Changes in Insulin Receptor Condensates Contribute to Insulin Resistance

Numerous recent reports indicate components of diverse signaling pathways can form dynamic clusters that have the characteristics of biomolecular condensates—cellular compartments where proteins and nucleic acids concentrate without being physically delimited by a membrane. Condensates form at the plasma membrane and in the cytoplasm and nucleus.

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Jesse M. Platt, PhD, MD, practicing gastroenterologist and graduate assistant in the Division of Gastroenterology at Massachusetts General Hospital and research fellow in Medicine at Harvard Medical School, and colleagues have published evidence that insulin signaling, too, involves dynamic condensates. Dysregulation of the condensates contributes to insulin resistance, they report in Nature Communications, so altered condensates may represent targets for new drugs.

Principal Observations

The research team's key findings are the following:

• The insulin receptor (IR) was part of dynamic condensates at the plasma membrane of human hepatocytes and adipocytes, and in their cytoplasm and nucleus
• In insulin-sensitive hepatocytes, insulin stimulation promoted further incorporation of IR into these condensates
• In insulin-resistant cells, the ability of insulin stimulation to promote further IR incorporation into condensates was diminished, but metformin administration rescued IR condensate dynamics and insulin responsiveness
• Levels of reactive oxygen species (ROS) levels were higher in insulin-resistant cells than insulin-sensitive cells, and metformin treatment of insulin-resistant cells reduced ROS levels to those found in insulin-sensitive cells
• Treating insulin-sensitive cells with a concentration of hydrogen peroxide known to cause oxidative stress reduced the incorporation of IR into condensates with insulin stimulation, mimicking the IR condensate dysregulation seen in insulin-resistant cells
• Treating insulin-resistant cells with clinically relevant concentrations of N-acetyl cysteine partially rescued the dynamic behavior of IR condensates

Therapeutic Implications

The latter results suggest chronic hyperinsulinemia leads to excess levels of ROS in insulin-resistant hepatocytes and high levels of ROS alter IR incorporation into condensates. Metformin probably rescued the behavior of IR condensates in insulin-resistant cells because of its effects in reducing ROS levels.

The experiments described here might be leveraged to develop new diabetes therapies for patients who can't tolerate metformin or become resistant to the drug after prolonged use. Such drugs might also be beneficial in other settings where failure to control condensate properties leads to protein aggregation, which is often the cause of aging-associated diseases.

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