which is a major factor in atheroma plaque formation and development
of thrombosis. ^ The mechanisms by which obesity influences the risk of glucose
intolerance is not well understood, but it is known that obesity is an important
independent risk factor for the onset of diabetes but also has joint effects on
hyperglycemia, hypertension, and dyslipidemia. 24 Recently, Steppan and colleagues
have identified a new hormone, called resistin, that is secreted by the fat cells,
adipocytes, and may be an important part of the link between obesity and type 2
diabetes.1 ^ The authors suggest that resistin causes insulin resistance through its
effects on the adipocytes and perhaps other tissues as well. A group of drugs called
thiazoladinediones used to treat type 2 diabetes appears to be effective by reducing
insulin resistance and suppressing the expression of resistin by the adipocytes.
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67
4.6.5 Joint Effects of Hyperglycemia, Hypertension, Dyslipidemia and Obesity
in Native Americans
The Strong Heart Study was initiated to investigate cardiovascular disease and its
risk factors in Native Americans in 13 tribes residing in Arizona, Oklahoma, and
South/North Dakota. 79 Cardiovascular disease morbidity and mortality rates were
higher in men as compared with women and the significant independent predictors of
disease in women were diabetes, age, obesity (inverse), low density lipoprotein
cholesterol, albuminuria, triglycerides, and hypertension. In men, diabetes, age, low-
density lipoprotein cholesterol, albuminuria, and hypertension were independent
predictors of cardiovascular d is e a s e . 7 9 Additionally, low high-density lipoprotein
cholesterol was a risk factor for abnormal excretion of albumin in women, but not in
men, among the Pima population. 91
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68
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progression of long-term complications in insulin-dependent diabetes mellitus.
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66. Brownlee M. Glycation of Macromolecules. In: Alberti K, Zimmet P, DeFronzo
R, Keen H, eds. International Textbook o f Diabetes Mellitus. Chichester: John Wiley
and Sons; 1997:745-755.
67. Strowig S, Raskin P. Gycemic Control and the Complications of Diabetes. In:
Alberti K, Zimmet P, De Fronzo R, Keen H, eds. International Textbook o f Diabetes.
Chichester: John Wiley and Sons; 1997:1321-1338.
68. Nelson R, Knowler W, Pettitt D, Bennett P. Kidney Disease in Diabetes. In:
Group NDD, ed. Diabetes in America. Second ed. Bethesda: National Institues of
Health; 1995.
69. Kunzelman CL, Knowler WC, Pettitt DJ, Bennett PH. Incidence of proteinuria in
type 2 diabetes mellitus in the Pima Indians. Kidney Int. 1989;35:681-7.
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70. Anonymous. Implications of the United Kingdom Prospective Diabetes Study.
American Diabetes Association. Diabetes Care. 1998;21:2180-4.
71. Anonymous. United Kingdom Prospective Diabetes Study 24: a 6-year,
randomized, controlled trial comparing sulfonylurea, insulin, and metformin therapy
in patients with newly diagnosed type 2 diabetes that could not be controlled with
diet therapy. United Kingdom Prospective Diabetes Study Group [see comments].
Ann Intern Med. 1998;128:165-75.
72. Nelson RG, Gohdes DM, Everhart IE, et al. Lower-extremity amputations in
NIDDM. 12-yr follow-up study in Pima Indians. Diabetes Care. 1988;11:8-16.
73. Wingard D, Barrett-Connor E. Heart Disease and Diabetes. In: Group NDD, ed.
Diabetes in America. Second ed. Bethesda: National Institues of Health; 1995.
74. Tuomilehto J, Rastenyte D. Epidemiology of Macrovascular Disease and
Hypertension in Diabetes Mellitus. In: Alberti K, Zimmet P, DeFronzo R, Keen H,
eds. International Textbook o f Diabetes Mellitus. Chichester: John Wiley and Sons;
1997:1560-1583.
75. Cowie D, Harris M. Physical and Metabolic characteristics of persons with
diabetes. In: Group NDD, ed. Diabetes in America. Second ed. Bethesda: National
Institutes of Health; 1995.
76. Sievers ML, Bennett PH, Roumain J, Nelson RG. Effect of hypertension on
mortality in Pima Indians. Circulation. 1999;100:33-40.
77. Welty TK, Lee ET, Yeh J, et al. Cardiovascular disease risk factors among
American Indians. The Strong Heart Study. Am J Epidemiol. 1995;142:269-87.
78. Howard BV. Blood pressure in 13 American Indian communities: the Strong
Heart Study. Public Health Rep. 1996; 111 :47-8.
79. Howard BV, Lee ET, Cowan LD, et al. Rising tide of cardiovascular disease in
American Indians. The Strong Heart Study. Circulation. 1999;99:2389-95.
80. Nelson RG, Wolfe JA, Horton MB, Pettitt DJ, Bennett PH, Knowler WC.
Proliferative retinopathy in NIDDM. Incidence and risk factors in Pima Indians.
Diabetes. 1989;38:435-40.
81. Lee ET, Lee VS, Kingsley RM, et al. Diabetic retinopathy in Oklahoma Indians
with NIDDM. Incidence and risk factors. Diabetes Care. 1992;15:1620-7.
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82. Hu YH, Pan XR, Liu PA, Li GW, Howard BY, Bennett PH. Coronary heart
disease and diabetic retinopathy in newly diagnosed diabetes in Da Qing, China: the
Da Qing IGT and Diabetes Study. Acta Diabetol. 1991;28:169-73.
83. Knowler WC, Bennett PH, Ballintine EJ. Increased incidence of retinopathy in
diabetics with elevated blood pressure. A six-year follow-up study in Pima Indians.
NEngl J Med. 1980;302:645-50.
84. Weidmann P, Boehlen L. Arterial Hypertension in Diabetes. In: Alberti K,
Zimmet P, DeFronzo R, Keen H, eds. International Textbook of Diabetes Mellitus.
Chichester: John Wiley and Sons; 1997:1645-1656.
85. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and
12-yr cardiovascular mortality for men screened in the Multiple Risk Factor
Intervention Trial. Diabetes Care. 1993;16:434-44.
86. Taskinen M, Nestel P. Hypolipidemic Agents: Their Role in Diabetes Mellitus.
In: Alberti K, Zimmet P, DeFronzo R, Keen H, eds. International Textbook of
Diabetes Mellitus. Chichester: John Wiley and Sons; 1997:883-897.
87. Taskinen MR. Strategies for the management of diabetic dyslipidaemia. Drugs.
1999;58:47-51; discussion 75-82.
88. Steiner G, Stewart D, Hosking JD. Baseline characteristics of the study
population in the Diabetes Atherosclerosis Intervention Study (DAIS). World Health
Organization Collaborating Centre for the Study of Atherosclerosis in Diabetes. Am
J Cardiol. 1999;84:1004-10.
89. Serrano Rios M. Relationship between obesity and the increased risk of major
complications in non-insulin-dependent diabetes mellitus. E urJ Clin Invest.
1998;28:14-7, discussion 17-8.
90. Steppan C, Bailey S, Bhat S, et al. The hormone resistin links obesity to diabetes.
Nature. 2001;409:307-312.
91. Fagot-Campagna A, Nelson RG, Knowler WC, et al. Plasma lipoproteins and the
incidence of abnormal excretion of albumin in diabetic American Indians: the Strong
Heart Study. Diabetologia. 1998;41:1002-9.
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5.0 REVIEW OF THE LITERATURE
Interventions to Prevent or Delay Com plications
Summary of Key Points
» Diabetes Control and Complications Trial and the United Kingdom Prospective
Diabetes Study have demonstrated that tight control o f blood glucose levels and
hypertension can reduce rates o f microvascular complications including decreased
nephropathy, retinopathy, and neuropathy among persons with type 1 and type 2
diabetes.
» Steno Study found that an intensified lifestyle and clinical intervention in people
with type 2 diabetes with microalbuminuria slowed progression to nephropathy,
retinopathy and neuropathy.
» Clinical and lifestyle interventions complement each other and may provide the
individual with diabetes the best chance o f avoiding the complications o f diabetes.
5.1 Interventions to Prevent or Belay Complications
Diabetes is a chronic progressive disease that requires on-going medical attention
and patient education to prevent the acute complications and reduce the risk of long
term complications. * Although people with diabetes are at risk for complications
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77
that reduce their quality of life and may be life threatening, the clinical progression
is not inevitable.
Control of hyperglycemia, hypertension, dyslipidemia, and obesity can prevent or
delay the progression of diabetes-related complications. A number of clinical
interventions have been identified for primary and secondary prevention including
pharamacologic therapy and early detection and treatment of complications.
However, clinical interventions by themselves may not be maximally effective.
Interventions are needed to influence lifestyle factors related to complications
including diet, physical activity, support and self-management. Together clinical and
lifestyle interventions complement each other and may provide the individual with
diabetes the best chance of avoiding the complications of diabetes.
5.2 Clinical Interventions
The primary goals of clinical interventions are to reduce hyperglycemia, control
hypertension and to normalize lipid levels. Two important trials, the Diabetes
Control and Complications Trial and the United Kingdom Prospective Diabetes
Study, have demonstrated that tight control of blood glucose levels and hypertension
can reduce rates of microvascular complications including decreased nephropathy,
retinopathy, and neuropathy.^* 3 Fewer trials have investigated the effects of drug
treatment of dyslipidemia on occurrence of complications.^
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5.2,1 Diabetes Control and Complications Trial
78
In a landmark study, the Diabetes Control and Complications Trial (DCCT), a
definitive relationship was demonstrated in type 1 diabetes between hyperglycemia
and diabetes-related microvascular complications, including retinopathy,
nephropathy, and neuropathy.2 The DCCT was a ten-year randomized, clinical trial
conducted between 1983-1993 at 29 medical centers in the US and Canada and
included 1,441 persons who had type 1 diabetes.2 Participants had diabetes for at
least 1 year, but not longer than 15 years and were required to have no, or only early
signs of, diabetes-related eye disease. The study compared the effects of two
treatments, standard therapy and intensive control, on the complications of diabetes.
Participants were randomly assigned to each treatment group, the intensive diabetes
treatment arm consisted of three or more daily insulin injections or a continuous
subcutaneous insulin infusion, or the conventional treatment arm which included one
or two daily injections of insulin. Results showed that the intensive treatment
reduced the risk for developing retinopathy by 76%. In participants with some eye
damage at the beginning of the study, intensive treatment slowed the progression of
the disease by 54%. Participants were also followed for the development of
nephropathy and results showed that intensive treatment prevented the development
and slowed the progression of diabetes-related nephropathy by 50%. In addition,
neuropathy was reduced by 60% in persons in the intensive treatment arm. 2
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79
The DCCT was an important study as it leaves no doubt that the goal of achieving
near normal blood glucose levels can significantly reduce the development and
progression of type 1 diabetes and it's complications. However, the study also found
that achieving and maintaining near normal blood glucose was extremely difficult for
the participants. Only 5% of the participants in the intensive treatment group
maintained a near normal blood glucose level for the duration of the study and only
44% ever attained a "normal" HbAlc at least once during the trial 2 Yet even with
the limited success in controlling blood sugar, large reductions in clinical
complications were observed. The DCCT found that every percentage reduction in
HbAlc was associated with reduction in complications in a linear fashion.
The DCCT included only people with type 1 diabetes and therefore the question of
whether tight control would reduce the complications of type 2 diabetes, remained
open. The following second landmark study was conducted to answer this remaining
question.
5,2.2 United Kingdom Prospective Diabetes Study
The United Kingdom Prospective Diabetes Study (UKPDS) was a 20-year
randomized multi-center clinical trial conducted from 1977-1997 with newly
diagnosed people with type 2 diabetes A 5 The study was designed to study to
clarify the role of glycemic and hypertension control in improving morbidity and
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80
mortality in persons with type 2 diabetes. The study enrolled more than 2500
participants in outpatient diabetes clinics in the UK who were randomized to
treatment with medication, (chlorpropamide, glibenclamide, insulin, or metformin, if
obese), or diet alone. At the end of the study, the impact of treatment on
microvascular and macrovascular risk was evaluated. Persons randomized to the
medication arm versus the diet alone arm had significantly lower glucose levels and
lower HbAlc levels. A 1.0% absolute decrease in HbAlc level correlated with a
35% overall risk reduction. The intensive treatment group had a HbAlc of 7.0%
compared to the conventional therapy group who had a HbAlc of 7.9%. Over the 20
years of the study, persons in the treatment arm reduced their risk of any diabetes-
related complications by 12%, microvascular endpoints by 25%, and
microalbuminuria by 33%. There was also a non-significant 16% reduction for
myocardial infarction (p=0.052). As observed in the DCCT, weight gain was
significantly higher in the medication group (mean 2.9 kg) compared with the
conventional group and patients who received insulin therapy had an even greater
weight gain (4.0 kg) compared with those who received oral treatment. Among the
obese participants, metformin was associated with a significant reduction in mean
fasting plasma insulin concentration and participants had no change in mean body
weight. Although the medications lowered glucose levels, most patients remained
hyperglycemic. The UKPDS also showed that it was the quantity of hypertension
reduction that was even more important than the type of medication used, and that
good control of hypertension was as important as good glycemic control. Blood
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pressure reduction was significantly higher in the participants in the intensive
treatment group as compared with those in the conventional therapy group, 144/82
mm/Hg versus 154/87 mmHg, respectively. Control of hypertension reduced the risk
of diabetes-related endpoints by 24%, diabetes-related deaths by 32% and
microvascular endpoints by 37%. In this study 59% of deaths were due to
cardiovascular disease and an examination of participant characteristics found that
many of the risk factors for cardiovascular disease-related deaths were modifiable
risk factors, and included hyperglycemia, hypertension, dyslipidemia, and smoking.
