title: TPN-evoked dysfunction of islet lysosomal activity mediates impairment of glucose-stimulated insulin release.
abstract: We examined the relation between nutrient-stimulated insulin secretion and the islet lysosome acid glucan-1,4-alpha-glucosidase system in rats undergoing total parenteral nutrition (TPN). During TPN treatment, serum glucose was normal, but free fatty acids, triglycerides, and cholesterol were elevated. 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 impairment of glucose-stimulated insulin release was only slightly ameliorated by the carnitine palmitoyltransferase 1 inhibitor etomoxir. However, in parallel with the impaired insulin response to glucose, islets from TPN-infused animals displayed reduced activities of islet lysosomal enzymes including 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 pseudotetrasaccharide acarbose, a selective inhibitor of acid alpha-glucosidehydrolases, dose dependently suppressed islet acid glucan-1,4-alpha-glucosidase 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 or glucose-induced insulin release. Moreover, when acarbose was added directly to TPN islet homogenates, the dose-response effect on the catalytic activity of the acid alpha-glucosidehydrolases was shifted to the right compared with control homogenates. We suggest that a general dysfunction of the islet lysosomal/vacuolar system and reduced catalytic activities of acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase may be important defects behind the impairment of the transduction mechanisms for nutrient-stimulated insulin release in islets from TPN-infused rats.
authors.affiliation: Institute of Physiological Sciences, Department of Pharmacology, University of Lund, S-221 84 Lund, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Salehi
authors.forename: B G
authors.initials: BG
authors.lastname: Fan
authors.forename: M
authors.initials: M
authors.lastname: Ekelund
authors.forename: G
authors.initials: G
authors.lastname: Nordin
authors.forename: I
authors.initials: I
authors.lastname: Lundquist
mesh_terms: D020909:Acarbose / Q000494:pharmacology; D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005087:Glucan 1,4-alpha-Glucosidase / Q000037:antagonists & inhibitors; D005947:Glucose / Q000494:pharmacology*; D005959:Glucosidases / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008247:Lysosomes / Q000201:enzymology / Q000502:physiology*; D008297:Male; D010289:Parenteral Nutrition, Total / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000097:blood
chemical_list: D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D014280:Triglycerides; D000135:Acid Phosphatase; D005959:Glucosidases; D005087:Glucan 1,4-alpha-Glucosidase; D005947:Glucose; D020909:Acarbose