TPN-evoked dysfunction of islet lysosomal activity mediates impairment of glucose-stimulated insulin release

We examined the relation between nutrient-stimulated insulin secretion and the islet lysosome acid glucan-1,4-alpha -glucosidase system in rats underg oing total parenteral nutrition (TPN). During TPN treatment, serum glucose was normal, but free fatty acids, triglycerides, and cholesterol were eleva ted. Islets from TPN-infused rats showed increased basal insulin release, a normal insulin response to cholinergic stimulation but a greatly impaired response when stimulated by glucose or alpha -ketoisocaproic acid. This imp airment of glucose-stimulated insulin release was only slightly ameliorated by the carnitine palmitoyltransferase 1 inhibitor etomoxir. However, in pa rallel with the impaired insulin response to glucose, islets from TPN-infus ed animals displayed reduced activities of islet lysosomal enzymes includin g the acid glucan-1,4-alpha -glucosidase, a putative key enzyme in nutrient -stimulated insulin release. By comparison, the same lysosomal enzymes were increased in liver tissue. Furthermore, in intact control islets, the pseu dotetrasaccharide acarbose, a selective inhibitor of acid alpha -glucosideh ydrolases, dose dependently suppressed islet acid glucan-1,4-alpha -glucosi dase and acid alpha -glucosidase activities in parallel with an inhibitory action on glucose-stimulated insulin secretion. By contrast, when incubated with intact TPN islets, acarbose had no effect on either enzyme activity o r glucose-induced insulin release. Moreover, when acarbose was added direct ly to TPN islet homogenates, the dose-response effect on the catalytic acti vity of the acid alpha -glucosidehydrolases was shifted to the right compar ed with control homogenates. We suggest that a general dysfunction of the i slet lysosomal/vacuolar system and reduced catalytic activities of acid glu can-1,4-alpha -glucosidase and acid alpha -glucosidase may be important def ects behind the impairment of the transduction mechanisms for nutrient-stim ulated insulin release in islets from TPN-infused rats.