Masters Theses

To-Yu Huang

Date of Award

5-1997

Degree Type

Thesis

Degree Name

Master of Science

Major

Biochemistry and Cellular and Molecular Biology

Major Professor

John W. Koontz

Committee Members

Wesley D. Wicks, Barry B. Bruce

Abstract

Insulin resistance in skeletal muscle has been proposed as the primary inherited basis for non-insulin-dependent diabetes mellitus (NIDDM). To overcome the peripheral resistance to insulin-stimulated glucose disposal, NIDDM subjects commonly develop compensatory hyperinsulinism to maintain glucose homeostasis. Moreover, as insulin's antilipolytic action is amplified by hyperinsulinamia, over 80% of NIDDM patients exhibit fatty obesity as expected. Using genetically obese Zucker rats which display insulin resistance and hyperinsulinemia. preliminary studies by our collaborator have shown that in a dose-dependent fashion, diazoxide, an inhibitor of insulin secretion. attenuates hyperinsulinamia and improves insulin sensitivity in isolated adipocytes. Although the cellular mechanism for insulin to stimulate glucose uptake is not fully understood, glucose transporter 4 (Glut4) appears to play an important role, as evidenced by it's tissue-specific expression and it's intracellular translocation in response to insulin stimulation. Interestingly in particular, an improved glucose transport was observed in diazoxide-treated lean animals, leading us to suggest diazoxide has an additional insulin-independent effect in adipocytes. Furthermore, since ATP-dependent K+ channel, the cellular target for diazoxide, is also found in skeletal muscle as well as in pancreatic beta-cells, we speculate diazoxide may also have insulin-independent effects on the glucose transport system in skeletal muscle. Therefore, the effects of diazoxide on glucose transporters in the skeletal muscle of Zuckers were examined in this study. The results presented in this study demonstrate that insulin resistance in the skeletal muscle of obese Zucker rats is not due to a diminished Glut4 gene expression. Moreover, diazoxide treatment, which improves insulin sensitivity in the adipose tissue of obese Zucker rats by at least partially increasing Glut4 protein levels, does not have a similar effect on skeletal muscle. Nevertheless, the measurements of Glut4 mRNA levels and Glut4 protein levels suggest that an extrapancreatic action of diazoxide exists in both the obese and the lean animals. The extrapancreatic action is proposed to modify post-transcriptional mechanisms in Glut4 expression. Lastly, because the decreased glucose uptake cannot be accounted for by a diminished Glut4 expression, a defective Glut4 translocation in response to insulin is proposed as the cause of insulin resistance in the skeletal muscle of obese Zucker rats.

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