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Munc13-1 Deficiency Reduces Insulin Secretion and Causes Abnormal Glucose Tolerance

¹ Department of Physiology, University of Toronto, Toronto, Ontario, Canada
² Department of Medicine, University of Toronto, Toronto, Ontario, Canada
³ Molecular Nutrition Unit, Department of Nutrition, University of Montreal, the Centre Hospitalier de l’Universite de Montreal and the Montreal Diabetes Research Center, Montreal, Quebec, Canada
⁴ Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany

Address correspondence and reprint requests to Dr. Herbert Gaisano, Medical Sciences Bldg., Rm. 7226, 1 King’s College Circle, University of Toronto, Toronto, Ontario M5S 1A8, Canada. E-mail: herbert.gaisano{at}utoronto.ca

Abbreviations: C_m, membrane capacitance; DAG, diacylglycerol; GSIS, glucose-stimulated insulin secretion; IPGTT, intraperitoneal glucose tolerance test; KRBH, Krebs-Ringer bicarbonate buffer containing 10 mmol/l HEPES; PKC, protein kinase C; PMA, phorbol 12-myristate 13-acetate ester; RRP, readily releasable pool; SNARE, soluble N-ethylmaleimide–sensitive factor attachment protein receptor

Munc13-1 is a diacylglycerol (DAG) receptor that is essential for synaptic vesicle priming. We recently showed that Munc13-1 is expressed in rodent and human islet ß-cells and that its levels are reduced in islets of type 2 diabetic humans and rat models, suggesting that Munc13-1 deficiency contributes to the abnormal insulin secretion in diabetes. To unequivocally demonstrate the role of Munc13-1 in insulin secretion, we studied heterozygous Munc13-1 knockout mice (+/–), which exhibited elevated glucose levels during intraperitoneal glucose tolerance tests with corresponding lower serum insulin levels. Munc13-1^+/– mice exhibited normal insulin tolerance, indicating that a primary islet ß-cell secretory defect is the major cause of their hyperglycemia. Consistently, glucose-stimulated insulin secretion was reduced 50% in isolated Munc13-1^+/– islets and was only partially rescued by phorbol ester potentiation. The corresponding alterations were minor in mice expressing one allele of a Munc13-1 mutant variant, which does not bind DAG (H567K/+). Capacitance measurements of Munc13-1^+/– and Munc13-1^H567k/+ islet ß-cells revealed defects in granule priming, including the initial size and refilling of the releasable pools, which become accentuated by phorbol ester potentiation. We conclude that Munc13-1 plays an important role in glucose-stimulated insulin secretion and that Munc13-1 deficiency in the pancreatic islets as occurs in diabetes can reduce insulin secretion sufficient to cause abnormal glucose homeostasis.

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