K-ATP channel-dependent and independent pathways of insulin secretion in isolated islets from fa/fa Zucker rats

We hypothesized that altered insulin secretory patterns in obese (fa/fa) Zucker rats might be caused by changes in downstream stimulus-secretion coupling events, such as ATP-dependent potassium (K-ATP) channel activity. The functions of K-ATP-dependent and -independent pathways of insulin secretion were therefore compared in lean and fa/fa Zucker rat isolated islets. K-ATP channel function was normal in fa/fa rat islets, as assessed by responsiveness to direct channel inactivators glybenclamide and quinine and by the receptor-mediated response to epinephrine and somatostatin. Altered sensitivity to glucose and mannoheptulose were explained by upstream alterations in glucose metabolism documented earlier. Despite normal inactivation of K-ATP channels by ATP depletion of fa/fa rat islets, glucose-stimulated insulin secretion was not inhibited, leading to studies of a putative K-ATP-independent pathway. When islets were depolarized by incubating with 30 mM potassium and 0.25 mM diazoxide to bypass K-ATP channels, glucose elicited a concentration-dependent response in both phenotypes. This response required glucose metabolism and Ca2+, as proven by experiments with nonmetabolizable glucose analogs and calcium chelation, but was only partially inhibited by a glycolytic inhibitor. Intermediates or products of oxidative metabolism are likely involved because alpha-ketoisocaproate also elicited a K-ATP-independent insulin response. The pattern of responses was similar in lean and fa/fa rat islets, indicating that neither of these pathways explains the insulin secretion by fa/fa rat islets depleted of ATP. In conclusion, phenotype-related differences in K-ATP channel function were consistent with upstream changes in glucose metabolism in fa/fa rat islets. Further studies are required to understand the basis of insulin secretion in ATP-depleted islets from fa/fa rats.