期刊
DIABETES
卷 58, 期 4, 页码 894-905出版社
AMER DIABETES ASSOC
DOI: 10.2337/db08-1187
关键词
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资金
- Wellcome Trust [067081/Z/02/Z, 081958/Z/07/Z]
- MRC [G0401641]
- National Institutes of Health [ROI DKO71962-01]
- European Union FP6
- Juvenile Diabetes Research Foundation (JDRF) [3-2005-112]
- European Foundation
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK071962] Funding Source: NIH RePORTER
- Medical Research Council [G0401641] Funding Source: researchfish
OBJECTIVE-Polymorphisms in the human TCF7L2 gene are associated with reduced insulin secretion and an increased risk of type 2 diabetes. However, the mechanisms by which TCF7L2 affect insulin secretion are still unclear. We define the effects of TCF7L2 expression level on mature beta-cell function and suggest a potential mechanism for its actions. RESEARCH DESIGN AND METHODS-TCF7L2 expression in rodent islets and beta-cell lines was altered using RNAi or adenoviral transduction. beta-Cell gene profiles were measured by quantitative real-time PCR and the effects on intracellular signaling and exocytosis by live cell imaging, electron microscopy, and patch clamp electrophysiology. RESULTS-Reducing TCF7L2 expression levels by RNAi decreased glucose- but not KCl-induced insulin secretion. The glucose-induced increments in both ATP/ADP ratio and cytosolic free Ca2+ concentration ([Ca2+](i)) were increased compared with controls. Overexpression of TCF7L2 exerted minor inhibitory effects on glucose-regulated changes in [Ca2+](i), and insulin release. Gene expression profiling in TCF7L2-silenced cells revealed increased levels of mRNA encoding syntaxin 1A but decreased Munc18-1 and ZnT8 mRNA. Whereas the number of morphologically docked vesicles was unchanged by TCF7L2 suppression, secretory granule movement increased and capacitance changes decreased, indicative of defective vesicle fusion. CONCLUSION-TCF7L2 is involved in maintaining expression of beta-cell genes regulating secretory granule fusion. Defective insulin exocytosis may thus underlie increased diabetes incidence in carriers of the at-risk TCF7L2 alleles. Diabetes 58: 894-905, 2009
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