IDENTIFICATION OF BIOCHEMICAL DEFECTS IN PANCREATIC-ISLETS OF FA FA RATS - A DEVELOPMENTAL-STUDY/

Adult obese (fa/fa) Zucker rats hypersecrete insulin in response to gl ucose and other secretagogues. Functional changes in islet alpha(2)-ad renoceptors (8) and glycolytic regulation (9) have been reported. In t his study, the development of these biochemical lesions in islets isol ated from suckling (3 week old) and weanling (5 week old) lean and fa/ fa rats was investigated and compared to results in adult animals. Glu cose (15 mM)-induced insulin secretion was inhibited by mannoheptulose (MH) in lean (n=8) but not fa/fa (n=10) adult rats, indicating loss o f sensitivity of glucokinase to competitive inhibition. Sensitivity to MH was somewhat reduced in the islets of 3- and 5-week-old fa/fa (n=7 and 12) compared to lean (n=15 and 9) rats, requiring 30-100 fold hig her concentrations to achieve significant inhibition. At 3 weeks of ag e fa/fa rats did not differ from lean controls in either islet insulin content or body weight, but both parameters were increased in fa/fa r ats by 5 weeks. The presence of altered alpha(2)-adrenoceptor function in fa/fa rats could not be confirmed in this study. Unlike the previo us report, prazosin did not antagonize alpha(2)-agonist mediated inhib ition of insulin secretion. The presence of defective regulation of th e glycolytic pathway by mannoheptulose in suckling and weanling rats m ay contribute to development of hyperinsulinemia in fa/fa rats.