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Muscle-Specific Insulin Receptor Overexpression Protects Mice From Diet-Induced
Glucose Intolerance but Leads to Postreceptor Insulin Resistance.
Wang G, Yu Y, Cai W, Batista TM, Suk S, Noh HL, Hirshman M, Nigro P, Li ME,
Softic S, Goodyear L, Kim JK, Kahn CR
Submitted Externally on 11/10/2020
Volume : Pages
69 : 2294 - 2309
Skeletal muscle insulin resistance is a prominent early feature in the
pathogenesis of type 2 diabetes. In attempt to overcome this defect, we
generated mice overexpressing insulin receptors (IR) specifically in skeletal
muscle (IRMOE). On normal chow, IRMOE mice have body weight similar to that of
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 with 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 postreceptor
insulin resistance. RNA sequencing reveals downregulation of several
postreceptor signaling proteins that contribute to this resistance. Thus,
enhancing early insulin signaling in muscle by overexpression of the IR protects
mice from diet-induced obesity and its effects on glucose metabolism. However,
chronic overstimulation of this pathway leads to postreceptor desensitization,
indicating the critical balance between normal signaling and hyperstimulation of
the insulin signaling pathway.
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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
) under the MICROMouse Program, grants DK076169.
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