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

• Published in: Diabetes (New York, N.Y.) Vol. 55; no. 5; pp. 1421 - 1429
• Main Authors: KWAN, Edwin P, LI XIE, SHEU, Laura, NOLAN, Christopher J, PRENTKI, Marc, BETZ, Andrea, BROSE, Nils, GAISANO, Herbert Y
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.05.2006
• Subjects: Animals; Biological and medical sciences; Brain - metabolism; Brain - physiology; Care and treatment; Crosses, Genetic; Diabetes; Diabetes mellitus; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose; Glucose Intolerance - genetics; Glucose Tolerance Test; Glucose tolerance tests; Health aspects; Homeostasis; Insulin; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - metabolism; Islets of Langerhans - physiology; Medical sciences; Mice; Mice, Knockout; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Pancreatic beta cells; Patch-Clamp Techniques; Polymerase Chain Reaction; Proteins; Risk factors; Veins & arteries; Canada; Endocrinopathy; Pancreatic hormone; Secretion; Diabetes mellitus; Deficiency; Impaired glucose tolerance; Insulin
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db05-1263

Munc13-1 Deficiency Reduces Insulin Secretion and Causes Abnormal Glucose Tolerance Edwin P. Kwan 1 , Li Xie 2 , Laura Sheu 2 , Christopher J. Nolan 3 , Marc Prentki 3 , Andrea Betz 4 , Nils Brose 4 and Herbert Y. Gaisano 1 2 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 Abstract 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 β-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 β-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 β-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. Cm, 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 Footnotes 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 U.S.C. Section 1734 solely to indicate this fact. Accepted February 8, 2006. Received September 27, 2005. DIABETES