The role of glucocorticoids in the development of insulin resistence in the obese Zucker rat

Stubbs, Mark (1991) The role of glucocorticoids in the development of insulin resistence in the obese Zucker rat. University of Southampton, Doctoral Thesis.

Abstract

The obese Zucker rat, when homozygous for the recessive `fa' gene displays obesity, hyperphagia, insulin resistance and hyperinsulinaemia and is regarded as an animal model of human type II diabetes/obesity. The development of obesity in the obese rat is dependent on glucocorticoids; adrenalectomy normalises body weight gain. Administration of exogenous glucocorticoids to adrenalectomised animals will restore the body weight gain. The aim of my project was to determine whether glucocorticoids are acting on the central nervous sytem or on peripheral tissues to promote obesity in the Zucker rat. Initial work comprised the development of methods for measuring the insulin sensitivity of glucose clearance and insulin secretion in anaesthetised rats. Adult obese Zucker rats showed decreased metabolic clearance rates of glucose during hyperinsulinaemic clamp and a hypersecretion of insulin in response to a glucose load when compared to lean animals. Pretreatment of obese rats with the cholinergic blocker atropine and adrenalectomy reduced the increase in plasma insulin following a glucose load. Both treatments were without effect in lean rats. Atropine pretreatment of adrenalectomised obese rats did not reduce the post-glucose plasma insulin levels further. Insulin-stimulated metabolic clearance rates of glucose in obese rats were increased by adrenalectomy. Chronic peripheral treatment of adrenalectomised obese rats with corticosterone restored the hypersecretion of insulin following a glucose load. Chronic peripheral treatment of adult obese rats with the glucocorticoid antagonist RU 486 also reduced insulin secretion. Administration of small doses of glucocorticoid analogue dexamethasone chronically into the third ventrical of adrenalectomised obese rats increased the levels of plasma insulin following glucose load compared to saline infused controls. Atropine pretreatment of adrenalectomised dexamethasone infused obese rats before glucose administration reduced plasma insulin levels to control values. These results suggest that there is a central oversensitivity to glucocorticoids in the obese Zucker rat.

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