5.3 Lifestyle Interventions
Lifestyle interventions can be utilized to complement clinical interventions and assist
in the control of blood glucose levels, blood pressure, lipid levels and weight.
Changes in diet and physical activity can have major effects on blood glucose
levels.^ Reductions in energy intake have been shown to improve blood glucose
levels and decrease the need for medication.^, 6 Depending on the insulin
concentration, physical activity can increase insulin sensitivity and reduce the dose
of medication required to achieve a certain blood glucose level.1 6, ? Furthermore, the
weight gain associated with drug treatment of hyperglycemia may be reduced by
alterations in diet and physical activity levels.
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Alterations in lifestyle behaviors, such as weight reduction, can have many health-
related benefits, especially for people with type 2 diabetes. It has been shown that
even a moderate weight loss of 5-10% of baseline, can improve glycemic control,
reduce hypertension, and control dyslipidemia.^'^ Unfortunately, weight reduction
is "notoriously difficult in obese individuals". 1 * It is estimated that 50-90% of
persons with type 2 diabetes are obese. ^ To further complicate matters, many
diabetes medications, particularly insulin, are associated with further weight gain and
thereby make good glucose control even more difficult, although the
thiazoladinediones medications may be associated with less weight gain A 13-15
Among people without diabetes, the body of evidence from clinical trials indicates
that lifestyle interventions that use a variety of theoretical frameworks can reduce
hypertension and dyslipidemia through weight control, diet alterations and increased
physical a c t i v i t y . 1 6 - 1 9 Few studies have assessed these endpoints of lifestyle
interventions on people with diabetes.
There are no effective and safe medications for weight loss; a reduced calorie diet
and increased physical activity are the cornerstones of weight reduction.20-22
During the run-in period of the UKPDS, participants received dietary intervention
and had a highly significant weight loss.23 in a prospective study of Swedish men
who received dietary intervention and/or physical activity or training intervention,
body weight was reduced by 2.3-3.7% among participants, whereas weight increased
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83
by 0.5-1.7% among the non-intervened participants.22 Weight loss associated
with physical activity is greatest for intraabdominal fat, which is the most
metabolically active fat compartment. Therefore, physical activity may have a
greater effect than reflected by overall weight reduction.24
A number of interventions have targeted physical activity to improve risk factor
profiles and reduce complications. Increasing energy expenditure by walking is an
attractive strategy because walking can be done by people of all fitness levels and
requires no special equipment or facilities. A twelve-week, study of women with and
without diabetes was conducted to assess the impact of a walking program on body
composition and risk factors for cardiovascular d i s e a s e . 2 5 Before the study, women
were taken on group walks by a qualified physical education instructor and
instructed on proper clothing, shoes and then instructed to begin a walking program.
Participants were asked to keep a log of their start and stop times for each day's walk.
The log was returned to the instructor each month and inconsistencies in the log were
clarified. Participants were fitted with a heart rate monitor at the beginning and end
of the twelve- week intervention. Participants were told to walk one hour per day on
five days each week for twelve weeks. At the end of the study, fitness level was
measured by estimated V02max and assessed with a 1.6 km walking test, body
composition was measured by dual-energy X-ray absorptiometry and serum lipid
concentrations were measured. Estimated V02max improved significantly in both
groups of women, but among the women with diabetes, body mass index and fat
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84
content of the upper body and android waist region were decreased significantly,
as well as a significant decrease in fasting blood glucose, HbAlc level, total
cholesterol, and iow-density lipoprotein cholesterol High-density lipoprotein
cholesterol levels remained unchanged. In contrast, the women without diabetes did
not lose body fat but their HbAlc, total cholesterol, and LDL cholesterol decreased
significantly. The decrease in centralized body fat, but not the change in V02max,
was associated with the change in fasting blood glucose.
In a retrospective evaluation of a community-based exercise program, that included
weekly aerobic exercises done in groups among the Zuni population in New Mexico,
medical records of 30 participants with type 2 diabetes who were participants in the
exercise program were compared with the records of 56 non-participants with type 2
diabetes 26, 27 Participants were matched on age, sex, health-care provider, and
duration of diabetes. Participants had a significantly greater weight loss, 4 kg,
compared to non-participants, 0.9 kg. Participants' fasting blood glucose levels were
significantly lowered, 43 mg/dl, compared with 2 mg/di among the non-participants.
Participants were significantly more likely than non-participants to have
discontinued their medication (relative risk 4.2) and to have decreased their
medication dosage (relative risk 2.2). These results suggest that participation in a
community-based exercise program can produce significant weight loss and
improvement in glycemic control among a group of Native Americans with type 2
diabetes.
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85
The effectiveness of lifestyle interventions to increase physical activity may be
increased by including weight reduction as an integral part of the intervention. A
randomized study of 64 overweight African-Americans men and women aged 55-79
years with type 2 diabetes participated in a three month long weight loss and exercise
program and were compared to usual care control group. ^ The participants were
randomized to either intervention or usual care. The intervention consisted of twelve
weekly group sessions, one individual session and six biweekly group sessions. The
usual care control group received one individual session, and six biweekly group
sessions. At the end of six months, there were significant differences in weight in the
intervention as compared with the usual care control, -2.4 kg and mean HbAlc
values, -2.4%. Blood pressure improved significantly in the intervention group as
compared to the control group. Lipid levels improved in the intervention group as
compared with the control, but the difference was not significant.
In minority populations, diabetes interventions that include culturally relevant
materials may enhance effectiveness. Among the Pima of Arizona, a twelve-month
pilot trial was conducted with 95 obese men and women without diabetes to test
compliance to specific lifestyle interventions and to compare them for changes in
risk factors for type 2 diabetes. 28 Participants were randomized to one of two
treatments: 'Pima Action' or 'Pima Pride'. The Pima Action intervention involved
structured activities and nutrition interventions, and Pima Pride included
unstructured activities, emphasizing Pima history and culture. In addition, 35 eligible
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subjects who declined to be randomized to the intervention and were followed as
an 'observational' group and 22 members of tWs group were examined once at a
median of 25 months for changes in weight and glucose concentration. After twelve
months of intervention, members of both intervention groups reported increased
levels of physical activity, Pima Action reported 7.3 hours/month and Pima Pride
reported 6.3 hours/month. Body mass index, blood pressure, weight, blood glucose
and insulin levels increased significantly among the Pima Action members. Pima
Action members gained more weight than Pima Pride members, 2.5 kg compared
with 0.8 kg, respectively. Pima Action members had a greater increase in blood
glucose levels than Pima Pride members. Participants in the observational group
gained an average of 1.9 kg/year and had an increase in their blood glucose level.
Interventions that intervene on multiple risk factors with a variety of approaches
have the greatest potential to reduce complications. The Steno Type 2 Randomized
trial in Denmark is one of the few interventions that have evaluated a realistic
multifactorial intervention that involves a stepwise lifestyle and pharmacological
intervention targeting hyperglycemia, hypertension, dyslipidemia, and
microalbuminuria.
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5,3.1 The Steno Type 2 Randomized Trial
87
The Steno randomized trial was designed to determine the effect of a complementary
clinical and lifestyle, called a multifactorial intervention, that included lifestyle and
pharmacological treatment to slow the initiation and progression of microvascular
complications in persons with type 2 diabetes who also had microalbuminuria as
compared to a standard pharmacological treatment. 29 The multifactorial arm
received dietary instruction with the goal of eating less than 30% of total daily
energy intake from fat, and encouraged participants to exercise moderately at least
30 minutes three to five times a week. Moderate exercise was defined as any
physical activity other than work or daily chores. Participants who smoked were
invited to smoking cessation courses. All participants received an anti-hypertensive
agent, were advised to stop smoking, to take vitamin C, vitamin E and an aspirin
daily. Participants who had a HbAlc level greater than 6.5% were placed on oral
hypoglycemic agents and obese participants received metformin. If HbAlc was
greater than 7.0%, insulin at bedtime was recommended. The primary endpoint was
the development of nephropathy (median albumin excretion rate >300 mg per 24 h in
at least one of the two-yearly examinations). Secondary endpoints were the incidence
or progression of retinopathy and neuropathy. The mean age was 55.1 years and
participants were followed up for 3.8 years. Participants in the intensive group had
significantly less risk of progression to nephropathy, OR = 0.27 (95% Cl 0.10-0.75),
progression of retinopathy, OR = 0.45 (95% Cl 0.21-0.95), and progression of
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88
neuropathy, OR = 0.32 (95% Cl 0.12-0.78) than those in the standard group.
Therefore, it appears that an intensified lifestyle and clinical intervention in people
with type 2 diabetes with microalbuminuria slows progression to nephropathy,
retinopathy and neuropathy.
5.4 Motivation for Intervention among Native American Populations
The prevalence, incidence, and mortality of type 2 diabetes have been rapidly
increasing among Native American populations.30-32 The risk factors for preventing
or delaying the onset of diabetes complications are interdependent and interventions
that target multiple risk factors must include comprehensive clinical and lifestyle
interventions. Ideally, both clinical and lifestyle interventions should target
individual s at all levels of the complication spectrum. The Native American Diabetes
Project was developed as a lifestyle intervention for secondary and tertiary
prevention of type 2 diabetes.
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89
References for Chapter 5
1. ADA. Standards of Medicai Care for Patients With Diabetes Mellitus. Diabetes
Care. 1998;21:1514-1522.
2. DCCT. The effect of intensive treatment of diabetes on the development and
progression of long-term complications in insulin-dependent diabetes mellitus.
NEJM. 1993;329:977-86.
3. UKPDS. Intensive blood-glucose control with sulphonylureas or insulin compared
with conventional treatment and risk of complications in patients with type 2
diabetes. Lancet. 1998;352:837-853.
4. Hanefeld M, Fischer S, Schmechel H, et al. Diabetes Intervention Study. Multi-
intervention trial in newly diagnosed NIDDM. Diabetes Care. 1991;14:308-17.
5. UKPDS. Effect of intensive blood-glucose control with metformin on
complications in overweight patients with type 2 diabetes (UKPDS 34). UK
Prospective Diabetes Study (UKPDS) Group [see comments] [published erratum
appears in Lancet 1998 Nov 7;352(9139):1557], Lancet. 1998;352:854-65.
6. Skyler J, Cohen M. Self-monitoring of Blood Glucose. In: Alberti K. Zimmet P,
DeFronzo R, Keen H, eds. International Textbook o f Diabetes Mellitus. Chichester:
John Wiley and Sons; 1997:1031-1046.
7. Wallberg-Henriksson H, Rincon J, Zierath JR. Exercise in the management of
non-insulin-dependent diabetes mellitus [published erratum appears in Sports Med
1998 Feb;25(2):130]. Sports Med. 1998;25:25-35.
8. Serrano Rios M. Relationship between obesity and the increased risk of major
complications in non-insulin-dependent diabetes mellitus. Eur J Clin Invest.
1998;28:14-7, discussion 17-8.
9. Whelton PK, Kumanyika SK, Cook NR, et al. Efficacy of nonpharmacologic
interventions in adults with high-normal blood pressure: results from phase 1 of the
Trials of Hypertension Prevention. Trials of Hypertension Prevention Collaborative
Research Group. Am J Clin Nutr. 1997;65:652S-660S.
10. Taskinen M, Nestel P. Hypolipidemic Agents: Their Role in Diabetes Mellitus.
In: Alberti K, Zimmet P, DeFronzo R, Keen H, eds. International Textbook of
Diabetes Mellitus. Chichester: John Wiley and Sons; 1997:883-897.
