GLP-1 diabetes drugs may not work for about one in ten people

Researchers report that variants in the PAM enzyme are linked to reduced response to GLP-1–based diabetes medications in roughly 10% of people; study participants with a PAM variant had higher circulating GLP-1 but showed less blood‑sugar lowering, and the biological mechanism remains unknown.

Researchers report that genetic changes affecting the PAM enzyme appear to reduce how some people respond to GLP-1 receptor agonist diabetes medications. The team studied a PAM variant (including p.S539W) in adults without diabetes and in mouse models. People with the variant had higher measured GLP-1 after a glucose challenge but did not show stronger blood‑sugar lowering, a pattern the authors describe as resistance. The researchers confirmed the observation in multiple experiments but have not identified why the resistance occurs. Key findings: - Variants that impair the PAM enzyme (for example p.S539W) are associated with a reduced biological response to GLP-1–based medications. - People carrying the variant showed higher circulating GLP-1 after a glucose drink but required more GLP-1 to achieve the same blood‑sugar effect, consistent with resistance. - Mouse models lacking PAM showed similar signs of GLP-1 resistance, supporting the human observations. - The research team confirmed the results across several experiments but has not yet determined the exact biological mechanism. Summary: The study suggests that PAM-related genetic variants may help explain why some people do not respond as well to GLP-1 therapies, affecting an estimated one in ten individuals. Researchers say knowing who is likely to respond could shorten the time to an effective regimen and contribute to precision medicine, and laboratory and clinical studies to define the mechanism are ongoing. Undetermined at this time.