Jan 27, 2009

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

Diabetes
Gabriela Da Silva XavierGuy A Rutter

Abstract

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. 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. 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, sec...Continue Reading

  • References41
  • Citations107

References

Mentioned in this Paper

Gene Polymorphism
Real-Time Polymerase Chain Reaction
Diabetes Mellitus, Non-Insulin-Dependent
Microarray Analysis
STX1A gene
Exertion
TCF Transcription Factors
Structure of Beta Cell of Islet
Insulin/Insulin Receptor Signaling Pathway
TCF7L2

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