Human Molecular Genetics Advance Access published online on April 21, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp178
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Decreased TCF7L2 protein levels in T2DM correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function
1 Centre for Biomolecular Interactions Bremen, University of Bremen, Germany 2 Larry L. Hillblom Islet Research Center, Department of Medicine, UCLA, Los Angeles, CA, USA 3 Thérapie Cellulaire du Diabète, INSERM /Université de Lille, France 4 Department of Endocrinology, Kangnam St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea 5 Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada
* Address correspondence to: Kathrin Maedler, Ph.D., Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen, University of Bremen, Leobener Straße im NW2, Room B2080, 28359 Bremen, Germany mailbox 330440, 28334 Bremen, phone: +49-15229580517, Fax: +49(421)218-7433, E-mail: kmaedler{at}uni-bremen.de
Received January 24, 2009; Revised April 7, 2009; Accepted April 7, 2009
Recent human genetics studies have revealed that common variants of the TCF7L2 (T-cell factor 7-like 2, formerly known as TCF4) gene are strongly associated with type 2 diabetes mellitus (T2DM). We have shown that TCF7L2 expression in the β-cells is correlated with function and survival of the insulin producing pancreatic β-cell. In order to understand how variations in TCF7L2 influence diabetes progression, we investigated its mechanism of action in the β-cell.
We show robust differences in TCF7L2 expression between healthy controls and models of T2DM. While mRNA levels were 
2-fold increased in isolated islets from the diabetic db/db mouse, the Vancouver Diabetic Fatty (VDF) Zucker rat and the high fat/ high sucrose diet treated mouse compared to the non-diabetic controls, protein levels were decreased. A similar decrease was observed in pancreatic sections from patients with T2DM.
In parallel, expression of the receptors for glucagon-like peptide 1 (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIP-R) was decreased in islets from humans with T2DM as well as in isolated human islets treated with siRNA to TCF7L2 (siTCF7L2). Also, insulin secretion stimulated by glucose, GLP-1 and GIP, but not KCl or cAMP was impaired in siTCF7L2 treated isolated human islets.
Loss of TCF7L2 resulted in decreased GLP-1 and GIP stimulated AKT phosphorylation, and AKT mediated Foxo-1 phosphorylation and nuclear exclusion.
Our findings suggest that β-cell function and survival are regulated through an interplay between TCF7L2 and GLP-1R/ GIP-R expression and signaling in T2DM.
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