Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We have found that IR is incorporated into biomolecular condensates during the response to insulin stimulation and that the activity of IR in these condensates is altered in insulin resistance. In normal cells, insulin stimulation results in accumulation of IR in bodies that display dynamic molecular characteristics expected of liquid-like condensates. In insulin-resistant cells, both IR accumulation in condensates and the normal dynamic behavior of these condensates are reduced, suggesting a physico-mechanical link between insulin response and the dynamic molecular behavior of IR condensates. The observed defects in IR condensate behaviors are caused, at least in part, by an increase in oxidative stress in insulin-resistant cells, which is known to interfere with normal condensate dynamics. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue accumulation and dynamic behavior of IR condensates. This rescue corresponds with metformin’s effect of reducing the levels of reactive oxygen species. The observation that IR is incorporated into biomolecular condensates during the response to insulin stimulation, and evidence that changes in the physico-mechanical features of IR condensates contribute to insulin resistance, have implications for improved therapeutic approaches for patients.
A.Dall’agnese: Consultant; Dewpoint Therapeutics. J.Platt: None. T.Lee: None. J.F.Jeppesen: Employee; Novo Nordisk A/S. R.A.Young: Research Support; Novo Nordisk.