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

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 affects insulin secretion are still unclear. Here 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 signalling 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 Ca 2+ concentration ([Ca 2+ ] i ) were increased compared to controls. Over-expression 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 allelles.