The Pseudotetrasaccharide Acarbose Inhibits Pancreatic Islet Glucan-1,4-α-glucosidase Activity in Parallel With a Suppressive Action on Glucose-Induced Insulin Release

The pseudotetrasaccharide acarbose, previously known as a potent inhibitor of intestinal α-glucoside hydrolases, was investigated with regard to its influence on islet lysosomal enzyme activities and the insulin secretory processes. We observed that acarbose was a potent inhibitor of mouse islet lysosomal acid glucan-l,4-α-glucosidase activity, EC50 ∼5 μmol/l, as well as of acid α-glucosidase activity. In contrast, acarbose did not influence other lysosomal enzyme activities such as acid phosphatase and N-acetyl-β-D-glucosaminidase. Neutral a-glucosidase (endoplasmic reticulum) was only moderately inhibited in homogenate and was unaffected in intact islets. Incubation of isolated mouse islets with acarbose revealed that the pseudotetrasaccharide was a strong inhibitor of glucose-induced insulin secretion, EC50 ∼500 nmol/1, and a significant inhibition was already observed at a concentration of acarbose as low as 100 nmol/1. The acarbose analogue maltotetrose did not influence either glucoseinduced insulin release or islet lysosomal enzyme activities. Further, acarbose as well as two other α-glucoside hydrolase inhibitors, the deoxynojirimycin derivatives miglitol and emiglitate, did not affect islet glucose oxidation at low or high glucose levels. Acarbose also inhibited insulin release induced by the sulfonylurea glibenclamide, whereas insulin secretion stimulated by the cholinergic muscarinic agonist carbachol or the phosphodiesterase inhibitor isobutylmethylxanthine was unaffected by the drug. Moreover, complementary in vivo experiments showed that pretreatment of mice with acarbose to allow for endocytosis of the compound markedly suppressed the insulin secretory response to an intravenous glucose load. In contrast, acute intravenous injection of acarbose did not influence insulin secretion (no membrane effect) either when injected alone or when injected together with glucose. Since the action of acarbose is known to be restricted to the vacuolar apparatus, the present results, together with previous observations, suggest that an activation of the acid glucan-l,4-α-glucosidase and the lysosomal system may serve as one of several transduction signals for insulin release stimulated by glucose and glibenclamide.