Transcription factor 7-like 2 regulates beta-cell survival and function in human pancreatic islets.
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 (P < 0.001), and 2.6-fold decrease in GSIS (P < 0.01) 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.
Shu
Luan
L
Larry L. Hillblom Islet Research Center, Department of Medicine, University of California, Los Angeles, California, USA.
Sauter
Nadine S
NS
Schulthess
Fabienne T
FT
Matveyenko
Aleksey V
AV
Oberholzer
José
J
Maedler
Kathrin
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D034741:RNA, Small Interfering; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein
D016207:Cytokines; D007328:Insulin; D034741:RNA, Small Interfering; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D005947:Glucose