THRESHOLD FOR GLUCOSE-STIMULATED INSULIN-SECRETION IN PANCREATIC-ISLETS OF GENETICALLY-OBESE (OB OB) MICE IS ABNORMALLY LOW

Pancreatic islets were isolated from 8-9-wk-old female genetically obe se (ob/ob) and lean mice to determine the glucose threshold for insuli n secretion, and to examine effects of acetylcholine on insulin secret ion. Only equal-sized islets from ob/ob and lean mice were incubated t o eliminate confounding effects of phenotypic differences in islet siz e. Even after this adjustment, islets from ob/ob mice still hypersecre ted insulin in response to 20 mmol/L glucose. The threshold for glucos e-induced insulin secretion determined by perifusing islets with a lin ear glucose gradient averaged 1.9 +/- 0.1 mmol/L glucose in fed ob/ob mice and 3.1 +/- 0.1 mmol/L glucose in ob/ob mice after 24 h of food d eprivation. These low thresholds indicate that islets from ob/ob mice are constantly stimulated by glucose. Islets from lean mice exhibited considerably higher thresholds (4.8 +/- 0.1 and 7.1 +/- 0.1 mmol/L glu cose in fed and 24-h food-deprived lean mice, respectively). Rates of insulin secretion per each unit (mmol/L) increase in glucose above thr eshold concentrations were unaffected by phenotype or feeding state. A ddition of acetylcholine to the perifusing buffer further lowered the threshold for insulin secretion to 0.5 mmol/L glucose in pancreatic is lets from ob/ob mice and also doubled the rate of increase in insulin secretion at glucose concentrations above the threshold. The combinati on of the very low threshold for glucose-induced insulin secretion and the exaggerated insulin secretory response to acetylcholine in pancre atic islets of ob/ob mice are likely critical factors in the hyperinsu linemia of these mice.