| Title: |
TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells. |
| Authors: |
da Silva Xavier G; Loder MK; McDonald A; Tarasov AI; Carzaniga R; Kronenberger K; Barg S; Rutter GA; da Silva Xavier, Gabriela; Loder, Merewyn K; McDonald, Angela; Tarasov, Andrei I; Carzaniga, Raffaella; Kronenberger, Katrin; Barg, Sebastian; Rutter, Guy A |
| Source: |
Diabetes; Apr2009, Vol. 58 Issue 4, p894-905, 12p |
| Abstract: |
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. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |