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Transcription Factor 7-Like 2 Regulates β-Cell Survival and Function in Human Pancreatic Islets
Open accessAbstract
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/γ-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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Metadata
- Authors
- Shu, L., Sauter, N. S., Schulthess, F. T., Matveyenko, A. V., Oberholzer, J., & Maedler, K.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2008-03-01
- Volume
- 57
- Issue
- 3
- Pages
- 645-653
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2161556085
- Cited by
- 265
- References
- 39
- FWCI
- 19.26
- Type
- journal article
- Language
- en
- Status
- Retracted
- Open access
- bronze
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