Researchers have identified a genetic variant in the insulin receptor gene that challenges conventional understanding of insulin resistance. The study, analyzing data from more than 458,000 participants in the UK Biobank, found that carriers of the INSR variant had a surprisingly favorable metabolic profile despite mild hyperinsulinemia.
The research team identified 524 carriers of the INSR variant through whole-genome sequencing. These individuals showed lower triglycerides, lower LDL cholesterol, and lower liver enzymes compared to non-carriers. They also had higher HDL cholesterol and no significant differences in BMI. Most notably, the carriers showed no excess risk of all-cause mortality.
The findings are set to be presented at the European Association for the Study of Diabetes annual meeting in Milan, Italy. There is currently no published paper; results will be shared during an oral presentation in September.
The Paradox of Insulin Resistance
Insulin resistance is typically associated with obesity, type 2 diabetes, and cardiovascular disease. However, some evidence in animal models suggests that reducing insulin signaling, particularly at the insulin receptor, can have beneficial effects on metabolism and aging.
Related: CTx-1301 and Centanafadine Show Promise for ADHD
The researchers hypothesize that mild, lifelong reduction in insulin receptor signaling may be biologically distinct from the more severe, acquired insulin resistance that develops in the context of obesity and metabolic disease. INSR variant carriers appear to compensate for reduced signaling by producing slightly more insulin, which may allow glucose regulation to be maintained.
Reduced insulin signaling could also alter downstream metabolic pathways involved in lipid metabolism, nutrient handling, or responses to metabolic stress in ways that prove beneficial. The lead researcher stressed, however, that the study identified only the association and tells researchers nothing about the underlying mechanism.
Expert Perspectives and Caveats
Dr. Tannaz Moin, a diabetes researcher at UCLA’s David Geffen School of Medicine, said she would like to see more details before drawing firm conclusions. “We have this understanding of insulin resistance, and there’s a lot of evidence to support that insulin resistance is not a good thing,” she said. “It’s not a good thing even in temporary states, like in pregnancy. Everything we know says this is bad.”
She noted that the abstract described “mild insulin resistance” but questions remain about how mild the condition actually was and whether there was variation over time. “We don’t really understand what the trajectory of this insulin resistance was,” she said. “And what else could be accompanying this variant?”
Related: British Open Winner Fox Returns Home for Sleep and Pie
Despite her concerns, Dr. Moin called the research interesting. “We want to always ask new questions and explore new hypotheses,” she said. “But I would say this: We need a lot more information about what they did here and how they did it.”
Next Steps for Research
The lead researcher, Jacques Murray Leech, a graduate research assistant in the Department of Clinical and Biomedical Science at the University of Exeter, noted that studying naturally occurring INSR variants allowed examination of insulin resistance outside the metabolic context of obesity and excess adiposity.
“Of course, we can’t possibly measure and adjust for every potential confounding factor,” he said. “That makes consistency across different datasets and populations particularly important. This is why we replicated our findings in independent cohorts, and why extending this work to larger and more genetically diverse populations will be an important next step.”
The researchers say their findings add to growing evidence that the effects of insulin resistance may depend on its underlying cause, the tissues involved, its severity, and how long it has been present. More research will be needed to validate these findings and understand the mechanisms at play.