LRP6 enhances glucose metabolism by promoting TCF7L2-dependent insulin receptor expression and IGF receptor stabilization in humans
| Autor: | Detlef Wencker, Masoud Sotoudeh, Robert S. Sherwin, Reza Malekzadeh, Arya Mani, Renata Belfort de Aguiar, Rajvir Singh, Sarita Naik, Sheida Mani, Kamal Ostadsharif |
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| Rok vydání: | 2012 |
| Předmět: |
Transcription
Genetic Physiology medicine.medical_treatment Receptor IGF Type 1 Mice Phosphoserine 0302 clinical medicine Hyperinsulinemia Insulin Wnt Signaling Pathway Cells Cultured Skin 0303 health sciences biology Protein Stability TOR Serine-Threonine Kinases Wnt signaling pathway LRP6 Gene Knockdown Techniques Low Density Lipoprotein Receptor-Related Protein-6 Transcription Factor 7-Like 2 Protein medicine.medical_specialty Insulin Receptor Substrate Proteins 030209 endocrinology & metabolism Mechanistic Target of Rapamycin Complex 1 Models Biological Article 03 medical and health sciences Insulin resistance Internal medicine 3T3-L1 Cells medicine Animals Humans Muscle Skeletal Molecular Biology 030304 developmental biology Insulin-like growth factor 1 receptor Cell Biology Fibroblasts Glucose Tolerance Test medicine.disease Receptor Insulin Insulin receptor Endocrinology Glucose Multiprotein Complexes Mutation biology.protein |
| Zdroj: | Cell metabolism. 17(2) |
| ISSN: | 1932-7420 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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