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 obese (ob/ob) and lean mice to determine the glucose threshold for insulin secretion, and to examine effects of acetylcholine on insulin secretion. Only equal-sized islets from ob/ob and lean mice were incubated to eliminate confounding effects of phenotypic differences in islet size. Even after this adjustment, islets from ob/ob mice still hypersecreted insulin in response to 20 mmol/L glucose. The threshold for glucose-induced insulin secretion determined by perifusing islets with a linear 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 deprivation. 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 glucose in fed and 24-h food-deprived lean mice, respectively). Rates of insulin secretion per each unit (mmol/L) increase in glucose above threshold concentrations were unaffected by phenotype or feeding state. Addition of acetylcholine to the perifusing buffer further lowered the threshold for insulin secretion to 0.5 mmol/L glucose in pancreatic islets from ob/ob mice and also doubled the rate of increase in insulin secretion at glucose concentrations above the threshold. The combination of the very low threshold for glucose-induced insulin secretion and the exaggerated insulin secretory response to acetylcholine in pancreatic islets of ob/ob mice are likely critical factors in the hyperinsulinemia of these mice.