Mechanism of action of derivative sulfonamide in glucose tolerance and in incretin and insulin secretion

Introduction: Sulfonamides were discovered as hypoglycemic agents in 1942 and gave rise to the class of sulphonylureas, insulin secretagogues compounds. From this, a sulfonamide based on the structure of glibenclamide, the sulfonamide 3 (sulf3) was synthesized to evaluate its therapeutic effect on glucose homeostasis. Aim: To assess the effect of sulf3 on glucose, insulin and GLP-1 levels in the glucose tolerance test (GTT). Next, evaluate insulin secretion and the mechanism of action of calcium induced by sulf3, in pancreatic islets as well as their activity on the intestinal disaccharidases. Methods: Male Wistar rats (50 days old) were divided into two experimental groups: Group I, Hyperglycemic rats (4g/kg glucose, via oral (v.o)), Group II, Hyperglycemic rats plus Sulf3 (10 mg/kg, v.o., 30 min before glucose overload). Sitagliptin (10 mg/kg, v.o., 1 h before glucose overload) was administered to analyze GLP-1 levels. Blood samples were collected prior to glucose overload (time 0); and 15, 30, 60 and 180 min after, to quantify glucose, insulin and GLP-1 levels. After the animals were euthanized and gut samples were taken to analyze the activity of the disaccharidases. Pancreatic islets were isolated to quantify insulin and mechanism of action of calcium, in vitro. Results expressed as Mean ± Standard Error Mean and level of significance of 95% (p <0.05), (CEUA protocol approved: PP00749). Results: Sulf3 reduced glycemia and stimulated insulin and GLP-1 secretion in vivo. In addition, sulf3 stimulated insulin secretion and calcium influx into isolated pancreatic islets. The mechanism of action of calcium influx involved K+-ATP channels, voltage-dependent calcium channels and phospholipase C. Sulf3 inhibited the activity of intestinal maltase, sucrase and lactase enzymes. Conclusions: Sulf3 regulates glycemia by a mechanism mediated by insulin secretion and incretin and contributes to the reduction of the absorption of different doses by inhibiting the activity of intestinal disaccharidases.