TY - JOUR
T1 - Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function
AU - Shu, Luan
AU - Matveyenko, Aleksey V.
AU - Kerr-Conte, Julie
AU - Cho, Jae Hyoung
AU - McIntosh, Christopher H.S.
AU - Maedler, Kathrin
N1 - Funding Information:
This work was supported by the European Foundation for the Study of Diabetes (EFSD) and Merck Sharp & Dohme (MSD) European Studies on Beta Cell Function and Survival: Basic Research Programme and the German Research Foundation (DFG, Emmy Noether Programm MA4172/1-1) and Canadian Institutes for Health Research (CM). Human islet isolation was supported by the National Center for Research Resources (NCRR), The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the Juvenile Diabetes Research Foundation (JDRF) and through the European Consortium for Islet Transplantation (ECIT), Islets for Research Distribution Program.
PY - 2009
Y1 - 2009
N2 - 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 approximately 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 with 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 cyclic adenosine monophosphate (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.
AB - 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 approximately 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 with 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 cyclic adenosine monophosphate (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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U2 - 10.1093/hmg/ddp178
DO - 10.1093/hmg/ddp178
M3 - Article
C2 - 19386626
AN - SCOPUS:67249096093
SN - 0964-6906
VL - 18
SP - 2388
EP - 2399
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 13
ER -