期刊
CELL REPORTS
卷 11, 期 8, 页码 1220-1235出版社
CELL PRESS
DOI: 10.1016/j.celrep.2015.04.037
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资金
- NIH [R01 DK-031036, R01AR42238]
- NIDDK of the NIH [K08DK100543]
- Mayo Clinic Metabolomics Resource Core grant from the NIDDK [U24DK100469]
- Mayo Clinic CTSA grant from NCATS of the NIH [UL1 TR000135]
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.
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