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Threshold for Glucose-Stimulated Insulin Secretion in Pancreatic Islets of Genetically Obese (ob/ob) Mice is Abnormally Low^1,2,

Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824-1224

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.

KEY WORDS: • genetically obese (ob/ob) mice • glucose • pancreatic islets • insulin secretion • acetylcholine

¹ Supported by NIH grant DK-15847 and the Michigan Agricultural Experiment Station.

² The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

³ To whom correspondence should be addressed.

Manuscript received 8 March 1993. Revision accepted 21 May 1993.