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- Title
Munc13-1 Deficiency Reduces Insulin Secretion and Causes Abnormal Glucose Tolerance.
- Authors
Kwan, Edwin P.; Xie, Li; Sheu, Laura; Nolan, Christopher J.; Prentki, Marc; Betz, Andrea; Brose, Nils; Gaisano, Herbert Y.
- 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 Munc13-1H567k/+ 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. Diabetes 55:1421-1429, 2006
- Subjects
DIGLYCERIDES; TYPE 2 diabetes; INSULIN resistance; GLUCOSE tolerance tests; PEOPLE with diabetes
- Publication
Diabetes, 2006, Vol 55, Issue 5, p1421
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db05-1263