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Munc13-1 deficiency reduces insulin secretion and causes abnormal glucose tolerance

MPG-Autoren
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Betz,  Andrea
Molecular neurobiology, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Brose,  Nils
Molecular neurobiology, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Zitation

Kwan, E. P., Xie, L., Sheu, L., Nolan, C. J., Prentki, M., Betz, A., et al. (2006). Munc13-1 deficiency reduces insulin secretion and causes abnormal glucose tolerance. Diabetes, 55(5), 1421-1429. doi:10.2337/db05-1263.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-002A-244B-8
Zusammenfassung
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 P-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 P-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.