THE PSEUDOTETRASACCHARIDE ACARBOSE INHIBITS PANCREATIC-ISLET GLUCAN-1,4-ALPHA-GLUCOSIDASE ACTIVITY IN PARALLEL WITH A SUPPRESSIVE ACTION ONGLUCOSE-INDUCED INSULIN RELEASE

The pseudotetrasaccharide acarbose, previously known as a potent inhib itor of intestinal alpha-glucoside hydrolases, was investigated with r egard to its influence on islet lysosomal enzyme activities, and the i nsulin secretory processes. We observed that acarbose was a potent inh ibitor of mouse islet lysosomal acid glucan-1,4-alpha-glucosidase acti vity, EC(50) similar to 5 mu mol/l, as well as of acid alpha-glucosida se activity. In contrast, acarbose did not influence other lysosomal e nzyme activities such as acid phosphatase and N-acetyl-beta-D-glucosam inidase. Neutral alpha-glucosidase (endoplasmic reticulum) was only mo derately inhibited in homogenate and was unaffected in intact islets. Incubation of isolated mouse islets with acarbose revealed that the ps eudotetrasaccharide was a strong inhibitor of glucose-induced insulin secretion, EC(50) similar to 500 nmol/l, and a significant inhibition was already observed at a concentration of acarbose as low as 100 nmol /l. The acarbose analogue maltotetrose did not influence either glucos e-induced insulin release or islet lysosomal enzyme activities. Furthe r, acarbose as well as two other alpha-glucoside hydrolase inhibitors, the deoxynojirimycin derivatives miglitol and emiglitate, did not aff ect islet glucose oxidation at low or high glucose levels. Acarbose al so inhibited release induced by the sulfonylurea glibenclamide, wherea s insulin secretion stimulated by the cholinergic muscarinic agonist c arbachol or the phosphodiesterase inhibitor isobutylmethylxanthine was unaffected by the drug. Moreover, complementary in vivo experiments s howed 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 injec tio n of acarbose did not influence insulin secretion (no membrane effect) either when injected alone or when injected together with glucose. Si nce the action of acarbose is known to be restricted to the vacuolar a pparatus, the present results, together with previous observations, su ggest that an activation of tile acid glucan-1,4-alpha-glucosidase and the lysosomal system may serve as one of several transduction signals for insulin release stimulated by glucose and glibenclamide.