Personalized phosphoproteomics of skeletal muscle insulin resistance and exercise links MINDY1 to insulin action.

Type 2 diabetes is preceded by a defective insulin response, yet our knowledge of the precise mechanisms is incomplete. Here, we investigate how insulin resistance alters skeletal muscle signaling and how exercise partially counteracts this effect. We measured parallel phenotypes and phosphoproteomes of insulin-resistant (IR) and insulin-sensitive (IS) men as they responded to exercise and insulin (n = 19, 114 biopsies), quantifying over 12,000 phosphopeptides in each biopsy. Insulin resistance involves selective and time-dependent alterations to signaling, including reduced insulin-stimulated mTORC1 and non-canonical signaling responses. Prior exercise promotes insulin sensitivity even in IR individuals by "priming" a portion of insulin signaling prior to insulin infusion. This includes MINDY1 S441, which we show is an AKT substrate. We found that MINDY1 knockdown enhances insulin-stimulated glucose uptake in rat myotubes. This work delineates the signaling alterations in IR skeletal muscle and identifies MINDY1 as a regulator of insulin action.