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NUTRIENTS AS SIGNAL FOR INSULIN RESISTANCE INDUCED
HYPERINSULINEMIC COMPENSATION
by
Darko Stefanovski
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)
December 2009
Copyright 2009 Darko Stefanovski
Object Description
| Title | Nutrients as signal for insulin resistance induced hyperinsulinemic compensation |
| Author | Stefanovski, Darko |
| Author email | stefanov@usc.edu; darkos@yahoo.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Physiology & Biophysics |
| School | Keck School of Medicine |
| Date defended/completed | 2009-09-23 |
| Date submitted | 2009 |
| Restricted until | Unrestricted |
| Date published | 2009-10-16 |
| Advisor (committee chair) | Bergman, Richard N. |
| Advisor (committee member) |
Chow, Robert HP Buchanan, Thomas A. Watanabe, Richard M. |
| Abstract | In normal individuals, the product of insulin sensitivity and insulin secretion is approximately a constant, referred to as disposition index (DI) and represents a quantitative measure of the ability of the glucose regulating system to renormalize glycemia after perturbation. However, the signal through which the b-cell detects the rise in insulin resistance and compensates with hyperinsulinemia remains unknown.; Independent of hyperplasia in fat depots, cell size is known to play a key role in the development of insulin resistance. Aim 1 of this dissertation examines the longitudinal changes in adipocytes and their distribution in visceral (VIS) and subcutaneous (SQ) fat depots during the development of obesity-induced insulin resistance and following treatment with rimonabant (RIM). We show that fat feeding increased mean adipocyte size and induced a multimodal cell size distribution pattern only in the VIS depot. RIM completely prevented the formation of large cells and essentially normalized cell size to pre-fat conditions in both VIS and SQ depots. We provide direct evidence that large adipocytes and their distribution in the visceral fat depot are critical predictors of insulin resistance, supporting the purported deleterious effects of visceral adiposity.; In dog model of obesity we examined the possibility that potential early-week changes in plasma FFA, glucose, or both could be part of cascade of signals that lead to compensatory hyperinsulinemia induced by insulin resistance. We found that the early-week change in plasma FFAs may directly, through signaling on the level of b-cell, or indirectly, by decreasing hepatic insulin clearance, resulted in the observed hyperinsulinemic compensation.; In aim 3 we investigated if a simulated rise in postprandial glucose alone, as seen in cases of hepatic IR, is sufficient nutrient signal to induce hyperinsulinemic compensation. For a period of 4 weeks, each day during the meal dogs were equipped with ambulatory pumps that infused glucose or saline solution. We have shown that simulated rise in postprandial glucose, as one of the possible manifestations of hepatic IR, in normal dogs was sufficient signal to induce HC. |
| Keyword | disposition index; hyperinsulinemic compensation; insulin resistance; metabolic syndrome; obesity; Type 2 diabetes |
| 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-m2673 |
| Contributing entity | University of Southern California |
| Rights | Stefanovski, Darko |
| 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-Stefanovski-3313 |
| Archival file | uscthesesreloadpub_Volume26/etd-Stefanovski-3313.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Full text | NUTRIENTS AS SIGNAL FOR INSULIN RESISTANCE INDUCED HYPERINSULINEMIC COMPENSATION by Darko Stefanovski 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) December 2009 Copyright 2009 Darko Stefanovski |
