Skeletal muscle insulin resistance is a prominent feature of type 2 diabetes (T2D) that precedes and predicts the development of disease in high risk populations. In individuals with T2D or pre-T2D, this insulin resistance is due, at least in part, to a decrease in the number of functional insulin receptors (IR) that localize on the cell membrane. To restore the number of IR, we generated mice that specifically overexpress IR in skeletal muscle (IRMOE). On chow diet, IRMOE mice had similar body weight compared to control, but displayed reduced body fat and higher lean mass percentage. Basal phosphorylation of IR, IRS and Akt were significantly higher in muscles from IRMOE mice compared to control, resulting in their improved glucose tolerance. Surprisingly, however, after i.v. injection of insulin, stimulated Akt phosphorylation was significantly lower in IRMOE muscle compared to control, despite persistent higher phosphorylation in IR and IRS, indicating activation of negative regulators in the IR signaling pathway when IR is chronically activated. Consistent with this, euglycemic-hyperinsulinemic clamp studies revealed significantly lower glucose infusion rate in insulin stimulated IRMOE mice compared to control. Increased basal and decreased insulin stimulated Akt phosphorylation was also observed in muscles of IRMOE mice after challenge with HFD. However, when fed HFD, IRMOE mice displayed both improved glucose tolerance and insulin tolerance which was in part due to being resistant to diet-induced obesity, despite consuming more calories. Taken together, these data indicate that muscle specific IR overexpression can protect mice from diet-induced obesity and its effects on glucose metabolism, but that chronic overexpression of IR can lead to post-receptor desensitization indicating additional post-receptor regulators of insulin signaling, which could provide new targets for therapy of T2D.
G. Wang: None. W. Cai: None. T.M. Batista: None. S. Softic: None. C. Kahn: Advisory Panel; Self; MedImmune. Board Member; Self; Kaleido Biosciences. Consultant; Self; AntriaBio, Inc., Cobalt Therapeutics, Flagship Pioneering. Research Support; Self; Alnylam.
American Diabetes Association (9-17-CMF-016 to G.W.)