TCF7L2 regulates late events in insulin secretion from pancreatic islet β-cells

Gabriela Da Silva Xavier, Merewyn K. Loder, Angela McDonald, Andrei I. Tarasov, Raffaella Carzaniga, Katrin Kronenberger, Sebastian Barg, Guy A. Rutter

Research output: Contribution to journalArticle

143 Citations (Scopus)

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 β-cell function and suggest a potential mechanism for its actions. RESEARCH DESIGN AND METHODS-TCF7L2 expression in rodent islets and β-cell lines was altered using RNAi or adenoviral transduction. β-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 ([Ca 2+]i) were increased compared with controls. Overexpression of TCF7L2 exerted minor inhibitory effects on glucose-regulated changes in [Ca 2+]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 β-cell genes regulating secretory granule fusion. Defective insulin exocytosis may thus underlie increased diabetes incidence in carriers of the at-risk TCF7L2 alleles.

Original languageEnglish
Pages (from-to)894-905
Number of pages12
JournalDiabetes
Volume58
Issue number4
DOIs
Publication statusPublished - 1 Apr 2009

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    Da Silva Xavier, G., Loder, M. K., McDonald, A., Tarasov, A. I., Carzaniga, R., Kronenberger, K., Barg, S., & Rutter, G. A. (2009). TCF7L2 regulates late events in insulin secretion from pancreatic islet β-cells. Diabetes, 58(4), 894-905. https://doi.org/10.2337/db08-1187