TCF7L2 regulates β-cell survival and function in human pancreatic islets

Abstract

Objective: Type 2 diabetes mellitus (T2DM) is characterized by impaired insulin secretion in response to increased metabolic demand. This defect in β-cell compensation seems to result from the interplay between environmental factors and genetic pre-disposition. Genome wide association studies reveal that common variants in the transcription factor TCF7L2 are associated with increased risk of T2DM. The aim of the present study was to establish if TCF7L2 plays a role in β-cell function and/or survival.

Research Design and Methods: To investigate the effects of TCFL7L2 depletion, isolated islets were exposed to TCF7L2 siRNA versus scrambled siRNA and β-cell survival and function were examined. For TCF7L2 over-expression islets were cultured in glucose concentrations of 5.5-33.3 mM and the cytokine mix IL-1β/IFN-γ with or without over-expression of TCF7L2. Subsequently, glucose stimulated insulin secretion (GSIS), β-cell apoptosis (by TUNEL assay and Western blotting for PARP and Caspase-3 cleavage) and β-cell proliferation (by Ki67 immunostaining) were analyzed.

Results: Depleting TCF7L2 by siRNA resulted in a 5.1-fold increase in β-cell apoptosis, 2.2-fold decrease in β-cell proliferation (p<0.001) and 2.6-fold decrease in GSIS (p<0.01) in human islets. Similarly, loss of TCF7L2 resulted in impaired β-cell function in mouse islets. In contrast, over-expression of TCF7L2 protected islets from glucose and cytokine induced apoptosis and impaired function.

Conclusions: TCF7L2 is required for maintaining glucose stimulated insulin secretion and β-cell survival. Changes in the level of active TCF7L2 in β-cells from carriers of at risk allele may be the reason for defective insulin secretion and progression of type 2 diabetes.