Effect of adrenalectomy on the development of a pancreatic islet lesion in fa/fa rats

Abstract

Adrenalectomy prevents development of obesity and hyperinsulinaemia in obese (fa/fa) Zucker rats, thereby implicating the hypothalamopituitary-adrenal axis in the pathogenesis of obesity. In this study glucose-induced insulin secretion and glucokinase activity were investigated in isolated islets from adrenalectomized and control obese and lean female rats. Islets from control fa/fa rats were more sensitive to glucose with a half-maximal effective concentration (EC50) of 6.1 ± 2.0 mmol · l-1 compared with 10.6 ± 2.7 mmol · l-1 for adrenalectomized fa/fa rat islets. Adrenalectomy did not alter the islet sensitivity to glucose in the lean rats (EC50 of 9.4 ± 1.5 mmol · l-1 and 9.3 ± 2.0 mmol · l-1 for adrenalectomized and control lean rats respectively). Mannoheptulose did not inhibit insulin secretion from control obese rats; however at concentrations of 1.0 mmol · l-1 or more it significantly inhibited glucose-induced insulin secretion in adrenalectomized obese and lean, and control lean rat islets (p < 0.05). In adrenalectomized fa/fa islets the glucokinase K(m) was increased twofold compared with the control fa/fa rats (9.5 ± 1.5 mmol · l-1 vs 5.0 ± 1.5 mmol · l-1, respectively), but there was no significant change in glucokinase K(m) in the lean rat islets after adrenalectomy. Mannoheptulose (10 mmol · l-1) caused a significant reduction in glucose phosphorylation in disrupted islets of adrenalectomized fa/fa and lean, and of control lean rats, but not of control fa/fa rats. These data demonstrate that development of abnormal regulation of glycolysis in pancreatic islet beta cells of fa/fa rats, as indicated by the insulin response to mannoheptulose and glucokinase activity, is dependent on an intact hypothalamo-pituitary-adrenal axis.