Dysfunction of the islet lysosomal system conveys impairment of glucose-induced insulin release in the diabetic GK rat

Accumulated evidence links an important signal involved in glucose-stimulat ed insulin release to the activation of the islet lysosomal glycogenolytic enzyme acid glucan-1,4-alpha-glucosidase. We have analyzed the function of the lysosomal system/lysosomal enzyme activities in pancreatic islets of yo ung (6-8 weeks), spontaneously diabetic, GK (Goto-Kabizaki) rats and Wistar control rats in relation to glucose-induced insulin release. The insulin s ecretory response to glucose was markedly impaired in the GK rat, but was r estored by the adenylate cyclase activator forskolin. Islet activities of c lassical lysosomal enzymes, e.g.. acid phosphatase, N-acetyl-beta-D-glucosa minidase, p-glucuronidase, and cathepsin D, were reduced by 20-35% in the G K rat compared with those in Wistar controls. In contrast, the activities o f the lysosomal alpha-glucosidehydrolases, i.e.. acid glucan1,4-alpha-gluco sidase and acid cu-glucosidase, were increased by 40-50%. Neutral cu-glucos idase (endoplasmic reticulum) was unaffected. Comparative analysis of liver tissue showed that lysosomal enzyme activities were of the same magnitude in GK and Wistar rats. Notably, in Wistar rats, the activities of acid gluc an-1,4-alpha-glucosidase and acid Lu-glucosidase were approximately 15-fold higher in islets than in liver. Other lysosomal enzymes did not display su ch a difference. Normalization of glycemia in GK rats by phlorizin administ ered for 9 days did not influence either the lysosomal alpha-glucosidehydro lase activities or other lysosomal enzyme activities in GK islets. Finally, the pseudotetrasaccharide acarbose, which accumulates in the lysosomal sys tem, inhibited acid glucan-1,4-alpha-glucosidase activity in parallel with its inhibitory action on glucose-induced insulin release in intact Wistar i slets, whereas no effect was recorded for either parameter in intact GK isl ets. In contrast, acarbose inhibited the enzyme activity equally in islet h omogenates from both GK and Wistar rats, showing that the catalytic activit y of the enzyme itself in disrupted cells was unaffected. We propose that d ysfunction of the islet lysosomal/vacuolar system is an important defect im pairing the transduction mechanisms for glucose-induced insulin release in the GK rat.