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HEMODYNAMIC FACTORS IN THE INSULIN RESISTANCE OF OBESITY AND
HYPERLIPIDEMIA
by
Jenny Dong-Nee Chiu
________________________________________________________________
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
(PHYSIOLOGY AND BIOPHYSICS)
August 2009
Copyright 2009 Jenny Dong-Nee Chiu
Object Description
| Title | Hemodynamic factors in the insulin resistance of obesity and hyperlipidemia |
| Author | Chiu, Jenny Dong-Nee |
| Author email | jenny.d.chiu@gmail.com; chiuey1@hotmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Physiology & Biophysics |
| School | Keck School of Medicine |
| Date defended/completed | 2009-05-29 |
| Date submitted | 2009 |
| Restricted until | Unrestricted |
| Date published | 2009-06-23 |
| Advisor (committee chair) | Bergman, Richard N. |
| Advisor (committee member) |
Watanabe, Richard Watts, Alan |
| Abstract | Insulin resistance is an important risk factor for the development of type 2 diabetes, obesity, cardiovascular disease, hypertension (24;73;241), and certain cancers (95). Although it is highly prevalent across the world, the pathophysiology remains unclear. Most studies concentrate on the defects observed at the target tissue, specifically at the cellular signaling level (150;217). However, before activating intracellular pathways in skeletal muscle, secreted insulin must first find its way through the vascular beds, cross the endothelial barrier, diffuse through the interstitial fluid, and bind insulin receptors. Although these steps are critical for insulin to act peripherally, these processes are poorly characterized (109;163). Intravenous insulin infusion rapidly increases plasma insulin, yet glucose disposal occurs at a much slower rate. This delay in insulin’s action may be related to the protracted time for insulin to traverse capillary endothelium. The purpose of the first study was to investigate whether bypassing the transendothelial insulin transport step and injecting insulin directly into the interstitial space would moderate the delay in glucose uptake observed with intravenous administration of the hormone.; To test this, I performed sequential intramuscular injections of saline (n=3) or insulin (n=10) administered directly into the vastus medialis of anesthetized dogs. Injections of 0.3, 0.5, 0.7, 1.0, and 3.0 units of insulin were administered hourly during a basal insulin euglycemic glucose clamp (0.2mU.min-1.kg-1). These injections with 30 gauge needles served to deliver insulin directly into the interstitial fluid that bathes the myocytes, thereby bypassing the potentially rate limiting step of insulin transport. Local glucose uptake in each leg was calculated based on arterio-venous glucose differences and Doppler-measured blood flow. Unlike the saline group, each incremental insulin injection caused interstitial (lymph) insulin to rise within 10 min, indicating rapid diffusion of the hormone within the interstitial matrix. Delay in insulin action was virtually eliminated, indicated by immediate dose-dependent increments in hindlimb glucose uptake. Additionally, bypassing insulin transport by direct injection into muscle revealed a fourfold greater sensitivity to insulin of in vivo muscle tissue than previously reported from intravenous insulin administration. These results indicate that the transport of insulin to skeletal muscle is a rate-limiting step for insulin to activate glucose disposal. Based on these results, one may speculate that defects in insulin transport across the endothelial layer of skeletal muscle will contribute to insulin resistance.; Elevated plasma levels of FFAs are often observed in obese and diabetic individuals and have thus been implicated as a causative link between obesity and insulin resistance. Although many have focused mainly on lipids’ effect to inhibit insulin signaling at the muscle cell, FFAs have several hemodynamic effects that may contribute to the development of insulin resistance. This second study was conducted to determine if insulin resistance, as mediated by elevated plasma FFAs, hinders transport of insulin to the interstitial space. I performed hyperinsulinemic euglycemic clamps (1 mU.min-1.kg-1) with saline infusion (n = 5, CON) or intralipid plus heparin (n=6, INL) in lean, healthy mongrel dogs. The intralipid plus heparin infusion (20% fat emulsion at 1.5 mL/min) served to create an acutely hyperlipidemic insulin resistant dog model. Intralipid infusion did not change blood pressure or macrovascular (femoral