LRP6 enhances glucose metabolism by promoting TCF7L2-dependent insulin receptor expression and IGF receptor stabilization in humans

Cell Metab. 2013 Feb 5;17(2):197-209. doi: 10.1016/j.cmet.2013.01.009.

Abstract

Common genetic variations in Wnt signaling genes have been associated with metabolic syndrome and diabetes by mechanisms that are poorly understood. A rare nonconservative mutation in Wnt coreceptor LRP6 (LRP6(R611C)) has been shown to underlie autosomal dominant early onset coronary artery disease, type 2 diabetes, and metabolic syndrome. We examined the interplay between Wnt and insulin signaling pathways in skeletal muscle and skin fibroblasts of healthy nondiabetic LRP6(R611C) mutation carriers. LRP6 mutation carriers exhibited hyperinsulinemia and reduced insulin sensitivity compared to noncarrier relatives in response to oral glucose ingestion, which correlated with a significant decline in tissue expression of the insulin receptor and insulin signaling activity. Further investigations showed that the LRP6(R611C) mutation diminishes TCF7L2-dependent transcription of the IR while it increases the stability of IGFR and enhances mTORC1 activity. These findings identify the Wnt/LRP6/TCF7L2 axis as a regulator of glucose metabolism and a potential therapeutic target for insulin resistance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3T3-L1 Cells
  • Animals
  • Cells, Cultured
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Knockdown Techniques
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • Humans
  • Insulin / pharmacology
  • Insulin Receptor Substrate Proteins / metabolism
  • Low Density Lipoprotein Receptor-Related Protein-6 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-6 / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Models, Biological
  • Multiprotein Complexes / metabolism
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Mutation / genetics
  • Phosphoserine / metabolism
  • Protein Stability / drug effects
  • Receptor, IGF Type 1 / metabolism*
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism*
  • Skin / cytology
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factor 7-Like 2 Protein / metabolism*
  • Transcription, Genetic / drug effects
  • Wnt Signaling Pathway / drug effects

Substances

  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Multiprotein Complexes
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein
  • Phosphoserine
  • TOR Serine-Threonine Kinases
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • Mechanistic Target of Rapamycin Complex 1
  • Glucose