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Cellular aberrations associated with insulin resistance in people without diabetes

Researchers have discovered a large network of cellular alterations in people with insulin resistance but without diabetes. Insulin resistance is a major risk factor for the development of metabolic syndrome and type 2 diabetes, and the impact of insulin resistance on metabolic syndrome is well studied. However, many people without diabetes have insulin resistance, and the molecular determinants underlying this remain elusive.

In this study, researchers generated myocytes—a type of muscle cell that absorbs glucose (sugar) in response to insulin—from blood samples of 20 individuals without diabetes over the range of insulin sensitivity. Ten individuals had insulin resistance (I-res), while the others had insulin sensitivity (I-sen), and both groups were equally divided between men and women. I-res individuals had elevated blood glucose levels compared to their I-sen counterparts, and an assessment of insulin-stimulated glucose uptake by the laboratory-grown myocytes showed this was significantly impaired in I-res cells compared to I-sen cells. Next, the team analyzed the spectrum of cellular signaling changes among these samples. The results indicated large differences in molecular signatures in cells based on I-res status and that many of the alterations in these I-res cells overlapped with alterations observed in cells from individuals with type 2 diabetes in a previous study by the same group. Many of these alterations were found in biological pathways not previously known to be involved in insulin signaling. Moreover, the researchers found striking molecular differences between cells from men and women, many of which occur in diabetes and could contribute to sex-specific differences in physiology and disease.

These findings point to critical points of regulation of cellular processes in insulin resistance that can potentially serve as novel sites for future therapeutic development. Further research is needed to clarify how sex-specific differences in molecular signatures affect normal physiology and the risk of metabolic disease between men and women.

Haider N, Lebastchi J, Jayavelu AK,…Kahn CR. Signaling defects associated with insulin resistance in nondiabetic and diabetic individuals and modification by sex. J Clin Invest 131: e151818, 2021.

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