title: LRP6 enhances glucose metabolism by promoting TCF7L2-dependent insulin receptor expression and IGF receptor stabilization in humans.
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.
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors: Rajvir
authors: R
authors: Singh
authors: Renata Belfort
authors: RB
authors: De Aguiar
authors: Sarita
authors: S
authors: Naik
authors: Sheida
authors: S
authors: Mani
authors: Kamal
authors: K
authors: Ostadsharif
authors: Detlef
authors: D
authors: Wencker
authors: Masoud
authors: M
authors: Sotoudeh
authors: Reza
authors: R
authors: Malekzadeh
authors: Robert S
authors: RS
authors: Sherwin
authors: Arya
authors: A
authors: Mani
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010768:Phosphoserine / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000166:cytology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D046912:Multiprotein Complexes; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D010768:Phosphoserine; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
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