Changes in islet glucan-1,4-alpha-glucosidase activity modulate sulphonylurea-induced but not cholinergic insulin secretion.

We have previously presented indirect in vivo evidence for the involvement 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 studied whether differential changes in islet acid amyloglucosidase activity would be related to the insulin secretory response induced by two mechanistically different secretagogues, the sulphonylurea derivative, glibenclamide and the acetylcholine receptor agonist, carbachol. It was observed that the selective alpha-glucosidehydrolase inhibitors emiglitate and acarbose markedly reduced glibenclamide-induced insulin release from isolated islets. Insulin release stimulated by carbachol or the protein kinase C activator TPA (12-O-tetradecanoylphorbol 13-acetate), was not inhibited. Basal insulin secretion was unaffected by emiglitate and acarbose. Further, pretreatment of mice with emiglitate resulted in a marked reduction of the in vivo insulin response to glibenclamide. Moreover, in vivo pretreatment with purified fungal amyloglucosidase ('enzyme replacement'), a procedure known to increase islet amyloglucosidase activity, greatly enhanced the insulin response to i.v. glibenclamide. This insulin release was accompanied by a marked depression of the blood glucose levels. In contrast, enzyme pretreatment did not influence the insulin response or the blood glucose levels after carbachol. The data strongly suggest that islet acid amyloglucosidase is involved in the insulin secretory processes induced by glibenclamide but not in those involving stimulation of muscarinic receptors or direct activation of protein kinase C. The results also indicate separate or at least partially separate pathways for insulin release induced by glibenclamide and cholinergic stimulation.