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Dysfunction of the Islet Lysosomal System Conveys Impairment of Glucose-Induced Insulin Release in the Diabetic GK Rat¹

Department of Pharmacology, University of Lund (A.S., R.H., H.M., I.L.), S-223 62 Lund; and the Department of Endocrinology, Karolinska Institute and Hospital (C.-G.O., S.E.), S-17176 Stockholm, Sweden

Address all correspondence and requests for reprints to: Prof. Ingmar Lundquist, M.D., Ph.D., Department of Pharmacology, University of Lund, Solvegatan 10, S-223 62 Lund, Sweden. E-mail: ingmar.lundquist{at}farm.lu.se

Accumulated evidence links an important signal involved in glucose-stimulated insulin release to the activation of the islet lysosomal glycogenolytic enzyme acid glucan-1,4--glucosidase. We have analyzed the function of the lysosomal system/lysosomal enzyme activities in pancreatic islets of young (6–8 weeks), spontaneously diabetic, GK (Goto-Kakizaki) rats and Wistar control rats in relation to glucose-induced insulin release. The insulin secretory response to glucose was markedly impaired in the GK rat, but was restored by the adenylate cyclase activator forskolin. Islet activities of classical lysosomal enzymes, e.g.. acid phosphatase, N-acetyl-ß-D-glucosaminidase, ß-glucuronidase, and cathepsin D, were reduced by 20–35% in the GK rat compared with those in Wistar controls. In contrast, the activities of the lysosomal -glucosidehydrolases, i.e.. acid glucan-1,4--glucosidase and acid -glucosidase, were increased by 40–50%. Neutral -glucosidase (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 glucan-1,4--glucosidase and acid -glucosidase were approximately 15-fold higher in islets than in liver. Other lysosomal enzymes did not display such a difference. Normalization of glycemia in GK rats by phlorizin administered for 9 days did not influence either the lysosomal -glucosidehydrolase activities or other lysosomal enzyme activities in GK islets. Finally, the pseudotetrasaccharide acarbose, which accumulates in the lysosomal system, inhibited acid glucan-1,4--glucosidase activity in parallel with its inhibitory action on glucose-induced insulin release in intact Wistar islets, whereas no effect was recorded for either parameter in intact GK islets. In contrast, acarbose inhibited the enzyme activity equally in islet homogenates from both GK and Wistar rats, showing that the catalytic activity of the enzyme itself in disrupted cells was unaffected. We propose that dysfunction of the islet lysosomal/vacuolar system is an important defect impairing the transduction mechanisms for glucose-induced insulin release in the GK rat.

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