Masters Theses

Jian Zhang

Date of Award

5-1996

Degree Type

Thesis

Degree Name

Master of Science

Major

Biochemistry and Cellular and Molecular Biology

Major Professor

John Kootz

Committee Members

Wesley Wicks, Barry Bruce

Abstract

Obesity is a type of functional defect which involves the glucose transporter-regulating process. The genetically obese Zucker rat (fa/fa) is characterized by hyperinsulinemia and markedly reduced glucose utilization in insulin responsive tissues. Diazoxide (DZ), a chronically administered drug for anti-hyperinsulinemia, had been previously documented to increase glucose uptake in adipocytes isolated from DZ- treated obese and lean Zucker rats. To understand the molecular basis for these observations and to evaluate the effects of DZ, the expression levels of glucose transporter 4 (Glut4) were measured in adipose and heart tissues excised from Zucker rats in the fasting state.

The obese and lean rats were divided into DZ-treated (150 mg/kg/day) and untreated groups. It was demonstrated that there was no remarkable reduction of Glut4 mRNA in the fat tissue from the obese rat compared with the lean rat. DZ resulted in significant increases in the levels of Glut4 mRNA in the fat tissues from both the obese (1.4 fold) and the lean (1.7 fold) rats. There were no significant differences in the level of Glut4 mRNA in the heart tissues from the obese and lean and DZ-treated and untreated animals.

The level of Glut4 protein in the adipose tissue from the untreated obese animal was significantly lower (60%) than that in the untreated lean rats. The level of Glut4 protein in the adipose tissue from the DZ-treated obese rats increased about 3.7 fold, to more than 2.2 times the DZ- induced increase in the level of Glut4 mRNA or the rate of glucose uptake in this tissue. This is in contrast to the tissue from the lean animal where there were virtually identical increases (1.4-1.7 fold) in Glut4 protein, Glut4 mRNA and glucose uptake rate caused by the DZ treatment.

From these results it was concluded that: (1) the lower basal and insulin-stimulated glucose uptake rates in the adipocytes from the obese animals can be attributed to a decrease in the amount of Glut4 protein with no significant change in the level of Glut4 mRNA. This suggests changes in the rate of translation or degradation of the Glut4 protein in the adipose tissue of obese animals; (2) DZ treatment caused a modest increase in the level of Glut4 mRNA but a substantial increase in the level of Glut4 protein in the adipose tissues from obese rats. This suggests a transcriptional effect of DZ accompanied by a reversal in the effects of obesity on the translation or degradation of the Glut4 protein; (3) DZ treatment also caused a modest increase in the level of Glut4 mRNA in the adipose tissues from lean rats. This increase was accompanied by an equivalent increase in the level of Glut4 protein in those tissues; (4) The increases in the level of Glut4 protein in the lean and obese animals by the DZ treatment are sufficient to account for the changes in glucose uptake observed with DZ treatment; and (5) extra-pancreatic effects of DZ played an apparent role in Glut4 regulation in the DZ-treated obese rats.

The roles of two Glut4 regulators, plasma insulin and glucose, are discussed. A mechanism to account for the observed lower rates of glucose uptake in the obese rats and the DZ improvement is proposed.

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