GLP-1 receptor agonists like Wegovy (semaglutide) and Mounjaro (tirzepatide) have fundamentally reshaped the treatment of diabetes and obesity. Yet, clinicians have long noted a significant gap in outcomes: while some patients see transformative weight loss and blood sugar stabilization, others experience unexpectedly modest results.
A new international study has identified a genetic culprit behind this disparity. Researchers suggest that a specific subset of the population—estimated at roughly 10%—may possess "GLP-1 resistance." In these individuals, the body may actually produce higher levels of the GLP-1 hormone but remains fundamentally less sensitive to its signaling.
The findings were published on March 29, 2026, in Genome Medicine, featuring contributions from Professor Anna L. Gloyn of the Stanford School of Medicine and Professor Markus Stoffel of ETH Zurich.
The PAM Gene: The body’s broken signal receiver
GLP-1 is a hormone secreted by the gut that regulates blood sugar by promoting insulin secretion and slowing gastric emptying. Drugs like Ozempic, Wegovy, and Mounjaro mimic this hormone to achieve their therapeutic effects. However, if the body’s internal "receiver" for this signal is compromised, the medication cannot perform as intended.
The study focused on the PAM (peptidyl-glycine alpha-amidating monooxygenase) gene, which encodes an enzyme vital for the proper functioning of various hormones, including GLP-1. Researchers identified two specific variants—p.S539W and p.p.D563G—that weaken the PAM enzyme. In carriers of these variants, the body fails to respond appropriately to GLP-1 signaling.
Interestingly, these individuals often have high natural levels of GLP-1 in their blood, yet they do not benefit from the hormone's typical glucose-lowering effects. This state of high supply but low impact is what the researchers define as "GLP-1 resistance."
Weaker real-world responses in humans and mice
To validate the genetic link, the team conducted parallel experiments in humans and animal models. In mice where the PAM gene was "knocked out," the typical effects of GLP-1—such as delayed gastric emptying—were significantly diminished. This confirmed that the issue lies not in a lack of receptors, but in the "downstream" signal transduction that happens after the hormone binds to its target.
Human data told a similar story. Analyzing clinical trials involving 1,119 patients with diabetes, the researchers found that those with PAM variants showed a slower decline in blood sugar when using GLP-1 drugs. These patients were also less likely to reach their target HbA1c levels—a key marker of long-term glucose control.
Notably, this resistance appeared specific to GLP-1 therapies. When these same patients were given other diabetes medications, such as metformin or DPP-4 inhibitors, the PAM variants did not seem to hinder the drugs' effectiveness.
A path toward personalized obesity treatment
While the study focused primarily on blood sugar regulation, the implications for obesity treatment are profound. Though more data is needed to confirm a direct link between PAM variants and weight-loss plateaus, the study provides the first concrete biological explanation for why some patients are "non-responders."
The discovery suggests that a patient's struggle to lose weight on Wegovy or Mounjaro may not be a matter of willpower or lifestyle habits, but rather a reflection of their genetic blueprint.
As the medical community moves further into the era of GLP-1 therapies, the PAM gene may become a critical marker for personalized medicine. Instead of a "trial and error" approach, genetic screening could eventually help doctors identify which patients will thrive on GLP-1s and which might be better served by alternative treatments from the start.
*Source paper: Type 2 diabetes risk alleles in peptidyl-glycine alpha-amidating monooxygenase influence GLP-1 levels and response to GLP-1 receptor agonists. Genome Medicine, 2026; DOI: 10.1186/s13073-026-01630-0.
