Researchers say genetic variants in the PAM gene may help explain why some people with Type 2 diabetes get less blood-sugar benefit from GLP-1 receptor agonist drugs such as Ozempic, a phenomenon they describe as “GLP-1 resistance.”
A study reported by Stanford Medicine and published in Genome Medicine says some people carry genetic variants that appear to make their bodies less responsive to the hormone GLP-1 (glucagon-like peptide-1), even though their circulating GLP-1 levels are higher. The research focused on two PAM (peptidyl-glycine alpha-amidating monooxygenase) variants, including p.S539W and p.D563G, which reduce the activity of an enzyme involved in activating multiple hormones, including GLP-1. In a human experiment described by the researchers, participants with the p.S539W variant showed increased GLP-1 levels after a glucose drink but did not show evidence of greater GLP-1 biological activity, consistent with what the team calls GLP-1 resistance. To test whether this resistance translated to treatment outcomes, the researchers analyzed data from three clinical trials involving 1,119 participants with diabetes taking GLP-1 receptor agonists. After six months of treatment, about a quarter of non-carriers reached the recommended HbA1c target, compared with 11.5% of participants with the p.S539W variant and 18.5% of participants with the p.D563G variant. The team also reported supportive findings in mice lacking the PAM gene, including higher GLP-1 levels alongside weaker glucose regulation and a diminished effect of GLP-1 drugs on gastric emptying—an effect often linked to both glucose control and weight loss. However, the researchers said the underlying biological mechanism for GLP-1 resistance has not been pinned down. Senior author Anna Gloyn, a professor at Stanford Medicine, said the results could help move diabetes care toward more personalized treatment choices—particularly if clinicians can identify likely non-responders earlier. The researchers also said the PAM variants did not appear to change responses to several other common diabetes medications, including metformin, sulfonylureas and DPP-4 inhibitor drugs. They added that two separate, company-funded trials not included in the meta-analysis produced different results, with similar responses in carriers and non-carriers, potentially because those studies used longer-acting GLP-1 receptor agonists.