artery) blood flow. Upon infusion, plasma FFA levels increased rapidly to a maximum level of 2.8 mM. Lymph FFAs rose much more slowly and were greatly attenuated increasing to a max of only 0.18 mM. Whole body glucose uptake rose from basal 3 to a steady state 7 mg.min-1.kg-1 in the CON group, compared to a marked decline from maximum 6 to 4 mg.min-1.kg-1 after 154 minutes of lipid infusion in the INL group. Endogenous glucose production was immediately suppressed in the CON group, while no suppression was observed in the INL animals. Interestingly, the time point when maximal FFA level in the interstitial fluid was achieved coincided with the time point glucose uptake began its decline. There was no significant difference in interstitial insulin concentrations between CON and INL groups (44.8 versus 50.7 mU/L, respectively). However, when resistance was established (t = 130-360 min), lymph to plasma insulin gradient was significantly different (0.58 versus 0.62; CON versus INL, p<0.001).; In addition, there existed a strong correlation between lymph insulin and glucose uptake rates (r=0.98) in the CON group, which was lost in the INL group (r=0.71). These data suggest that there is rapid induction of resistance in the liver and peripheral tissues with elevated plasma free fatty acids. The transport of FFAs is temporally associated with reduction of glucose disposal. Although FFAs do not cause a decrease in interstitial insulin concentrations, increased lymph to plasma insulin gradient in the INL group suggests that more insulin was able to enter the interstitial space, suggestive of an increase in capillary permeability. The interstitial insulin in the INL group was not able to effectively increase glucose uptake, which may suggest resistance at the cellular level. However, due to the steady state, saturating nature of this study, a more dynamic approach to examine FFAs’ role in altering hemodynamic transport of insulin is warranted.; In this next study, a non-saturated approach to determine whether FFAs hinder transport of insulin was examined. I tested the effect of insulin resistance induced by hyperlipidemia on the dynamics of insulin injected into skeletal muscle. The injections serve to bypass the endothelial barrier which if is truly rate limiting, then insulin sensitivity would be rescued and glucose uptake would be comparable to control animals. Basal insulin euglycemic clamps (0.2mU.min-1.kg-1) with or without lipid infusions (20% at 1.5ml/min) were performed on anesthetized dogs. Similar to the first study, sequential insulin doses were administered by intramuscular injection directly into the vastus medialis of one hindleg, using the contralateral leg for comparison. Intramuscular insulin injection in normal animals (n=10) caused a clear dose-dependent increment in interstitial insulin levels, as well as dose-dependent increase in leg glucose uptake. In a second group of animals (n=8), lipid was infused before and during intramuscular insulin injection to cause systemic increase in free fatty acids. In sharp contrast, systemic lipid infusion caused insulin resistance, indicated by reduced glucose infusion required to maintain euglycemia, and prevented injection-induced increase in lymphatic insulin and leg glucose uptake observed without lipid. The injected insulin was instead detected in the venous outflow from the leg. Lipid infusion caused intramuscular insulin to be diverted from interstitium into the capillary circulation, preventing a rise in intersitial insulin and any increase in local leg glucose uptake. This diversion of insulin from the interstitium under hyperlipidemic conditions may play a role in the insulin resistance observed in obesity. Further studies will be necessary to determine the mechanism for FFA’s ability to affect insulin’s hemodynamic actions. |
| Keyword | diabetes; endothelium; free fatty acids; insulin; interstitial; transendothelial transport |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m2318 |
| Rights | Chiu, Jenny Dong-Nee |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Chiu-3006 |
| Archival file | uscthesesreloadpub_Volume48/etd-Chiu-3006.pdf |
Description
| Title | Page 1 |
| Full text | HEMODYNAMIC FACTORS IN THE INSULIN RESISTANCE OF OBESITY AND HYPERLIPIDEMIA by Jenny Dong-Nee Chiu ________________________________________________________________ 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 (PHYSIOLOGY AND BIOPHYSICS) August 2009 Copyright 2009 Jenny Dong-Nee Chiu |
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