TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-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 journalArticlepeer-review

151 Citations (Scopus)


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.

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


  • Animals
  • DNA Primers
  • Diabetes Mellitus, Type 2/genetics
  • Gene Expression Regulation
  • Gene Silencing
  • Homeostasis
  • Humans
  • Insulin/secretion
  • Insulin-Secreting Cells/secretion
  • Mice
  • Polymerase Chain Reaction
  • Polymorphism, Genetic
  • Rats
  • TCF Transcription Factors/genetics
  • Transcription Factor 7-Like 2 Protein


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