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11. NIH, Consensus development conference on diet and exercise in non-insulin-
dependent diabetes mellitus. Diabetes Care. 1987;10:639-644.
12. Rosenbloom AL, Joe JR, Young RS, Winter WE. Emerging epidemic of type 2
diabetes in youth. Diabetes Care. 1999;22:345-54.
13. UKPDS. United Kingdom Prospective Diabetes Study 24: a 6-year, randomized,
controlled trial comparing sulfonylurea, insulin, and metformin therapy in patients
with newly diagnosed type 2 diabetes that could not be controlled with diet therapy.
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15. Boyne MS, Saudek CD. Effect of insulin therapy on macrovascular risk factors
in type 2 diabetes. Diabetes Care. 1999;22:C45-53.
16. Lewis CE, Raczynski JM, Heath GW, Levinson R, Hilyer JC, Jr., Cutter GR.
Promoting physical activity in low-income African-American communities: the
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17. Coates RJ, Bowen DJ, Kristal AR, et al. The Women’ s Health Trial Feasibility
Study in Minority Populations: changes in dietary intakes. Am J Epidemiol.
1999;149:1104-12.
18. Colman E, Katzel LI, Rogus E, Coon P, Muller D, Goldberg AP. Weight loss
reduces abdominal fat and improves insulin action in middle-aged and older men
with impaired glucose tolerance. Metabolism: Clinical & Experimental.
1995;44:1502-8.
19. Croft JB, Temple SP, Lankenau B, et al. Community intervention and trends in
dietary fat consumption among b l a c k and white adults. J Am Diet Assoc.
1994;94:1284-90.
20. Story M, Evans M, Fabsitz RR, Clay TE, Holy Rock B, Broussard B. The
epidemic of obesity in American Indian communities and the need for childhood
obesity-prevention programs. Am J Clin Nutr. 1999;69:747S-754S.
21. Agurs-Collins TD, Kumanyika SK, Ten Have TR, Adams-Campbell LL. A
randomized controlled trial of weight reduction and exercise for diabetes
management in older African-American subjects [see comments]. Diabetes Care.
1997;20:1503-11.
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22. Eriksson KF, Lindgarde F. Prevention of type 2 (non-insulin-dependent)
diabetes mellitus by diet and physical exercise. The 6-year Malmo feasibility study.
Diabetologia. 1991;34:891-8.
23. UKPDS. Effect of diet, sulphonylurea, insulin or biguanide therapy on fasting
plasma glucose and body weight over one year. Diabetologia. 1983;24:404-411.
24. Despres IP, Tremblay A, Nadeau A, Bouchard C. .Physical training and changes
in regional adipose tissue distribution. Acta Medica Scandinavica - Supplementum.
1988;723:205-12.
25. Walker KZ, Piers LS, Putt RS, Jones JA, K OD. Effects of regular walking on
cardiovascular risk factors and body composition in normoglycemic women and
women with type 2 diabetes. Diabetes Care. 1999;22:555-61.
26. Heath GW, Leonard BE, Wilson RH, Kendrick IS, Powell KE. Community-
based exercise intervention: Zuni Diabetes Project. Diabetes Care. 1987;10:579-83.
27. Leonard B, Leonard C, Wilson R. Zuni Diabetes Project. Public Health Rep.
1986;101:282-88.
28. Narayan KM, Hoskin M, Kozak D, et al. Randomized clinical trial of lifestyle
interventions in Pima Indians: a pilot study. Diabet Med. 1998;15:66-72.
29. Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial
intervention in patients with type 2 diabetes mellitus and microalbuminuria: the
Steno type 2 randomised study [see comments]. Lancet. 1999;353:617-22.
30. Charles MA, Eschwege E, Bennett PH. [Non-insulin-dependent diabetes in
populations at risk: the Pima Indians]. Diabetes & Metabolism. 1997;23:6-9.
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92
6.0 MANUSCRIPT
The Native American Diabetes Project: Results of a Lifestyle Intervention for
Native American Adults with Diabetes in New Mexico
Summary of Key points
• Diabetes lifestyle interventions may be an effective method to improve diabetes
outcome measures among Native American populations.
• To determine the effects o f a diabetes lifestyle intervention on diabetes risk
factors for complications a commimity-based intervention trial was conducted in
three Native American sites in New Mexico from 1993-1997.
• Culturally appropriate diabetes lifestyle intervention was delivered in family and
friends (FF) setting or a one-on-one (00) appointment versus usual medical
care (UC) to a total o f 104 adult Native Americans with type 2 diabetes.
• Adjusted mean change in HbAlc value varied significantly across the three arms
(p=0.05). The UC arm showed a statistically significant increase in adjusted
mean HbAlc change (1.2%p=0.001), while both intervention arms showed a
small nonsignificant increase in the adjusted mean change (0.5% and 0.2% for
FF and 0 0 arms, respectively) (p>0.05). The increase was statistically
significantly smaller in the combined intervention arms (0.4%) compared with
UC (1.2%) (p=0.02). Both intervention arms showed a nonsignificant decrease
in weight, 2.0 (1.5) pounds in FF and 1.8 (1.5) pounds in 00, while a non
significant increase of 1.7 (1.8) pounds was observed in UC (p= - 0.14). Weight
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93
decreased 1.9 (1.2) pounds in combined intervention arms compared with a 1.7
(1.8) pound increase in UC (p=0.05)
• Because level of HbAlc has been shown to be predictive of morbidity and
mortality, the ~1% difference in the change in HbAlc value among participants
o f the intervention may have the potential to substantially reduce microvascular
complications, mortality and health care utilization and costs, if the change can
be sustained over time.
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6.1 Introduction
94
Many Native American tribes suffer from a high and rising prevalence of type 2
diabetes, with some Native American tribes experiencing upwards of 50%
prevalence among adults. * Moreover, Native populations suffer higher prevalence of
many of the complications associated with diabetes.2-8 The high prevalence of type
2 diabetes combined with a poorer prognosis contributes to a disproportionately large
and rising diabetes-related mortality rate among Native American populations. In
New Mexico, diabetes-related mortality increased by 564% and 1,110% for Native
American men and women respectively from 1958-1994.9,
One approach to reducing the disproportionate burden of type 2 diabetes is to
develop interventions directed toward reducing the risk factors for the complications
of this chronic disease. At the cornerstone of diabetes interventions are diet and
physical activity, yet their roles have been generally understated. Interventions focus
on clinical treatments, such as hypoglycemic medications, which have been shown to
reduce microvascular complications in persons with type 2 diabetes. ** However,
interventions that emphasize a combination of diet, physical activity and clinical
treatments may have the greatest potential to reduce the risk factors for diabetes-
related complications. ^ However, there is a paucity of effective lifestyle
interventions in general, and especially for Native Americans.
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95
In response to this need, the Native American Diabetes Project, a culturally
appropriate lifestyle intervention, was designed and developed. ^ The lifestyle
intervention was conducted in combination with usual clinical intervention to
evaluate the effectiveness of a lifestyle intervention specifically targeted for Native
American adults with diabetes. The hypothesis was that participation in a culturally
appropriate intervention in conjunction with comprehensive clinical care would
positively affect glycemic control.
6.2 Methods
6.2.1 Study Design
This community-based intervention was developed and conducted from August 1993
through July 1997 in eight Rio Grande Pueblo communities in New Mexico. All
communities were served by three Indian Health Service (IHS) clinics that
participate in an IHS diabetes registry and had an expressed interest in testing this
new community-based intervention model. Participants were identified through the
diabetes registries through an agreement with the IHS. All Native American women
and men, >18 years of age, with a diagnosis of type 2 diabetes who were physically
and mentally able, and who resided in one of the eight communities were eligible to
participate in the intervention. Trained Native American interviewers invited
potential participants by telephone and/or in person. All participants gave written
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96
informed consent and the study protocol was approved by the Institutional Review
Boards of the IHS, the University of New Mexico and the participating tribes.
6.2,2 Chart Audit
A review of the IHS medical records was conducted for the entire population of
persons with diabetes served by the three IHS centers in 1994 (n=514) and 1996
(n=517). A 100% medical record review was conducted on the people who had a
diagnosis of diabetes as recorded through the IHS clinic database. A standardized
review protocol previously described by IHS Diabetes Headquarters West Program
was used. ^ Data items collected in the chart review from the IHS clinics included
duration of diabetes, time since diagnosis in years and months. Medication use was
recorded as diet alone, oral agent, insulin, and oral agent plus insulin. Additional
laboratory data included total cholesterol, triglyceride, and creatinine measured as
mg/dl. Proteinuria was defined as having 1+ (30 mg/dl) or more protein in a urine
dipstick in the past year. Hypertension was defined as having had a diagnosis of
hypertension or medicine for hypertension prescribed as documented in the medical
record. Cerebrovascular accident (CVA) or stroke and myocardial infarction (MI) or
heart attack were defined as having had a history of a CVA or MI as above.
Amputation was defined as having had either a toe/foot or leg amputation.
Nephropathy was defined as having a serum creatinine value of >2.0 mg/dl.
Retinopathy was defined as having background, proliferative, or macular edema
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97
documented by dilated fundoscopic examination. Laser treatment was defined as
ever having laser photocoagulation for retinopathy.
6.2.3 Intervention Outcome Measures
Measures were obtained at pre-intervention and post-intervention visits each
separated by approximately one year and, administered at the same time of year.
Trained staff members used a standardized protocol to measure and record weight to
the nearest half-pound and obtained demographic and lifestyle variables using
standardized in-person interview methods. Blood pressure was measured using the
American Heart Association standard protocol.^ Hemoglobin Ale (HbAlc) level is
measured as percent of hemoglobin that is glycated and is expressed as HbAlc
percent. Hemoglobin Ale was measured by a DC A 2000 analyzer using standardized
protocol as reported previously.^ Validity and reliability of the DCA 2000 was
assessed on a random sample of subjects pre-intervention. The correlation was .993
and the mean absolute relative difference between the DCA 2000 and high-
performance liquid chromatography (HPLC) system was 1.2%.
6.2.4 Intervention
A community-based diabetes lifestyle intervention was used in each of the two
intervention arms. One intervention arm received culturally appropriate diabetes
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educational materials, skill building and social support provided within family and
friends format (FF) and the second intervention arm received the same information
provided by one-on-one format (00) J 3 Participants in the control arm could access
the usual care medical services provided by the IHS clinics (UC).
The intervention was designed and developed using community preferences and
principles of social learning theory and consisted of five sessions: Get more
exercise!. Eat less fat!, Eat less sugar!, Together we can!, and Staying on the Path!
17,18 Through focus group sessions the community requested that the intervention
include traditional Native American values, Native foods, information about exercise
and diet and videos featuring Native faces. To incorporate traditional Native values
the community coordinator wrote stories that are used throughout the intervention.
Storytelling is a traditional method of Native American learning. Native foods and
Native Americans engaging in healthy lifestyle behaviors were featured in videos.
The intervention sessions were taught about six weeks apart and were conducted
over about a ten month period from 1995 to 1996 and have been described in more
detail elsewhere J 3, 19,20 Briefly, the information provided in the intervention
included written materials, and food and physical activity demonstrations. The FF
arm included activities that were designed to encourage social interaction and
discussion about diabetes among members of the group. During the intervention a
mentor led the participants through the written materials and encouraged participants
to discuss and to share their stories about living with diabetes. In addition,
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participants of the FF arm shared group physical activities and had a healthy meal
together. The 0 0 participants received the same written materials presented by a
mentor in individual sessions. The UC control group followed their usual schedule of
IHS clinic visits and activities.
6.2.5 Statistical Analysis
Demographic and pre-intervention levels of clinical and laboratory variables were
compared between intervention arms using either an analyses of variance for
continuous variables or chi-square or Fisher's exact tests for discrete variables. The
analyses of the primary study end points of HbAlc level and weight was conducted
for all evaluable participants (i.e. subjects with baseline and follow-up measures). To
test the hypothesis of intervention differences in HbAlc level and weight, analyses
of covariance was used. In addition to the planned covariates of gender, age, duration
of diabetes, pre and post-medication use, and factors found to be significantly
different at baseline across the intervention arms were included as covariates in all
subsequent analyses. During the planning year, two determinations were made of
HbAlc one year apart. For purposes of analyses the pre-intervention HbAlc level
serves as the baseline for the intervention period. The change in HbAlc level
between the first and second determinations will serve as a covariate since it reflects
possible changes due to clinical practice. Statistical testing was carried out at the .05
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level, using 2-sided p-values when two groups were compared. All statistical
analyses utilized SAS software. 21
6.3 Results
6.3.1 Description of Study Participants
Figure 6.1 summarizes the community intervention profile. During the planning year
a total of 514 Native American people with diabetes were listed in the IHS diabetes
registry. A total of 206 (40%) eligible men and women volunteered to participate in
interviews at the beginning of the planning year. During the planning year, 47
participants withdrew prior to receiving the intervention (23%) leaving 159
participants for the pre-intervention interview (77%). Forty-two participants dropped
out of the study during the intervention (26%) and did not have a post-intervention
assessment and 13 participants did not have information on covariates for analyses
(8%), leaving 104 evaluable participants (65%).
