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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.

SUBMITTER: Singh R

PROVIDER: S-EPMC3589523 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Project description:PurposeInsulin receptor (InsR) sensitizers represent a new type of therapeutic agent for the treatment of diabetes, with 2'-O-methylperlatolic acid (2-O-M) being a potential InsR targeting drug. The purpose of this study was to determine whether 2-O-M functions as an activator of the insulin signaling pathway, regulating glucose hemostasis through the InsR and exerting a glucose-lowering effect in an animal model of diabetes.MethodsSPR-based analyses were used to detect the binding of different concentrations of 2-O-M to the InsR. The protein levels of IR-β, p-IR, AKT, and p-AKT in Hepa and C2C12 cell lines and liver and muscle tissues were determined by western blotting. Glucose uptake capacity was determined in C2C12 cells. Streptozotocin-induced diabetic mice were randomly divided into four groups: the control, insulin treated, 2-O-M treated, and combined insulin and 2-O-M treated. Mice were injected with 2-O-M or normal saline and the average blood glucose concentration after 120 min, and the serum levels of insulin, glucagon, and C-peptide were measured. Next, qRT-PCR was performed to detect the mRNA expression of genes involved in lipid and glucose metabolism in the liver and muscle tissues.Results2-O-M binds to the extracellular domain of the InsR. Moreover, combination treatment with 2-O-M and insulin resulted in significant activation of the insulin signaling pathway in vitro and significant stimulation of the glucose uptake capacity of C2C12 myotubes. In mice with streptozotocin-induced diabetes, 2-O-M significantly prolonged the blood glucose-lowering effect of insulin, significantly reduced the secretion of exogenous insulin, and reduced the blood glucose concentration in vivo. In addition, treatment with 2-O-M alone significantly enhanced the phosphorylation of AKT in muscle tissue, which enhanced glucose uptake in C2C12 myotubes. Further, 2-O-M significantly increased glucagon secretion and enhanced liver gluconeogenesis to prevent hypoglycemia.Conclusion2-O-M enhances the hypoglycemic effect of insulin through the insulin signaling pathway and can be used as a complement to insulin. This synergetic effect may lower the required dose of insulin and protect β cells.

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

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