个性化文献订阅>期刊> Diabetes
 

Transcription factor 7-like 2 regulates beta-cell survival and function in human pancreatic islets

  作者 Shu, L; Sauter, NS; Schulthess, FT; Matveyenko, AV; Oberholzer, J; Maedler, K  
  选自 期刊  Diabetes;  卷期  2008年57-3;  页码  645-653  
  关联知识点  
 

[摘要]OBJECTIVE-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 P-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 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), P-cell apoptosis [by transferase-mediated dUTP nick-end labeling assay and Western blotting for poly(ADP-ribose) polymerase and Caspase-3 cleavage], and P-cell proliferation (by Ki67 immunostaining) were analyzed.RESULTS-Depleting TCF7L2 by siRNA resulted in a 5.1-fold increase in P-cell apoptosis, 2.2-fold decrease in beta-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 P-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 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.

 
      被申请数(0)  
 

[全文传递流程]

一般上传文献全文的时限在1个工作日内