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Figure 6.1 Intervention Profile of the Native American Diabetes Project.
Population with
Diabetes
N-514
I
Intervention
Planning Period
N=206
4-
Intervention
Period
N=159
I
Intervention
period 41 55 63 159
withdrew 9 16 30 55
Evaluable 32 39 33 104
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Using the chart audit databases, evaluable participants (N=104) were in general
representative of the target population and did not differ by duration of diabetes,
HbAlc level, weight, blood pressure, cholesterol, triglyceride or creatinine levels,
history of medication use, hypertension, retinopathy, nephropathy, proteinuria, laser
treatment, myocardial infarction or cerebrovascular accident (data not shown).
However, compared to the non-participants, the evaluable participants included more
females (79% versus 58%, p = 0.001) and were older (60 years versus 57 years p =
0.04).
Table 6.1 summarizes the pre-intervention characteristics for the 104 evaluable
participants. There were statistically significant differences between the three arms at
pre-intervention in HbAlc level, with the OO arm having the highest HbAlc value
and the UC arm having the lowest HbAlc value (p=0.03). The proportion of
participants receiving oral agents or oral agents plus insulin was significantly lower
in the UC arm than either of the intervention arms (p=0.Q3). Hypertension was
significantly more common in the participants in the FF and UC arms than the OO
. arm (p<0,05). Therefore subsequent analyses were adjusted for pre and post-
medication use, hypertension, and change in HbAlc level during the first year, as
well as the pre-selected covariates of age, gender and duration of diabetes.
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103
Table 6.1 Selected pre-intervention demographic and: clinical characteristics of
FF
n=32
OO
n=39
UC
n=33
p-value
Demographic & Clinical
Male 9 (28%) 10 (26%) 3 (9%) 0.12
Female 23 (72%) 29 (74%) • 30 (91%)
Age (yrs) 60.2 59.9(13.4) 60.2(11.8) 0.99
(12.1)**
Duration (yrs) 8.1 (5.3) 8.3 (6.4) 10.0 (6.6) 0.35
HbAlc (%) 8.3 (1.9) 9.2 (2.3) 7.9 (2.0) 0.03
Weight (lbs) 174.6(35.4) 172.2 (37.2) 168.9 (33.8) 0.81
BMI 31.0 (5.6) 31.2 (6.8) 32.0 (6.1) 0.78
DBF (mmHg) 80 (9) 81 (12) 78(10) 0.45
Choi (mg/dl) 199 (51) 218(50) 193 (43) 0.10
Trig (mg/dl) 224 (147) 290(214) 214(154) 0.21
Creat (mg/dl) 1.3 (0.9) 1.1 (0.5) 1.0 (0.9) 0.35
Medication Use
Diet 5 (16) 6 (15) 11(33) 0.12
Insulin 2 (6) 11 (26) 7 (21) 0.10
Oral Agents 25 (78)a 23 (59)a 15 (46)b 0.03
Complications
Hypertension (htn) 59a 33b 56a 0.05
Proteinuria (pro) 39 31 43 0.60
Retinopathy (ret) 19 33 25 0.41
Nephropathy (nep) 10 13 9 0.87
Laser Treatment 6 5 9 0.78
MI 6 5 9 0.89
CVA .
+„...... ... ■ + + ....
3 0 6 0.29
nep, laser treatment; ANOVA for age, duration, HbAlc, weight, body mass index,
diastolic blood pressure, cholesterol, triglycerides, creatinine; Fisher's Exact Test for
myocardial infarction, and cerebrovascular accident. a,b are statistically significantly
different by Tukey's Studentized Range (Honestly Significant Difference).
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6.3.2 Change in Outcomes
104
Figure 6.2 summarizes the results of the effects of the intervention on HbAlc level
across the three intervention arms for participants who completed the study. The
adjusted mean change in HbAlc level during the intervention period varied
significantly across the three intervention arms (p=0.Q5). The UC arm showed a
statistically significant increase in the adjusted mean change of HbAlc level, 1.2%,
(p=0.001), while both intervention arms showed a small non-significant (p>0.G5)
increase in the adjusted mean change (0.5% and 0.2% for FF and OO arms,
respectively). The intervention arms were combined and compared with the UC arm.
The increase in mean adjusted HbAlc level was statistically significantly smaller in
the combined intervention arms compared with the UC arm, 0.4% versus 1.2%,
respectively ^==0.02).
Figure 6.3 summarizes the results of the effects of the intervention on weight across
the three intervention arms. Weight decreased 2.0 (1.5) pounds in FF arm and 1.8
(1.5) pounds in OO arm and increased 1.7 (1.8) pounds in the UC arm, however
these differences were not statistically significant (p=0,14). The combined
intervention arms were compared with the UC arm. Weight decreased 1.9 (1.2)
pounds in the combined intervention arm, compared to the 1.7 (1.8) pound increase
in UC, a difference that was statistically significant (p<0.05).
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Figure 6.2 Post-Intervention Change in Adjusted* Mean HbAlc for Family
and Friends (FF) and One-on-One (OO) Intervention Arms and Usual Care
Control Arm, (UC) and Combined Intervention Arms. The mean (SD) for the FF,
OO and UC arms for all 104 evaluable participants were 0.5% (0.3), 0.2% (0.3) and
1.2% (0.4), p=0.05. The change in adjusted mean HbAlc from pre-intervention to
post-intervention within the UC Arm was statistically significant, p=0.001. The mean
(SD) for the FF + OO and the UC arm were 0.4% (0.2) and 1.2% (0.4), p=0.02.
+ Models were adjusted for age, gender, hypertension, duration of diabetes,
medication type pre-intervention and post-intervention, and change in HbAlc level
during first year.
1.2
1
< 0.8
A
W
- 0.6
m 0.4
a
Q
0.2
FF
p=0.05
Smm
OO UC
p=0.02
F F + O O
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106
Figure 6.3 Change in Adjusted* Mean Weight over the Intervention Period
for the Intervention Arms, Family and Friends (FF) and One-on-One (OO) and
Usual Care (UC) and Combined Intervention Arms. Results of ANACOVA
revealed non-significant differences across three arms (p=0.14). The mean (SD) for
the FF, OO and UC arms for all 104 evaluable participants were -2.0 pounds (1.5), -
1.8 pounds (1.5) and 1.7 pounds (l.S).Pairwise comparisons using Tukey procedures
showed FF + OO was statistically significantly different than UC (p<0.05). The
mean (SD) for the FF + OO and the UC arm were -1.9 pounds (1.2) and 1.7 pounds
(1.8), p=0.G5. + Models were adjusted for age, gender, duration of diabetes,
medication use, hypertension and pre-intervention weight.
p < 0 . Q 5
A
0 .5 -
&
ss
- 0.5 A
&
a -1 -
55
5 -1.51
F F + O O OO UC FF
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107
Table 6.2 summarizes the post-intervention change in adjusted mean diastolic
blood pressure and serum lipid levels. Diastolic blood pressure decreased 6 mmHg in
the FF arm and remained essentially unchanged in the OO and UC arms. This
difference across the three arms was statistically significant (p= 0.02); however, the
combined intervention compared with the UC arm was not statistically significant
(p>0.05). Cholesterol and triglyceride levels also decreased across the arms
respectively; however, this decrease in lipid levels was not statistically significant
across the three arms or between the combined intervention arm compared with the
UC arm (p>0.05).
Table 6.2. Post-intervention Change in Adjusted Mean Diastolic Blood
Pressure, Cholesterol and Triglyceride Levels for Family and Friends (FF) and
One-on-One (OO) Intervention Arms and Usual Care Control Arm, (UC) and
Combined Intervention Arms. + Models were adjusted for age, gender,
hypertension, duration of diabetes, medication type and baseline levels of each
respective variable.
FF
n=32
OO
ii=39
UC
h=33
p-value
Diastolic blood
pressure (mmHg) -6.5 (2.0) -0.4 (1.7) -0.3 (2.1) 0.02
Cholesterol
(mg/dl)
-22(11) -20(11) -10(16) 0.79
Trigylcerides
(mg/dl)
-178(78) -48 (48) -69 (63) 0.21
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6.4 Discussion
108
Our primary finding from this community-based intervention was that participants in
the intervention had significant benefit in glycemic control and weight compared
with the UC control after adjusting for covariates. Because HbAlc level has been
shown to be predictive of morbidity and mortality the intervention has the potential
to substantially reduce microvascular complications, mortality, and health care
utilization and costs if the change can be sustained over time. 11.22,23
Our findings are consistent with a number of studies and trials that show
interventions are efficacious in improving glycemic control. We observed an
absolute difference of 0.7% in HbAlc level between the FF and OO and UC arms
even though overall HbAlc level increased. Although the mechanisms are not fully
understood, our findings are consistent with the results of the UKPDS, which found
that HbAlc and fasting blood glucose levels progressively increased over the
study. The effectiveness of lifestyle interventions among Native Americans with
diabetes is illustrated by a retrospective evaluation of 30 participants with type 2
diabetes who participated in a community-based exercise intervention of weekly
group aerobic exercises. Medical records were compared with records of 56 non-
participants with type 2 diabetes.24 Participants’ fasting blood glucose levels and
weight were significantly lowered, 43 mg/dl and 4 kilograms compared with 2 mg/dl
and 0.9 kilograms among the non-participants.24-26 xhe results of the present study
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109
provide more evidence that participation in a community-based lifestyle
intervention may result in improvement in glycemic control among Native American
people with type 2 diabetes.
There is little data on the sustainability of lifestyle changes following community
interventions in minority communities. Agurs-Collins conducted, a three month
randomized study of 64 overweight African-American men and women aged 55-79
years with type 2 diabetes. The subjects were randomized to either a weight loss and
exercise program or usual c a r e . 2 7 The intervention consisted of twelve weekly group
sessions, one individual session and six biweekly group sessions. At the end of six
months, there were significant differences in mean HbAlc values; -2.4% compared
with the usual care control. There was no further follow-up beyond six months and
whether the beneficial effects were sustainable were not addressed by the study. The
results of the present study indicate that the effect of a lifestyle intervention were
observed at 1 year and suggest that changes may be maintained over a longer term.
How might one account for the effects of the intervention? First, because the risk
factors for preventing or delaying the onset of diabetes complications are complex
and interdependent, it may be that interventions that include comprehensive clinical
and culturally appropriate lifestyle interventions have the greatest potential to reduce
the risk factors associated with diabetes complications. The Steno type 2 randomized
trial in Denmark is one of the few interventions that have evaluated a realistic
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110
combined clinical and lifestyle intervention. The trial was designed to determine
the effect of a combined clinical and lifestyle intervention as compared to standard
pharmacological intervention. 12 The primary endpoint was the development of
nephropathy in at least one of the two yearly examinations and the secondary
endpoints were the incidence or progression of retinopathy and neuropathy.
Participants in the multifactorial intervention had significantly lower rates of
progression to nephropathy (OR=0.27 (95% Cl 0.10-0.75)), neuropathy, (OR=0.32
(0.12-0.78)) and retinopathy, (GR=0.45 (0.21-0.95)), than those in the standard
pharmacological intervention. Therefore, a combined clinical and lifestyle
intervention in people with type 2 diabetes may be the more effective than either one
alone.
Second, the intervention materials were designed and developed with input from
focus group sessions of Native American community members to determine their
p r e f e r e n c e s . 13,19,20 -phe intervention uses a traditional Native American method,
story telling, to convey information about diabetes. Traditional Native foods and
physical activities are included in the intervention and are featured in the videos with
Native peoples engaging in healthy lifestyle behaviors. Therefore, the intervention
content was culturally relevant and contained values pertinent to the Native
communities. 13, 19,20 Moreover, the intervention used traditional Native American
educational messages that were culturally appropriate and more effectively
communicated than standard diabetes education materials and this may have
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I l l
improved the effectiveness of the intervention. Narayan has reported that in a
twelve-month pilot trial with 95 obese Native American men and women without
diabetes, that an intervention that was culturally appropriate appeared to enhance the
effectiveness of the intervention.^ The authors compared a structured activity and
diet intervention to a less structured intervention, which emphasized Pima culture. At
the end of twelve months the authors reported that participants of the Pima culture
intervention had less of an increase in glucose levels than the more structured group,
0.03 mM (0.54 mg/dl) and 1.33 mM (23.94 mg/dl), respectively (p = 0.007) and
gained less weight, (0.5 kg vs 2.5 kg), respectively (p - 0.06). 28 These results lend
support to the usefulness of interventions that use culturally appropriate materials.
