Rare insulin receptor gene variants may protect against metabolic disease, study suggests

Research presented at the European Association for the Study of Diabetes indicates that certain inherited insulin receptor mutations could be associated with a healthier cardiometabolic profile, challenging traditional notions of insulin resistance as solely harmful.

A rare inherited form of insulin resistance may not be the metabolic bad actor scientists have long assumed. According to research due to be presented at the European Association for the Study of Diabetes annual meeting, adults carrying a damaging variant in the insulin receptor gene appeared to have a healthier cardiometabolic profile than non-carriers, despite showing signs of mild insulin resistance.

The findings, reported by Healio, centred on heterozygous variants in the INSR gene, which encodes the insulin receptor and helps regulate blood glucose by allowing cells to take up sugar from the bloodstream. As the National Center for Biotechnology Information explains, changes in this gene are known to cause severe insulin-resistance syndromes in rare cases, although the Exeter-led study focused on a milder, lifelong impairment that is separate from obesity.

Jacques Murray Leech, a graduate research assistant at the University of Exeter, said the team analysed whole-genome sequencing data from 458,784 adults in the UK Biobank and identified 524 carriers of INSR variants. Those participants had slightly higher insulin levels, but also lower triglycerides, lower LDL cholesterol, lower liver enzymes, a lower waist-to-hip ratio and higher HDL cholesterol, with no meaningful difference in body mass index. The pattern was seen across BMI groups and was also observed in the All of Us Biobank.

The UK Biobank analysis found no clear difference in risk of diabetes, cardiovascular disease, cancer or all-cause mortality between carriers and non-carriers. Leech said the results suggest insulin resistance may be a more varied condition than clinicians traditionally treat it as, and could point to biological pathways that are relatively benign or even protective. The researchers said larger and more diverse studies will be needed before any clinical implications can be drawn.