Differential Role of Insulin/IGF-1 Receptor Signaling in Muscle Growth and Glucose Homeostasis

•Insulin receptors (IRs) and IGF-1 receptors (IGF1Rs) are required for muscle growth•Deletion of muscle IRs/IGF1Rs is not sufficient to impair glucose tolerance•Loss of IRs/IGF1Rs in muscle increases Glut4 and glucose uptake via decreased TBC1D1•A dominant-negative IGF1R impairs glucose tolerance, even without functional IRs/IGF1Rs

SummaryInsulin 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.

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