Our study has a number of limitations as well as strengths. The study was not a
randomized study and therefore may be subject to residual confounding. A
randomized protocol was not acceptable to the communities involved. Due to close
kinship ties within communities, randomization would bring potential confounding
as well. Although pre-intervention differences in the study arms were accounted for,
the study may be confounded from unmeasured or poorly measured covariates.
There was a relatively small sample size to precisely estimate the magnitude of
effects between the intervention arms. Nearly forty percent of the population of
people with diabetes participated in the study and there were few differences
between participants and non-participants and therefore the results are likely to be
generalizable to the community members with diabetes. However, as only people
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112
from. Rio Grande Pueblo Native American communities were included in this
study the findings may not be generalizable to other tribes. More than 70% of
participants who started the intervention completed it. More women and older
participants were evaluable suggesting the intervention may be more amenable to
these groups. Future studies may need to develop interventions that appeal to males
and younger people with diabetes. An important strength of the study is that the
intervention was well accepted in these Native American communities as previously
documented. 20
The effectiveness of the Native American Diabetes Project intervention may likely
be due to the use of: 1) a culturally appropriate lifestyle intervention in conjunction
with comprehensive medical care 2) intervention materials that were designed and
developed with input from Native American community members and therefore,
contained more culturally relevant materials and values to the Native communities
and 3) social learning theory as an approach to how people learn.
In summary, type 2 diabetes among Native American people is projected to increase
over the coming decades and is associated with rapidly increasing morbidity and
mortality. Although the diagnosis of diabetes implies a relatively poor prognosis, this
study shows that culturally competent lifestyle interventions are well accepted and
effective among Native Americans. There is an urgent need for the development and
dissemination of more interventions that are both culturally appropriate and
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clinically comprehensive in order to prevent and/or delay complications of
diabetes in this high-risk population.
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114
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weight control: diabetes risk reduction and glycemic control in Zuni Indians. Am J
Clin Nutr. 1991;53:1642S-1646S.
27. Agurs-Collins ID, Kumanyika SK, Ten Have TR, Adams-Campbell LL. A
randomized controlled trial of weight reduction and exercise for diabetes
management in older African-American subjects [see comments]. Diabetes Care.
1997;20:1503-11.
28. Narayan KM, Hoskin M, Kozak D, et al. Randomized clinical trial of lifestyle
interventions in Pima Indians: a pilot study. Diabet Med. 1998;15:66-72.
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7.0 GRANT PROPOSAL
Enhancing Lifestyle and Self-management Activities
Among Native Americans with Diabetes
Summary of Key Points
• Rate o f diabetes related complications such as kidney failure, blindness,
amputations and infections are disproportionately higher among Native Americans
than the general US population.
• Achieving near normal glycemic levels through medication, diet, physical activity
and daily self-monitoring o f glucose, can significantly reduce complications.
• Clear need for diabetes intervention strategies to promote healthful lifestyle and
increase self-management activities to reduce the risk o f complications.
9 This proposal builds on the success o f the Native American Diabetes Project, a
lifestyle intervention, and seeks to develop, implement and evaluate a new culturally
appropriate comprehensive lifestyle and self-management intervention among the
Native Americans with type 2 diabetes to improve blood glucose levels and reduce
the risk o f diabetes complications.
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7.1 Specific Aims
118
Diabetes is a major health problem among Native American populations. The
prevalence and mortality associated with diabetes in Native American populations
has been rapidly increasing since 1950.1 The rate of diabetes related complications
such as kidney failure, blindness, amputations and infections are disproportionately
higher among Native Americans than the general US p o p u la tio n . 2 However, the
clinical progression to complications is not inevitable. With the results of the United
Kingdom Prospective Diabetes Study (UKPDS), there is little doubt that the goal of
achieving near normal blood glucose levels can significantly reduce the development
and progression of the complications of type 2 diabetes A 4
Glycemic control can be improved with medication, diet, and physical activity and
daily self-monitoring of blood glucose l e v e l s A 8 However, healthful lifestyle
changes are often difficult to make and sustain. 9 In addition, a recent US study
reported that self-monitoring of blood sugar was below that necessary to avoid
complications, from -30% of people surveyed in Hawaii, to 65.5 percent in
Montana. ^ Therefore, the need for diabetes intervention strategies to promote
healthy lifestyles and increase self-management of diabetes activities to reduce the
risk of complications of diabetes is clear. Yet, studies of interventions lag behind,
especially in minority populations.
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119
The long-range goal of this study is to promote healthy lifestyles and increase
self-management activities to improve glycemic control to reduce the risk of diabetes
complications. The proposed intervention builds upon the successful lifestyle
intervention that was developed specifically for Native Americans with type 2
diabetes, the Native American Diabetes Project. Participants in the lifestyle
intervention had significant benefit in glycemic control and weight compared with
the control arm after adjusting for covariates. Because HbAlc level is predictive of
morbidity and mortality the Native American Diabetes Project lifestyle intervention,
has the potential to substantially reduce microvascular complication and mortality if
the change can be sustained over time. 11-13 with the addition of a culturally
appropriate self-management of diabetes intervention further improvements can be
made in glycemic control in this high-risk Native American population.
The specific aim of this proposal is to develop, implement and evaluate a
comprehensive culturally appropriate lifestyle plus self-management intervention to
further reduce the risk of diabetes complications among Native Americans. The
primary outcome measures will include:
a) HbAlc (primary outcome measure)
b) Blood pressure
c) Weight
d) Lipid levels
e) Proteinuria/microalbuminuria
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120
The secondary outcome measures will include:
a) Medication taking behaviors
b) Self-monitoring of blood glucose (SMBG) behaviors
c) Foot care behaviors
d) Dental care behaviors
e) Foot/Dental/Eye examinations
f) Overall health-related quality of life and diabetes specific quality of
life
A community intervention study design will be used with two Native American
communities: one community will be assigned to the intervention and the second
community will be assigned to the usual care control who will receive delayed
intervention. Because of the close kinship ties in these communities it is not feasible
to randomize participants to intervention or control arms. Measures will be obtained
at study office sites that will be located on or near the reservation at pre and post-
intervention and at twelve months post-intervention. The target population is all
Native American people with type 2 diabetes, age ten to 80 years, who attend the
Indian Health Service Clinics in Pima and Tohono O'Odham communities.
The following hypotheses will be tested:
i) intervention participants will have improvement in HbAlc, blood pressure, weight,
lipid levels, and proteinuria/microalbuminuria compared to usual care control
participants.
ii) intervention participants will have improvement in medication taking, SMBG,
foot, dental and eye care compared to usual care control participants.
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1 2 1
iii) intervention participants will have improvement in overall and diabetes-
specific quality of life compared to usual care control participants.
iv) intervention participants will maintain improvement at twelve months post-
intervention compared to usual care control participants.
7,2. Background and Significance
7.2.1 Magnitude of Type 2 Diabetes among Native American Populations
Type 2 diabetes is a major public health concern among Native American
populations. Diabetes was virtually unknown among Native American people at the
turn of the century, but since the 1950's type 2 diabetes has been on the increase.^
Today there is an epidemic of type 2 diabetes among many Native American
populations. 14-16 Among the Pima of Arizona, diabetes prevalence reaches 70% in
the 55-64 year age group and because prevalence is increasing at younger ages, there
is concern that other southwestern tribes are not far behind the Pima. ^
Diabetes was initially thought to be a benign disease among NA people, but today
we know that diabetes accounts for much of the morbidity and mortality in Native
c o m m u n itie s .^ * 18,19 j n jqew Mexico, from 1958-1994, mortality due to diabetes
showed an increase of 564% and 1,100% among NA men and women respectively,
and increased most rapidly during the most recent ten-year period. ^ Type 2 diabetes
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has reached epidemic proportions in many Native communities and is likely to get
worse due to trends in incidence for children.20,21 while type 2 diabetes has been
regarded as a rare event in children, it is increasing among NA children.20
7.2.2 Diabetes Complications and Native American Populations
Type 2 diabetes accounts for a substantial portion of the morbidity and mortality in
Native communities. 1 * 19, 22 Native American populations are at higher risk for
nephropathy, retinopathy, lower extremity amputations, periodontal dipease,
infections, gallbladder disease and cataracts as compared with the general
population^ 15
7.2.2.1 Nephropathy
Native American populations are at high risk for kidney failure. 1 > 2 During a survey
among the Native Canadian population from 1981-1986, rates of end stage renal
disease were 2.5 - 4 times higher as compared with national rates and one-quarter of
the cases were related to diabetes. 1 In the US, end stage renal disease incidence rates
for Native Americans were 2 .8 times the rate of non-Hispanic whites. 1 Duration of
diabetes was one of the most important risk factors for diabetes nephropathy and end
stage renal d is e a s e .2 3 A study among the Pima found that children of a parent with
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123
diabetes and proteinuria were at greater risk of developing nephropathy than
children of parents with diabetes and no p r o te i n u r ia .2 4
1,22.2 Retinopathy
Retinopathy due to diabetes is found in many Native American populations. *
Increasing duration of diabetes is an important risk factor for the development of
retinopathy. * The prevalence of retinopathy varies among tribes. Among the
Oklahoma tribes the prevalence was 49.3% and among the Pima, 18%. ^ 25 jn a 20-
year follow-up study among the Pima population, researchers found a 14% incidence
rate of proliferative retinopathy. 2 5
1.2,23 Neuropathy
Neuropathy rates vary by tribe but overall rates of lower extremity amputation are
high. 1 j 2 jn a study of the Chippewa tribe in Minnesota, persons with diabetes who
had lost the protective sensation in their feet had 9.9 times the rate of foot ulcers, and
17 times the rate of lower extremity amputation compared to people who also had
diabetes, but had their protective sensation i n ta .c t .2 6
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1.2.2A Diabetes-related Mortality
124
Trends in diabetes-related mortality among Native American populations are
remarkable. In New Mexico, from 1958-1994, mortality due to diabetes showed an
increase of 564% and 1,100% among Native American men and women
respectively, and increased most rapidly during the most recent ten-year period. ^
1 2 2 3 Infections
Among Native Americans infections are a serious concern. 1 In the early 1900's many
people with diabetes died of overwhelming infection. 27 Improved treatment
dramatically altered this situation, yet people with poorly controlled diabetes remain
at high risk of developing infections.27, 28 pe0pie with diabetes are particularly
prone to mycobacterial and anaerobic and fungal infections, including tuberculosis,
skin fungal infections, bacterial urinary infections and anaerobic infections of deep
tissues which can be serious and even life threatening.27,28 jn i9gy5 mortality due
to tuberculosis among all Native American populations was 5.8 times higher than the
rate for the US general population. 1 Among the Sioux tribes, people with diabetes
were 4.4 times as likely to develop tuberculosis compared with persons without
diabetes. *
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125
7.2.3 Risk Factors for the Complications of Type 2 Diabetes among Native
American Populations.
