Statement of Retraction. Transcription Factor 7-Like 2 Regulates β-Cell Survival and Function in Human Pancreatic Islets. Diabetes 2008;57:645–653. DOI: 10.2337/db07-0847; and erratum. Diabetes 2014:63:3974. DOI: 10.2337/db14-er11

Autor: Shu, Luan, Sauter, Nadine S., Schulthess, Fabienne T., Matveyenko, Aleksey V., Oberholzer, José, Maedler, Kathrin
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: Diabetes
ISSN: 1939-327X
0012-1797
Popis: Type 2 diabetes is characterized by impaired insulin secretion in response to increased metabolic demand. This defect in beta-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 beta-cell function and/or survival.To investigate the effects of TCFL7L2 depletion, isolated islets were exposed to TCF7L2 small interfering RNA (siRNA) versus scrambled siRNA, and beta-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-1 beta/gamma-interferon with or without overexpression of TCF7L2. Subsequently, glucose-stimulated insulin secretion (GSIS), beta-cell apoptosis [by transferase-mediated dUTP nick-end labeling assay and Western blotting for poly(ADP-ribose) polymerase and Caspase-3 cleavage], and beta-cell proliferation (by Ki67 immunostaining) were analyzed.Depleting TCF7L2 by siRNA resulted in a 5.1-fold increase in beta-cell apoptosis, 2.2-fold decrease in beta-cell proliferation (P0.001), and 2.6-fold decrease in GSIS (P0.01) in human islets. Similarly, loss of TCF7L2 resulted in impaired beta-cell function in mouse islets. In contrast, overexpression of TCF7L2 protected islets from glucose and cytokine-induced apoptosis and impaired function.TCF7L2 is required for maintaining GSIS and beta-cell survival. Changes in the level of active TCF7L2 in beta-cells from carriers of at-risk allele may be the reason for defective insulin secretion and progression of type 2 diabetes.
Databáze: OpenAIRE
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