Differential Role of Insulin/IGF-1 Receptor Signaling in Muscle Growth and Glucose Homeostasis
Year: 2015
Type: article
Abstract: Insulin and insulin-like growth factor 1 (IGF-1) are major regulators of muscle protein and glucose homeostasis. To determine how these pathways interact, we generated mice with muscle-specific knockout of IGF-1 receptor (IGF1R) and insulin receptor (IR). These MIGIRKO mice showed >60% decrease in muscle mass. Despite a complete lack of insulin/IGF-1 signaling in muscle, MIGIRKO mice displayed normal glucose and insulin tolerance. Indeed, MIGIRKO mice showed fasting hypoglycemia and increased basal glucose uptake. This was secondary to decreased TBC1D1 resulting in increased Glut4 and Glut1 membrane localization. Interestingly, overexpression of a dominant-negative IGF1R in muscle induced glucose intolerance in MIGIRKO animals. Thus, loss of insulin/IGF-1 signaling impairs muscle growth, but not whole-body glucose tolerance due to increased membrane localization of glucose transporters. Nonetheless, presence of a dominant-negative receptor, even in the absence of functional IR/IGF1R, induces glucose intolerance, indicating that interactions between these receptors and other proteins in muscle can impair glucose homeostasis.
Source: Cell Reports
Institutions: Joslin Diabetes Center, Harvard University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: Mayo Clinic, Joslin Diabetes Center, Georgia Clinical and Translational Science Alliance, National Institutes of Health, Diabetes Research Center, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences, Common Fund
Awards: Insulin Receptor Structure and Turnover, Exercise and Skeletal Muscle Signaling Mechanisms, Insulin Receptor Structure and Turnover, Mayo Clinic Center for Clinical and Translational Science (CCaTS), Insulin Receptor Substrates and Insulin Action, Mayo Clinic Metabolomics Resource Core, Regulation of Muscle Autophagy and Mitophagy by Insulin and IGF-1 Signaling, Training Grant in Diabetes and Metabolism, Diabetes Research Center
OpenAlex ID: W1578864848