Despite the great strides made in the treatment and understanding of diabetes,
complications associated with diabetes continue to be a major cause of morbidity and
early m o r t a lit y . 29 (Figure 7.1). The primary risk factors for diabetes-related
complications are hyperglycemia, hypertension, d y s l i p i d e m i a a n d o b e s i t y .^ O ^ S
7.2.3.1 Hyperglycemia
The primary causal factor for the development of most diabetes-related
complications is prolonged exposure to h y p e r g l y c e m i a . 3 . 34 Hyperglycemia is a
major risk factor for nephropathy.23 Among Pima Indians with diabetes, those
persons who had a 2-hour post-load plasma glucose level > 450 mg/dL at diagnosis,
had about three times the incidence of proteinuria after 15 years of diabetes duration
compared with those under that le v e l . 3 3 However, studies have shown that intensive
management of glucose levels significantly reduces the risk of development of
microalbuminuria and overt nephropathy. 3, 36
Hyperglycemia is strongly related to the risk of visual disorders, especially
r e t in o p a t h y . 3 The prevalence of retinopathy among Oklahoma and Pima adults with
diabetes ranged from 18-49.3%.25,37 Among the Sioux in South Dakota the
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126
prevalence of retinopathy among adults with diabetes was 4 5 J%.38 Incidence of
proliferative retinopathy among Minnesota Chippewa was found to be 12/1000
diabetes person years from 1 9 8 6 - 1 9 8 8 . 3 8 There are few' published studies of the
prevalence and incidence of cataracts among Native American populations. A Pima
incidence study in 1 9 8 5 reported the rate of cataract surgery for people with diabetes
was more than two times the rate of cataract surgery for people without diabetes. 1
Hyperglycemia is associated with lower-extremity amputations. 3 9 Lower extremity
amputations are an important problem for Native American populations. 2 A cross-
sectional study of non-traumatic lower extremity amputations from 1982 to 1987 in
four Indian Health Service areas was conducted. Compared with participants
without diabetes, people with diabetes had increased risks in each age group, with a
158-fold increased risk among those aged 15-44 years. 4® The average annual age-
adjusted incidence rates of all lower extremity amputations among people with
diabetes were 240.8/10,000 and 203.1/10,000 for the Tucson and Phoenix areas,
respectively, compared to the overall US rates of 73.1/10,000.40 Rates varied by
tribal group. The rates for the Navajo and Oklahoma areas, which have lower
prevalence of diabetes, were 74.0/10,000 and 87.3/10,000, respectively.40 In a study
of 4399 Pima subjects the incidence of lower extremity amputations was
estimated. 39 During the study, lower extremity amputations were performed on 84
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127
patients, 95% of whom had type 2 diabetes. Two-hour post-load hyperglycemia
was a significant risk factor for lower extremity a m p u ta tio n s .3 9
7.2.3.2 Hypertension
Hypertension further complicates diabetes as it often associated with diabetes.^ The
prevalence of hypertension in people with diabetes is about twice that of people
without diabetes in the same population.42 in a study of the Pima population in
Arizona, Sievers et ai studied the effect of hypertension on mortality among 5284
Pima people, 1698 of whom had type 2 diabetes at baseline or developed it during
follow-up. After 12.2 years of follow-up, 470 people without diabetes and 488
people with diabetes, died. Among the people with diabetes, 85 died of diabetes-
related nephropathy, 45 of the deaths were due to cardiovascular disease. Among the
people with diabetes, hypertension strongly predicted deaths from diabetic
nephropathy, but it had little effect on deaths from cardiovascular disease. It may be
that among the Pima population, there is a relatively greater effect of hypertension
on the progression of diabetes-related nephropathy that may be related to the
younger age at onset of type 2 diabetes, less smoking, good lipid profiles and,
possibly, an increased susceptibility to renal d is e a s e .4 3
Among the Native American population prevalence of hypertension and diabetes
varies significantly by tribe.44 In a study of 4549 people, aged 45 to 74 years, from
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128
13 tribal groups from South Dakota/North Dakota, southeastern Oklahoma, and
Arizona, the prevalence of hypertension ranged from 27% to 56% 45 Among the
participants from Arizona >60% had diabetes as compared with about 40% of the
participants from Oklahoma and the D a k o t a s .4 4 Among these tribes, diabetes and
hypertension were independent predictors of cardiovascular disease.^ Although
cardiovascular disease used to be rare among Native American tribes, the increasing
rates may be related to the high prevalence of diabetes and hypertension, ^
Hypertension is also a risk factor for visual disorders, especially retinopathy.25,46,
42 Studies among the Pima population have found that the higher the systolic blood
pressure the higher the incidence of retinopathy.48 Control of hypertension has been
demonstrated to reduce the rate of progression of diabetic nephropathy and to reduce
the cerebrovascular disease, including stroke, and cardiovascular disease.49
1 2 3 3 Dvsiinidemia and Obesity
The most common pattern of dyslipidemia in people with type 2 diabetes is elevated
triglyceride levels and decreased high density lipoprotein cholesterol levels while the
low density lipoprotein cholesterol is usually not significantly different from persons
without diabetes. 50 The Strong Heart Study was initiated to investigate
cardiovascular disease and its risk factors in Native Americans in 13 tribes residing
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129
in Arizona, Oklahoma, and South/North Dakota. ^ Cardiovascular disease
morbidity and mortality rates were higher in men as compared with women and the
significant independent predictors of disease in women were diabetes, age, obesity
(inverse), low density lipoprotein cholesterol, albuminuria, triglycerides, and
hypertension. In men, diabetes, age, low density lipoprotein cholesterol, albuminuria,
and hypertension were independent predictors of CVD. ^ Additionally, low high
density lipoprotein cholesterol was a risk factor for abnormal excretion of albumin in
women, but not in men, among the Pima population. ^1
7.2,4 Models for Intervention
There are opportunities for intervention to prevent or delay the onset of
complications associated with diabetes. (Figure 7.1) Methods to prevent the
development and progression of diabetes-related complications include control of
glucose levels, hypertension, lipid levels and w e i g h t . 3 0 - 3 2 Lifestyle interventions
focus on decreasing caloric intake and fat in the diet and increasing physical activity
to reduce hyperglycemia, hypertension and dyslipidemia and obesity. Self
monitoring of blood glucose levels can further reduce the risk factors for
complications of diabetes and improve health-related quality of life.
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130
Figure 7.1 Opportunities for Intervention to Prevent/Delay the
Complications Associated with Type 2 Diabetes
Onset of
diabetes-> Asymptomatic-> Complications-> Progression^
Early
Death
Hyperglycemia Hypertension
Dyslipidemia
Obesity
Neuropathy
Atherosclerotic
disease
Nephropathy
Lower
extremity
amputations
stroke
myocardial
infarction
ESRD
Death
Intervention:
decrease fat,
decrease
calories,
increase
physical
activity,
self-monitor
blood glucose
control glucose,
hypertension,
cholesterol
reduced QOL reduced QOL
We will use our experience from the Native American Diabetes Project lifestyle
intervention to develop and adapt an intervention for use in the Pima and Tohono
O'Odham populations. Social learning theory, community health development
process to determine community preferences, and the development of a collaborative
community team and provided an effective and practical framework for developing a
culturally appropriate community health intervention for type 2 diabetes for Native
American populations. Social learning theory considers that environmental,
behavioral and cognitive factors can affect behavior. The theory components include
behavioral capabilities (knowledge and behaviors), expectancies (values, attitudes
and incentives), issues of self-control (self-monitoring, goal-setting, problem
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131
solving, and self-reward), observational learning (role models), reinforcements,
self-efficacy (confidence in performing behavior), emotional coping responses, the
environment, and the situation (perceptions of the environment). The community
health development process develops a collaborative team where the cultural
knowledge and expertise resides with the community members who are full partners
in the process of intervention development. Programs are more likely to succeed if
they include community preferences and have a sound theoretical framework such as
social learning theory.
7.3 Preliminary studies
7.3.1 Native American Diabetes Project: Physical activity among Native
Americans with Diabetes
We described the current physical activity levels of Native Americans with diabetes
in the Native American Diabetes Project. 52 We found that while 37% of the
participants knew that exercise lowers blood sugar, 77% did not meet the Surgeon
General's recommendation for accumulating 30 minutes of leisure time exercise on
most days of the week. Therefore, Native American populations are an appropriate
target for a lifestyle intervention to increase physical activity to help reduce
hyperglycemia and prevent or delay the complications associated with diabetes.
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7.3.2 Native American Diabetes Project: Higher HbAlc Levels among
Younger Native American People with Diabetes
We investigated the determinants of high HbAlc levels in the participants of the
Native American Diabetes Project.^3 We found that age, dietary partem, and
medication use were determinants of HbAlc levels. Participants younger than 55
years had the highest adjusted HbAlc levels at 9.5% and those 65 years and older
had the lowest levels at 7.8%. According to a participant's dietary intake, HbAlc
levels were highest for those who consumed the most fat and sugar, and high
consumption of fat and sugar affected HbAlc levels most among those younger than
55 years. To avoid increased morbidity and mortality in the future young Native
American adults with diabetes need vigorous therapy and interventions that promote
a healthy lifestyle and teach diabetes self-management activities in order to achieve
and maintain tight glucose control.
7.3.3 Native American Diabetes Project: A Lifestyle Intervention
Investigators at UNM (Carter, Gilliland) conducted a population-based community-
directed lifestyle intervention of Native American people with diabetes. The
intervention was designed and developed using community preferences and
principles of social learning theory and consisted of five sessions: Get more
exercise!, Eat less fat!, Eat less sugar!, Together we can! and Staying on the Path!
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The culturally .appropriate diabetes lifestyle intervention was delivered in a family
and friends setting or a one-on-one appointment versus usual medical care. The main
outcome measures were changes in HbAlc level and weight. A community-based
diabetes lifestyle intervention was used in each of the two intervention arms. One
intervention arm received culturally appropriate diabetes educational materials, skill
building and social support provided within family and friends format (FF) and the
second intervention arm received the same information provided by one-on-one
format (00). ^ Participants in the control arm could access the usual care medical
services provided by the IHS clinics (UC). The intervention sessions were taught
about six weeks apart and were conducted over about a ten month period from 1995
to 1996 and have been described in more detail elsewhere. 54-56 The information
provided in the intervention included written materials, and food and physical
activity demonstrations. The FF arm included activities that were designed to
encourage social interaction and di scussion about diabetes among members of the
group. During the intervention a mentor led the participants through the written
materials and encouraged participants to discuss and to share their stories about
living with diabetes. In addition, participants of the FF arm shared group physical
activities and had a healthy meal together. The 0 0 participants received the same
written materials presented by a mentor in individual sessions. The UC control group
followed their usual schedule of IHS clinic visits and activities.
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134
Bilingual community members were trained in interview techniques,
administration of standardized questionnaires and performance of cl inical
measurements. Interviews took place in one of three offices in or near the
participating communities. Participants were paid ten dollars for their time. Height
and weight were recorded to the nearest half-inch and half pound, respectively, using
standardized protocol and converted to centimeters and kilograms. Hemoglobin Ale
was measured by DC A 2000 using standardized protocol as reported p r e v i o u s l y . 5 7
The adjusted mean change in HbAlc level during the intervention period varied
significantly across the three intervention arms (p=Q.05). The UC arm showed a
statistically significant increase in the adjusted mean change of HbAlc level, 1.2%,
(p=0.001), while both intervention arms showed a small non-significant (p>0.G5)
increase in the adjusted mean change (0.5% and 0.2% for FF and OO arms,
respectively). The intervention arms were combined and compared with the UC arm.
The increase in mean adjusted HbAlc level was statistically significantly smaller in
the combined intervention arms compared with the UC arm, 0.4% versus 1.2%,
respectively (p=0.G2).
Because HbAlc levels have been shown to be predictive of morbidity and mortality,
the ~!% difference in the change in HbAlc value among participants of the
intervention may have the potential to substantially reduce microvascular
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135
complications, mortality and health care utilization and costs, if the change could
be sustained over time. (Figure 7.2)
Figure 7.2 Post-Intervention Change in Adjusted Mean HbAlc for Family and
Friends, One on One versus Control versus Combined Intervention Arms.
0.8 •
3
FF O O UC F F + O O
Post-intervention change in adjusted m ean H bA lc.
(FF vs. O O . UC p=0.O5; FF + O O vs UC p=0.02)
7.3.4 Development of a Self-Management Intervention
The self-management intervention includes the clinical aspects of diabetes standards
of care which were not included in the Native American Diabetes Project lifestyle
intervention. Participatoty methods including focus group sessions with members of
the community, groups of patients, and health department staff were used to develop
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136
a self-management intervention for use in Native American populations.
Feedback from tribal health workers and other members of the community were
assessed to assure community preferences. The intervention has six sessions and they
are: Glucose balance makes a difference!, Medicines: Staying in balance!, Diabetes
and a Healthy heart, Healthy feet keep you going!, Staying healthy! Preventing
complications, and Getting the most out of living well! The intervention will be pilot
tested in a non-study site community.
7.4 Research Design and Methods
7.4.1 Overview of the Study Design
The comprehensive lifestyle and self-management intervention. Enhancing Lifestyle
and Self-management Activities, is a diabetes complications prevention program
targeting Native American people, ten to 80 years, with existing type 2 diabetes. The
research design will be a comprehensive community-based lifestyle and self
management intervention among Native Americans with diabetes who reside on the
Gila River (Pima) and Tohono O'Odham reservations. Persons with diabetes from
the Pima tribe will be invited to participate in the active intervention and persons
with diabetes from the Tohono O'Odham tribe will be invited to participate as the
control group and will receive usual care from the Indian Health Service. The control
group will subsequently receive delayed intervention at the end of the study as part
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137
of the Native American. Diabetes Projects' belief and practice of'giving back' to
the community. The Pima and Tohono O'Odham peoples have lived together in the
Sonoron Desert in Arizona for at least 2,000 years. The Pima and Tohono O'Odham
are closely related and are very .similar in culture and language, yet they are
geographically separated by some 100 miles. 58 Therefore, it is not feasible to
randomize the participants in the study to treatment or control arms due to close
kinship ties within communities; The target population will be 300 Native American
females and males aged ten to 80 years recruited through the Indian Health Service
Clinics. The intervention will consist of five lifestyle session and six self-
management sessions held one month apart. The intervention is based on the
community development process and social learning theory. Measures will be take at
pre and post-intervention and twelve months post-intervention.
