Tracking 12,000 Signals in Insulin-Resistant Muscle: Exercise 'Primes' the Signaling

A study that precisely maps how insulin resistance, which appears before type 2 diabetes, changes signaling inside muscle cells was published in Cell Metabolism. Researchers at the Charles Perkins Centre at the University of Sydney in Australia also presented a pathway by which exercise partly compensates for this defect.

114 biopsies, more than 12,000 phosphopeptides

The researchers took 114 skeletal muscle biopsies from 19 insulin-resistant and insulin-sensitive men while they responded to exercise and an insulin infusion. In each biopsy they ran a phosphoproteomics analysis, quantifying more than 12,000 phosphopeptides, which show the phosphorylation state of proteins.

Insulin resistance was not an even weakening of the whole signal but a selective disruption at particular pathways and time points. Insulin-induced mTORC1 signaling and non-canonical signaling responses were especially reduced. By contrast, prior exercise caused 'priming,' in which part of the signaling switches on before the insulin infusion even in people with insulin resistance, improving insulin sensitivity. Among these, serine 441 of the MINDY1 protein was identified as a substrate of the AKT enzyme, and reducing MINDY1 in mouse muscle cells increased glucose uptake in response to insulin stimulation.

A map of the mechanism, still far from a treatment target

The study is significant in that it directly mapped the signaling changes of muscle insulin resistance in human tissue. However, there were only 19 participants, all men, and no women were included. The functional validation of MINDY1 was limited to experiments in cultured mouse muscle cells, so it needs further confirmation that it plays the same role in the human body.