The relationship between the hypothalamo-pituitary-adrenal axis and the development and persistence of pancreatic islet defects in obese Zucker (fa/fa) rats

Using isolated pancreatic islets from adult, weanling and suckling rats, the time of onset of functional changes in $\alpha\sb2$-adrenergic receptors and abnormal regulation of glycolysis in B-cells was investigated in obese fa/fa Zucker rats.

Functional changes in $\alpha\sb2$-adrenergic receptors were not observed in these studies. These studies failed to confirm the existence of a prazosin-sensitive $\alpha\sb2$-adrenoceptor previously reported in islets of fa/fa rats.

Changes in the glucokinase sensitivity to inhibition by mannoheptulose were present in isolated islets from both adult and 5 wk old, but not 3 wk old preobese fa/fa rats. Mannoheptulose inhibited glucose stimulated insulin release in a dose dependent manner in isolated islets from adult, 5 wk and 3 wk old lean rats and in 3 wk old preobese fa/fa rats.

From these studies it is concluded that when isolated islets from fa/fa rats are incubated in glucose which is within the physiological range, functional changes in the $\alpha\sb2$-adrenoceptors are not expressed. Also, the sympathetic nervous system exerts its inhibitory regulation of the pancreatic islet B-cells through $\alpha\sb2$-adrenoceptors but not $\alpha\sb1$-adrenoceptors. Insensitivity to mannoheptulose arose concurrently with the reported onset of fasting hyperinsulinemia.

The dependence on the presence of an intact hypothalamo-pituitary-adrenal axis to the development of the reduced glucokinase response to mannoheptulose inhibition was further investigated by carrying out adrenalectomy in 5 wk old lean and fa/fa rats. Adrenalectomy was found to reduce the rate of weight gain in fa/fa rats but did not affect the pancreatic islet insulin content. There was no effect of adrenalectomy on either weight gain or islet insulin content in the lean rats. (Abstract shortened by UMI.).