The following hypotheses will be tested;
i) intervention participants will have improvement in HbAlc, blood pressure, weight,
lipid levels, and proteinuria compared to usual care control participants.
ii) intervention participants will have improvement in medication taking, SMBG,
foot, dental and eye care compared to usual care control participants.
iii) intervention participants will have improvement in overall and diabetes-specific
quality of life compared to usual care control participants.
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138
iv) intervention participants will maintain improvement at twelve months post-
intervention compared to usual care control participants.
7.4.2 Description of the Study
7.42,1 Target Population and Research Setting
The tribes were identified for the intervention because of their high prevalence of
diabetes and. diabetes-associated mortality. The Pima have the highest rates of type 2
diabetes in the world. ^ (Table 7.1) The highest age-adjusted diabetes-related
mortality rates are observed among the Pima tribe, 79.7/100,000 followed closely by
the Tohono O'Odham tribe with a rate of about 70/100,000. ^ Overall, for the entire
Indian Health Service population, the age-adjusted diabetes-related death rate is
46.4/100,000, three and one-half times the US rate of 13.3/100,000.
The research setting will be study office sites located on or near the reservations.
Native American female and males with type 2 diabetes between the ages of ten and
80 years will be recruited from the Indian Health Service clinics serving the Pima
and the Tohono O'Odham people. Recruitment will be 150 people in each
community.
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Table 7.1. Prevalence of Diabetes in North America Native Populations.
Adapted from Gohdes, Diabetes in North American Indians and Alaska Natives in
Diabetes in America, 1993.15
Tribe Age (years) Rate/1,000 Adjustment
Tohono O'Odham >18 183 none
Pima 30-64 500 age
7,42.2 Sources of Subjects
Participants will be identified through diabetes registry lists from the diabetes
registries located at the Pima and Tohono O’ Odham Indian Health Service clinics.
The Native American Diabetes Project successfully used this method and received
Institutional Review Board approval from the University, and the Indian Health
Service at the Service Unit and National level. All Native Americans residing on the
Pima or Tohono O'Odham reservation with a diagnosis of type diabetes and between
the ages of ten and 80 years will be eligible for the study. Exclusion criteria include
participants who have end-stage renal disease, are on dialysis or are too ill to
participate.
7A2.3 Recruitment
Three hundred (300) Native Americans with type 2 diabetes will be recruited
through the Indian Health Service clinics serving the Pima and Tohono O’ Odham
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140
tribes. Prior to contacting the study participants, we will obtain consent from the
primary care providers from the Indian Health Service (IHS). Using the diabetes
registry lists, a letter and passive physicians consent form will be delivered to the
physician who is providing diabetes care for the potential study participant(s). The
letter will ask what the vital status of the participant or participants is and if there is
any reason not to contact the participant(s). The physician will be asked to return the
consent form by fax within one week. If no response is received within one week, it
will be assumed that it is appropriate to make contact with the participants).
Recruitment methods are based on our successful experience from the Native
American Diabetes Project. We will recruit, hire, train and pay bilingual community
members from Pima and Tohono O'Gdham communities to contact and invite the
participants to the study. We will hire six full-time members from Pima and three
part-time members from Tohono O'Odham. Pima and Tohono O'Gdham language
will be used to explain the project and answer questions as needed. Initial participant
contact will be made by mail. An introductory letter will explain the study and
inform the potential participants that they will receive an in-person visit in five to
seven business days to further discuss the study. For participants without good
contact information, tracking will be accomplished through IHS databases and
community networking. Community staff members will facilitate the locating and
recruiting of participants. Participants will also be tracked using established methods
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141
available, including physician contact, credit tracking methods (Experian),
directory assistance, Internet databases, and reverse telephone directories.
Community staff members will be assigned to contact the participant in-person using
a standardized script that describes the study and invites the person to participate in
the study. All contacts and attempted contacts will be recorded on a log sheet.
Subjects will be contacted at various times of the day, different days of the week and
on the weekends. No messages will be left on recording machines for confidentiality
purposes. All participants will be asked to sign an informed consent form, which
includes an authorization of the release of medical record information to the study
investigators. Participants under the age of 18 will be required to have parental
consent and child assent to participate in the study. Two full-time nurses will be
hired and will be responsible for hiring and training community staff members in
standard interview protocol techniques and administration of standardized
questionnaires. The nurses will perform the clinical measurements at the study
offices. At the time of the interview, an appointment will also be made for the first
intervention session for Pima participants. Community staff members will make
reminder calls for the interview and the intervention session on the day before
appointments.
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7.4.2.4 Intervention Description
142
The intervention will consist of five months of the Native American Diabetes Project
lifestyle information, followed by six months of the self-management intervention.
(Table 7.2) Six bilingual Pima community members will be hired, trained, and paid
to teach the intervention. In order to provide the intervention in a non-threatening
environment, office space will be rented on or near the reservation. Assessments will
be made at pre-intervention, post-intervention and at twelve months post-
intervention. The intervention will be a written curriculum based on community
preference, the principles of social learning theory, and the objectives of the National
Standards for Diabetes Self-management with Education Programs of the American
Diabetes Association. We found that Steuarfs community health development
process and social learning theory were useful frameworks for developing culturally
competent community health interventions for type 2 diabetes in minority
populations.^’ 59,60 Therefore the intervention will focus on effective behavior
change strategies, realistic goal setting, and problem-solving skills.54, 61, 62
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143
Table 7.2 Titles for lifestyle Intervention, Native American Diabetes Project,
and the proposed self-management intervention, Enhancing Self-Management
Activities.
Native American Diabetes Project Enhancing Self-Management Activities
Get more exercise! Glucose balance makes a difference!
Eat less fat! Medicines: staying in balance!
Eat less sugar! Diabetes and a healthy heart!
Together we can! Healthy feet keep you going!
Staying on the path! Staying healthy! prevent complications!
Getting the most out o f living well!
A crucial element of the intervention design and development process is community
input. Therefore we will include communities as partners and key resources for
cultural expertise and for identifying what is likely to work in their community. The
content and style of the intervention will have "native faces" as reflections of both
the culture and community needs. Specific references to traditional customs,
practices and beliefs will be incorporated to bring relevance and acceptance to
community members.
The lifestyle intervention, the Native American Diabetes Project, will be adapted, if
needed, to suit the Pima and Tohono O'Odham culture, which is also, a Pueblo tribe.
It is anticipated that very few adaptations will be needed. The intervention is written
specifically with relevance for adults with diabetes from the Pueblo culture and is
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144
written in lay language at about the seventh grade level to facilitate and promote
understanding. The intervention is composed of information on ways to choose a
healthful diet, incorporate physical activity into one's lifestyle, how to ask for
support from family and community members to make lifestyle changes, and relate
behaviors and lifestyle to short and long-term effects of diabetes. The meetings will
be conducted in English, but Pima language will be used to explain or discuss some
topics. Each of the meetings will be about two hours in length and will be taught at
approximately four week intervals in a group format with three to ten people
attending with a healthy meal or snack served.
The goal of self-management intervention is to improve self-management of diabetes
responsibilities and diabetes health outcomes. The intervention will be a written
curriculum based on the objectives of the National Standards for Diabetes Self
management with Education Programs of the American Diabetes Association. The
intervention will include educational objectives, a content outline, instructor methods
and materials and an assessment of diabetes self-management responsibilities. The
intervention will have 'Native faces' including Native foods, artwork, and
storytelling. The intervention will consist of hands-on demonstrations (i.e. blood
glucose monitoring), videos of self-monitoring of blood glucose, and problem
solving activities to reinforce the newly learned skills and encourage positive
behaviors. Some of the topics that will be included are the importance of the good
glucose control and the risk of acute and chronic complications. Participants will
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145
receive a state of the art glucose monitor and a monthly supply of glucose strips.
Each participant will leam how to use the glucose monitor and how to record their
glucose results in a special calendar. Participants will be taught why medications are
important to take and how to record their medications. Participants will be taught to
bring their self-care records to the clinic staff for review at each of their diabetes-
care visits. Participants will learn how to do preventive foot and dental care and how
to recognize potentially serious complications, including infections and
cardiovascular diseases. Each participant will be taught the importance of clinic
appointments, what to expect at the clinic visit (i.e. foot examinations), ways to talk
to their provider about health-related concerns and howto navigate the clinic system.
The intervention will be pilot-tested in a non-study Native community and adapted
as needed.
7.4,3 Data Acquisition
Data will be collected from three sources: 1) interview administered questionnaire 2)
clinical measurements and 3) medical record review.
7.4.3.1 Interview Administered Questionnaire .
When the participants are contacted, agree to participate and sign an informed
consent, an appointment will be scheduled. The appointment will consist of 1) an in-
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146
person interview to collect demographic, medical history, and obtain a health-
related and diabetes-specific quality of life assessment and 2) clinical measures.
(Table 7.3) A protocol manual for standard interviewing technique will be developed
and the community staff members will be trained in standard interview protocol.
We will ask about demographic information including age, place of birth,
educational attainment and household income. We will collect medical history using
a calendar of life events with a focus on diabetes and comorbid conditions. The
interviewees will be asked if they were ever diagnosed with type 2 diabetes and what
year the diagnosis was made. Information on family history of type 2 diabetes and
obesity will also be collected. We will ask for the name of the participant's primary
care provider and/or facility, clinic and/or hospital, the city, state and last date they
were seen for diabetes.
To assess health-related quality of life we will utilize both the RAND SF-36 and the
diabetes specific quality of life measures. The RAND SF-36 will provide
information about a broad spectrum of physical, mental, and social functioning. A
diabetes specific quality of life measure is an essential addition to clinical measures
to assess the overall health status of people with diabetes. A diabetes specific quality
of life instrument will be adapted for use in the target communities.^
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147
7.43.2 Clinical Measures to Assess Complications Associated with Diabetes
The following clinical measures will be obtained: current weight will be measured to
the nearest 1/2 pound using standard protocol. Height will be measured to the nearest
1/2 inch. Blood pressure will be measured twice following the American Heart
Association standard protocol.'64 The nurse will perform a venipuncture for HbAlc,
serum cholesterol levels including total, LDL, triglycerides, and HDL. HbAlc will
be obtained following standard HPLC laboratory protocol.57 A urinalysis will be
conducted to assess microalbuminuria, proteinuria, and urinary to creatinine ratio.23
Serum creatinine level will be measured using standard colormetric a s s a y s .2 3 The
nurses will be trained to conduct an assessment of the participants understanding and
self-management behaviors of each of the appropriate content areas of the National
Standards will be conducted using the Diabetes Assessment and Teaching F o r a i .6 5
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148
Table 7.3 Data acquisition from in-person interview.
la.Demographic information age
place of birth
educational attainment
household income
lb. Medical history calendar of life events
what year diagnosed with diabetes
how old when diagnosed with diabetes
complete family history of diabetes
complete family history of obesity
smoking history
exposure to in utero diabetes
personal blood sugar records if available
medication use
oral agents - type, duration
insulin - type, duration
medical history of myocardial infarction,
cerebrovascular accident, hypertension,
retinopathy, laser therapy, proteinuria,
microalbuminuria
immunization record
tuberculosis status
2) Health-related quality of life assess health-related quality of life with RAND
SF-36 and a diabetes quality of life measure
3) Clinical measures HbAlc
blood pressure
weight
height
urinary protein and microalbuminuria
urinary to creatinine ratio
serum creatinine
fasting serum cholesterol (HDL, LDL, total) and
triglycerides
4) Self-management measures Assess participants understanding and self
management behaviors
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7.43.3 Medical Record Review
149
The nurses will collect clinical information from the medical records. (Table 7.4)
Information collected will include clinical examinations performed in the last three
years. Information will also be collected on medication use, self-monitoring of blood
glucose activities and comorbid conditions. Immunization records will be checked
for vaccination status. Additional medical information will be collected to validate
the diagnosis of diabetes and obtain information on diabetes diagnosis date (year),
how diabetes was diagnosed, diabetes treatment regimen, fasting and random blood
sugar levels, HbAlc, and height and weight. Medical records will also be reviewed
for chronic comorbid conditions, family history of diabetes, and family history of
obesity. This information will be used to supplement the interview data.
