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Munc13-1 deficiency reduces insulin secretion and causes abnormal glucose tolerance
- Source :
- Diabetes. 55(5)
- Publication Year :
- 2006
-
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.
- Subjects :
- medicine.medical_specialty
Patch-Clamp Techniques
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
Nerve Tissue Proteins
Biology
Polymerase Chain Reaction
Impaired glucose tolerance
Islets of Langerhans
Mice
Internal medicine
Diabetes mellitus
Glucose Intolerance
Insulin Secretion
Internal Medicine
medicine
Animals
Insulin
Crosses, Genetic
Mice, Knockout
geography
geography.geographical_feature_category
Pancreatic islets
Brain
Glucose Tolerance Test
medicine.disease
Islet
Abnormal glucose homeostasis
Insulin oscillation
Endocrinology
medicine.anatomical_structure
Synaptic vesicle priming
Subjects
Details
- ISSN :
- 00121797
- Volume :
- 55
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....54c809ea3ec2612211ac98400dcfd26b