Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function

Hum Mol Genet. 2009 Jul 1;18(13):2388-99. doi: 10.1093/hmg/ddp178. Epub 2009 Apr 21.


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 beta-cells is correlated with function and survival of the insulin-producing pancreatic beta-cell. In order to understand how variations in TCF7L2 influence diabetes progression, we investigated its mechanism of action in the beta-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 beta-cell function and survival are regulated through an interplay between TCF7L2 and GLP-1R/GIP-R expression and signaling in T2DM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Down-Regulation*
  • Female
  • Gastric Inhibitory Polypeptide / metabolism
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • In Vitro Techniques
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / physiology*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Rats
  • Rats, Zucker
  • Receptors, Gastrointestinal Hormone / genetics*
  • Receptors, Gastrointestinal Hormone / metabolism
  • Receptors, Glucagon / genetics*
  • Receptors, Glucagon / metabolism
  • Signal Transduction
  • TCF Transcription Factors / genetics
  • TCF Transcription Factors / metabolism*
  • Transcription Factor 7-Like 2 Protein


  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Insulin
  • Receptors, Gastrointestinal Hormone
  • Receptors, Glucagon
  • TCF Transcription Factors
  • TCF7L2 protein, human
  • Tcf7l2 protein, mouse
  • Tcf7l2 protein, rat
  • Transcription Factor 7-Like 2 Protein
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1
  • gastric inhibitory polypeptide receptor