Contact information for medical providers will be obtained during interview. All
participants will be asked to sign a consent form to authorize the release of medical
information. We will contact the medical facility to verify that a health provider at
that facility saw the patient. We will mail the medical record release and a standard
request form from the provider requesting copies of records rather than request forms
that require extensive record review and completion by the medical staff. If there is
no response from the medical provider, we will phone the provider's office and fax
the medical record release form and ask that the medical records be faxed to the
investigator's office. We will abstract the medical records using standard pre-coded
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150
forms with a staff member trained in medical record abstraction. Ten percent of
the charts will be re-abstracted independently for quality control purposes.
Table 7.4 Data acquisition from medical record review.
1) Medical record review 1 . Medication records
2. Self-management of blood
glucose (SMBG)
3. Comorbid conditions
4. Immunization records
review
5. Diabetes history, treatment,
glucose and HbAlc levels,
height and weight, family
history of diabetes and obesity
6. Any eye, dental, and foot
examinations performed over
the last three years.
7.43.4 Data Editing
Most of the data will be entered using pre-coded forms. The nurse will code any non-
pre-coded items using written coding rales. Medical record reviews will be done
using a standard pre-coded form following IHS standard protocol for diabetes chart
audit. All of the data will be entered using a double key entry system with
consistency and logic checks for unusual or impossible values. PROC COMPARE
will be used to check for any inconsistent entries between the 2 datasets. Data will be
entered and edited in small batches so that as inconsistencies arise, call backs can be
made to participants in a timely fashion and the errors corrected. All errors in the
datasets will be identified and resolved. All corrections will be documented in a data
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151
management logbook. We will develop an extensive logic check system that will
check for inconsistencies in the data. Missing values will be coded as 9 ,99,999, as
appropriate. All questionnaire items will include a response category for "don't
know" that will be created and coded separately from the missing values. Efforts will
be made to minimize missing values. If a few individuals are missing values on
many of the variables they will excluded from the analyses.
7.4.3.5 Quality Control
The interview questionnaires will be pre-tested in the study population to minimize
potential problems. The study protocol will be available to the study staff who will
be trained to follow the protocol as written. Callbacks will be made by the nurse to
5% of all subjects interviewed and participants will be asked several key questions to
verify the interview. Interviews will be edited twice for completeness and callbacks
will be done to obtain any missing, unclear or conflicting information. The study
staff will edit the interview at the time of the interview and the nurse will conduct an
additional edit at a later time. Careful written documentation will be kept of all
editing decisions. For people who refuse to participate in the study, the nurse will be
assigned to call back the person and using a brief questionnaire try to obtain the
reasons for non-participation.
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152
The medical record abstraction forms and methods will be pre-tested to minimize
potential problems. A trained abstractor using standard forms will abstract medical
records. The medical abstract forms will be pre-coded and edited by the nurse with a
second editing done by study staff before data entry. A 10% sample of the charts will
be re-abstracted by the nurse. If excess errors occur measures will be taken to correct
the situation including re-training or reassign a new abstractor as the situation
indicates.
7.4.4 Statistical Analyses
The analyses involve testing whether a participatory lifestyle and self-management
intervention have an effect on clinical outcomes including HbAlc, weight and lipid
levels as well as self-management responsibilities including medication taking,
glucose testing, foot care, eye exams, and pneumonia and flu vaccinations.
7.4.4.1 Overall Analysis
Demographic and pre-intervention levels of clinical and laboratory variables, will be
compared between intervention and control arm using either an analyses of variance
for continuous variables or chi-square or Fisher's exact tests for discrete variables.
The analyses of the primary clinical study end points of HbAlc and self
management behaviors including self-monitoring of blood glucose will be conducted
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. 153
for all evaluable (i.e. measurements at pre and post-intervention time points)
participants. To test the hypothesis of a difference in HbAlc level change between
intervention and control arms, we will use analyses of covariance and. adjust for
differences between the arms. In addition to the planned covariates factors found to
be significantly different across the intervention arms will be included as covariates
in all subsequent analyses. All statistical analyses will utilize SAS software.^
7.4A 2 Sample Size and Power
The sample size for this study is based on the results of the Native American
Diabetes Project. We found a 0.7% change in HbAlc percent between the
intervention and control arms (0.5% versus 1.2% respectively). We calculated the
sample size needed over a range of standard deviations consistent with those found
in the Native American Diabetes Project and two different power levels, .80 and .90.
We used a two-tailed significance level at alpha of 0.05. (Table 7.5)
Table 7.5 Sample size needed to detect 0.7% difference in HbAlc between
intervention and control arms, alpha=0.05,1-Beta=0.8,0.9.
Intervention Control std dev .80 .90
0.5 1.2 1.5 72 96
0.5 1.2 1.8 104 139
0.5 1.2 2.0 128 172
Over the expected range of standard deviations and two power levels we would need
approximately 125 participants in each of the arms. Based on the 25% drop-out rate
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154
observed in the Native American Diabetes Project we will need to recruit a total
.of 300 people with diabetes, 150 Pima and 150 Tohono O'Odham participants, for
the study. The Pima and Tohono O'Odham communities have large enough
populations of people with diabetes to meet the sample size requirements.
7,4,5 Timeline
During months one through three we will recruit, hire and train nine community
members, six full-time from Pima and three part-time members from Tohono
O'Odham and two nurses, one at Pima and one at Tohono O'Odham. The community
members will locate, recruit and conduct in-person interviews of the study
participants during months three to twelve. During the interview visits the nurses will
obtain clinical measures including HbAlc, weight, and BP.
In the intervention community, the Pima community members will be trained to
teach the intervention. From months twelve to 24 the Pima community members will
teach the intervention. In the control community, the three part-time Tohono
O'Odham members will be responsible for yearly assessments and sending 'care
packages' at times corresponding to the intervention sessions.
While the intervention is being conducted the nurses will be responsible for
supervising the community staff members including training and teaching of the
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intervention, data quality assurance, abstracting medical records and data
management and editing. Data analyses will be conducted in the last year of the
study and delayed intervention will be provided for participants in the control arm.
7 . 5 Potential Limitations
Recruitment and retention of participants that do not result in an adequate sample
size may reduce power to detect clinically meaningful differences between the
intervention and control arms. Due to nature of the diabetes some participants may
become too ill to participate resulting in loss to follow-up. We anticipate that
recruiting 25% more participants than our projected sample size will guard against
substantially reduced power. We will also employ a variety of retention techniques to
maximize participation in the control arm. Such as offering delayed intervention to
the control arm.
Based on our experience with the Native American Diabetes Project we expect to
have full Indian Health Service clinical cooperation. We will insure this by including
the clinical staff members early on in the project and maintain their support by
including them in a study advisory group.
All employees of the study will be informed as to the necessity of maintaining strict
confidentiality of all participant information. All employees must sign a
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156
confidentiality pledge. Any breach in subject confidentiality will result in
termination from the study. All interviews will be stored in locked filing cabinets.
All computers will have password protection to assure restricted access. All reports
and summaries will be without personal identifiers.
This study has a number of strengths that outweigh the potential problems.
Diabetes has been associated with very poor outcome and the main hope for
Improved prognosis is the development of effective secondary and tertiary
prevention measures. This study represents a unique opportunity to evaluate
the long-term effects of an intervention developed specifically to improve self-
management behaviors and reduce the risk of complications associated with
diabetes.
7.6 Human Subjects
Involvement of human subjects: Participants will be men and women, age ten and
80 years, with type 2 diabetes who attend the Indian Health Service clinics at the
Pima and Tohono O'Odham Health Center and agree to participate. Participants
under the age of 18 will be required to have parental consent and child assent to
participate in the study.
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157
Research materials: Participants who agree to participate and give consent will
have the following data collected:
1) Questionnaire data including demographic information, health-related quality of
life and participant's understanding and self-management behaviors.
2) Clinical measures including blood (HbAlc, serum lipid levels, and serum
creatinine) height, weight, blood pressure and urine sample (proteinuria,
microalbuminuria, urinary-to-creatinine ratio).
3 ) Medical record review.
Recruitment and Consent: Through an agreement with the Indian Health Service,
when a participant is contacted, an appointment will be scheduled and all participants
will be asked to sign a consent form before the interview begins. Participants under
the age of 18 will be required to have parental consent and child assent to participate
in the study.
Potential Risks: There are minimal risks involved in this research. Blood sample
could cause some discomfort or possible bruising, but these risks will be minimized
by good technique by experienced and trained nursing staff. It is possible that
obtaining a urine specimen or being questioned about medical history may be
considered uncomfortable, however, this risk is expected to be minimal. Lack of
confidentiality is a possible risk.
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158
Minimizing Risks: Personnel will be experienced and trained in methods of
blood and urine samples, in following standard protocols and in patient concerns and
confidentiality. All staff members will sign a confidentiality pledge. All data will be
stored in locked file cabinets and computers will be protected by passwords.
Risks versus Benefits: There are no direct personal benefits to participants.
However, there is a benefit to the tribes to try to understand ways to control diabetes
so the benefits outweigh the potential risks.
7.7 Vertebrate Animals
None involved.
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159
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164
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8,0 SUMMARY. CONCLUSIONS AND RECOMMENDATIONS
165
8.1 Summary
Diabetes mellitus was essentially unknown among Native Americans in 1900.
However, since the 1950's the prevalence of type 2 diabetes has risen dramatically
and has reached epidemic proportions in many Native American tribes. Native
American tribes have some of the highest prevalence of type 2 diabetes in the world.
Trends in this epidemic are ominous. Native American children, once thought to be
at low risk for type 2 diabetes, are now being diagnosed with type 2 diabetes at
increasing frequency.
Native populations not only have a high and rising prevalence of type 2 diabetes,
they also suffer a disproportionate burden of many of the complications associated
with diabetes. The disproportionate burden arises from several sources. First,
diabetes complications become clinically apparent then to 20 years after disease
onset and are often the first sign of the disease. Native Americans are diagnosed at
younger ages and have a long duration of pre-clinical and clinical diabetes placing
them at high risk for serious complications. Secondly, control of risk factors for
complications such as glucose level, hypertension and dyslipidemia has not been
optimal. Furthermore, younger Native American people have poorer glucose control
than older Native Americans suggesting that the disease is becoming more severe.
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The trends in age-specific prevalence and disease severity could result in an even
greater burden, among Native Americans if control of risk factors for complications
is not improved. The increase in mortality associated with type 2 diabetes over last
40 years provides further evidence for the consequences of ignoring the urgent need
to prevent or delay the complications of diabetes.
Therefore, based on these alarming trends for potentially very poor outcomes, there
is an urgent need for the development and dissemination of effective prevention
interventions that are culturally appropriate and clinically comprehensive. The
results of the Native American Diabetes Project presented in this dissertation, are
encouraging. The study shows that a culturally competent lifestyle intervention is
well accepted, practical and effective in improving glycemic control among Native
American people with diabetes.
8.2 Conclusions
Our primary finding from the Native American Diabetes Project intervention was
that participants in the intervention had significant benefit in glycemic control that
may have the potential to substantially reduce microvascular complications and
mortality. The effectiveness of the Native American Diabetes Project intervention
may be due to the use of; 1) a culturally appropriate lifestyle intervention in
conjunction with comprehensive medical care 2) intervention materials that were
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167
designed and developed with input from Native American community members
and therefore, contained culturally relevant materials and values pertinent to the
Native communities and 3) social learning theory as an approach to how people
leam.
8.3 Recommendations
To build on the success of the Native American Diabetes Project more research is
needed in the following areas:
1) To effectively disseminate the Native American Diabetes Project lifestyle
intervention to interested Native American tribes. There has been wide interest in
dissemination of the intervention, and dissemination activities are currently
occurring using the model of community centered approach and Native American
mentors. The research challenge is to understand how to make dissemination
successful in the 500+ Native American tribes throughout the nation.
2) To further reduce the risk of complications by developing effective and accepted
interventions to improve self-management behaviors with the aim of further
improving glycemic levels to prevent and/or delay the complications of diabetes in
this high-risk population. The proposal presented within this dissertation represents
an opportunity to evaluate the long-term effects of an intervention developed
specifically to promote healthy lifestyles and improve self-management behaviors
and reduce the risk of complications associated with diabetes.
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3) Lastly, communities themselves need to take ownership of this important
health issue, as the diabetes epidemic may threaten their very existence.
Interventions that build on the strengths of Native American culture, community and
traditional values may not only address the consequences of the epidemic but
perhaps make tribes stronger to meet many of today's other challenges as well.
The culturally appropriate lifestyle intervention, the Native American Diabetes
Project, offers hope in reducing the disproportionate burden of type 2 diabetes in
minority populations.
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169
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Gilliland, Susan Smith
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Risk factors, sequellae and intervention studies for the treatment of diabetes mellitus in Native American populations
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