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Muscle Specific Insulin Receptor Overexpression Protects Mice from Diet-Induced Glucose Intolerance but Leads to Post-Receptor Insulin Resistance

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posted on 31.08.2020 by Ada Admin, Guoxiao Wang, Yingying Yu, Weikang Cai, Thiago M. Batista, Sujin Suk, Hye Lim Noh, Michael Hirshman, Pasquale Nigro, Mengyao Ella Li, Samir Softic, Laurie Goodyear, Jason K. Kim, C. Ronald Kahn
Skeletal muscle insulin resistance is a prominent early feature in the pathogenesis of type 2 diabetes (T2D). In attempt to overcome this defect, we generated mice overexpressing insulin receptors (IR) specifically in skeletal muscle (IRMOE). On normal chow, IRMOE mice have similar body weight as controls, but an increase in lean mass and glycolytic muscle fibers and reduced fat mass. IRMOE mice also show higher basal phosphorylation of IR, IRS-1 and Akt in muscle and improved glucose tolerance compared to controls. When challenged with high fat diet (HFD), IRMOE mice are protected from diet-induced obesity. This is associated with reduced inflammation in fat and liver, improved glucose tolerance and improved systemic insulin sensitivity. Surprisingly, however, in both chow and HFD-fed mice, insulin stimulated Akt phosphorylation is significantly reduced in muscle of IRMOE mice, indicating post-receptor insulin resistance. RNA sequencing reveals downregulation of several post-receptor signaling proteins that contribute to this resistance. Thus, enhancing early insulin signaling in muscle by overexpression of the insulin receptor protects mice from diet-induced obesity and its effects on glucose metabolism. However, chronic overstimulation of this pathway leads to post-receptor desensitization, indicating the critical balance between normal signaling and hyperstimulation of the insulin signaling pathway.

Funding

This project was funded by ADA postdoc fellowship to G.W. (1-18-PDF-171), NIH grants R01DK031036 to C.R.K and R01DK101043 to L.J.G., the Joslin DRC Grant P30DK036836, and the Mary K. Iacocca Professorship (to C.R.K.). W.C. was supported by NIH grants K01 DK120740 and P30 DK057521-20. Part of this study was performed at the National Mouse Metabolic Phenotyping Center at UMass supported by NIH grant 5U2C-DK093000 to J.K.K.

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