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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 2020-08-31, 18:21 authored by Ada AdminAda 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 KahnSkeletal 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.