CHANGES IN ISLET GLUCAN-1,4-ALPHA-GLUCOSIDASE ACTIVITY MODULATE SULFONYLUREA-INDUCED BUT NOT CHOLINERGIC INSULIN-SECRETION

We have previously presented indirect in vivo evidence for the involve ment of islet acid glucan-1,4-alpha-glucosidase (acid amyloglucosidase ), a lysosomal glucose-producing enzyme, in certain insulin secretory processes. In the present in vitro and in vivo investigation, we studi ed whether differential changes in islet acid amyloglucosidase activit y would be related to the insulin secretory response induced by two me chanistically different secretagogues, the sulphonylurea derivative, g libenclamide and the acetylcholine receptor agonist, carbachol. It was observed that the selective alpha-glucosidehydrolase inhibitors emigl itate and acarbose markedly reduced glibenclamide-induced insulin rele ase from isolated islets. Insulin release stimulated by carbachol or t he protein kinase C activator TPA (12-0-tetradecanoylphorbol 13-acetat e), was not inhibited. Basal insulin secretion was unaffected by emigl itate and acarbose. Further, pretreatment of mice with emiglitate resu lted in a marked reduction of the in vivo insulin response to glibencl amide. Moreover, in vivo pretreatment with purified fungal amyloglucos idase ('enzyme replacement'), a procedure known to increase islet amyl oglucosidase activity, greatly enhanced the insulin response to i.v. g libenclamide. This insulin release was accompanied by a marked depress ion of the blood glucose levels. In contrast, enzyme pretreatment did not influence the insulin response or the blood glucose levels after c arbachol. The data strongly suggest that islet acid amyloglucosidase i s involved in the insulin secretory processes induced by glibenclamide but not in those involving stimulation of muscarinic receptors or dir ect activation of protein kinase C. The results also indicate separate or at least partially separate pathways for insulin release induced b y glibenclamide and cholinergic stimulation.