title: Munc13-1 deficiency reduces insulin secretion and causes abnormal glucose tolerance.
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 beta-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 beta-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 beta-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.
authors.affiliation: Department of Physiology, University of Toronto, Medical Sciences Building Rm. 7226, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Kwan
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.forename: Laura
authors.initials: L
authors.lastname: Sheu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Nolan
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
authors.forename: Andrea
authors.initials: A
authors.lastname: Betz
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Gaisano
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000502:physiology; D003433:Crosses, Genetic; D018149:Glucose Intolerance / Q000235:genetics*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics*; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction
chemical_list: D007328:Insulin; D009419:Nerve Tissue Proteins; C503321:Unc13a protein, mouse