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Transcription Factor 7-Like 2 Regulates β-Cell Survival and Function in Human Pancreatic Islets

¹ Larry L. Hillblom Islet Research Center, Department of Medicine, University of California, Los Angeles, Los Angeles, California
² Division of Transplantation, University of Illinois at Chicago, Chicago, Illinois

Address correspondence and reprint requests to Kathrin Maedler, PhD, Centre for Biomolecular Interactions Bremen, University of Bremen, NW2, Box 33 04 40, D-28334 Bremen, Germany. E-mail: kmaedler{at}uni-bremen.de

Key Words: DAPI, 4,6-diamidino-2-phenylindole • FITC, fluorescein isothiocyanate • GLP-1, glucagon-like peptide 1 • GSIS, glucose-stimulated insulin secretion • IFN-, -interferon • IL, interleukin • KRBB, Krebs-Ringer bicarbonate buffer • PARP, poly(ADP-ribose) polymerase • siRNA, small interfering RNA • siScr, scrambled control siRNA • siTCF7L2, islets depleted for TCF7L2 by siRNA to TCF7L2 • SNP, single nucleotide polymorphism • TCF7L2, transcription factor 7-like 2 • TUNEL, transferase-mediated dUTP nick-end labeling

OBJECTIVE—Type 2 diabetes 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 predisposition. Genome-wide association studies reveal that common variants in transcription factor 7-like 2 (TCF7L2) are associated with increased risk of type 2 diabetes. The aim of the present study was to establish whether 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 small interfering RNA (siRNA) versus scrambled siRNA, and β-cell survival and function were examined. For TCF7L2 overexpression, islets were cultured in glucose concentrations of 5.5–33.3 mmol/l and the cytokine mix interleukin-1β/-interferon with or without overexpression of TCF7L2. Subsequently, glucose-stimulated insulin secretion (GSIS), β-cell apoptosis [by transferase-mediated dUTP nick-end labeling assay and Western blotting for poly(ADP-ribose) polymerase 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, overexpression of TCF7L2 protected islets from glucose and cytokine-induced apoptosis and impaired function.

CONCLUSIONS—TCF7L2 is required for maintaining GSIS 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.

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