More than one in four adults with type‑2 diabetes take medicines that act on the GLP‑1 receptor. These drugs, such as Ozempic and Wegovy, are popular for lowering blood sugar and helping with weight loss.
Scientists at Stanford Medicine and several international partners have found that the drugs do not work well for everyone. Roughly 10 % of the population carries special genetic changes that create a condition called GLP‑1 resistance. People with this condition have higher levels of the natural hormone GLP‑1, but the hormone cannot lower blood sugar as it should.
The researchers published their findings on March 29 in Genome Medicine. The study combined experiments in people, mouse models, and large clinical‑trial datasets, covering more than a decade of work.
PAM Gene Variants Lead to Resistance
The focus was on two tiny changes in the PAM gene. PAM makes an enzyme that fine‑tunes many hormones, including GLP‑1. When PAM does not work properly, hormones may not become fully active.
Earlier studies showed that PAM variants are more common in people with diabetes and can reduce insulin release. The new work asked whether these variants also interfere with GLP‑1’s ability to control blood sugar after a meal.
To test this, volunteers without diabetes drank a sugary drink while researchers measured their blood every five minutes for four hours. Some participants carried the PAM change called p.S539W.
Surprisingly, those with the PAM variant had **higher** GLP‑1 levels, not lower. Even though more hormone was present, it did not act stronger. The extra GLP‑1 could not lower blood sugar faster, showing that the body was resistant to the hormone.
Mouse Experiments Confirm the Pattern
Scientists in Zurich studied mice that completely lack the PAM gene. These mice also showed high GLP‑1 levels but poor blood‑sugar control, mirroring the human findings.
One important job of GLP‑1 is to slow how quickly food leaves the stomach. In PAM‑deficient mice, food moved through the stomach faster, and GLP‑1 drugs could not slow it down.
Further work in Copenhagen showed that the PAM defect does not change how GLP‑1 binds to its receptor. The problem appears later in the signaling chain, leading to resistance.
Clinical Trial Data Reveal Lower Success Rates
The team examined three large trials that included 1,119 people with diabetes. Participants who carried PAM variants were less likely to reach the recommended HbA1c target after six months of GLP‑1 therapy.
About 25 % of patients without the variant hit the goal, compared with 11.5 % for the p.S539W group and 18.5 % for the p.D563G group.
These genetic differences did not affect responses to other diabetes medicines such as metformin, sulfonylureas, or DPP‑4 inhibitors, indicating that the resistance is specific to GLP‑1 drugs.
Two additional industry‑sponsored trials using longer‑acting GLP‑1 formulations showed no clear difference between carriers and non‑carriers, suggesting that extended‑release drugs might bypass the resistance.
What We Still Don't Know
Scientists first noticed hints of GLP‑1 resistance almost ten years ago, before the drugs became popular for weight loss. Limited data on body‑weight outcomes make it hard to know if the PAM variants also affect weight loss.
More genetic information from clinical studies could help explain why some patients are poor responders, but accessing that data remains difficult.
Even though the exact biological reason for GLP‑1 resistance is still a mystery, researchers hope that new drug designs or longer‑acting versions will improve outcomes for affected patients.
The study was supported by Wellcome, the Medical Research Council, the European Union Horizon 2020 programme, the U.S. National Institutes of Health, the National Institute for Health Research Oxford Biomedical Research Centre, the Canadian Institutes of Health Research, the Novo Nordisk Foundation, Boehringer Ingelheim, and Diabetes Australia.