More than a quarter of people with type 2 diabetes take GLP-1 receptor agonists, but common diabetes drugs may be less effective for people with certain genetic mutations, according to a new study by Stanford Medicine scientists and their collaborators.
This genetic mutation, carried by about 10% of the general population, causes a surprising and still mysterious phenomenon that researchers call GLP-1 resistance. This phenomenon results in high levels of the hormone GLP-1 (glucagon-like peptide-1), which helps regulate blood sugar, but with low biological efficacy.
It’s unclear whether the variant will affect weight loss from drugs such as Ozempic and Wigovy, which are increasingly prescribed to treat obesity. These are usually taken in higher doses for weight loss than for diabetes.
The new study was published on March 29th. genomic medicinefocused on regulating blood sugar levels. This was a 10-year international effort that included experiments in humans and mice and analysis of data from diabetes drug trials.
Some trials have found that people with these mutations are unable to effectively lower their blood sugar levels even after six months of treatment. ”
Anna Grohn, DPhil, professor of pediatrics and genetics and one of the study’s senior authors
At that point, the doctor will likely change the patient’s medication regimen. Knowing in advance who is likely to react would allow patients to get the right medication sooner, a step toward precision medicine, Grohn said.
The other senior author is Markus Stoffel, MD, professor of metabolic diseases at the Institute of Molecular Health Sciences at the Swiss Federal Institute of Technology Zurich. The study’s lead authors are Dr. Mahesh Umapathishivam, MBBS, DPhil, an endocrinologist and clinical researcher at the University of Adelaide in Australia and a former resident of Grown, and Dr. Elisa Araldi, MBBS, DPhil, an associate professor of medicine and surgery at the University of Parma in Italy and a former trainee of Stoffel.
“When we treat patients in diabetes clinics, we see wide variation in response to these GLP-1-based drugs, but this response is difficult to predict clinically,” Umapathysivam said. “This is the first step toward being able to use someone’s genetic makeup to improve their decision-making process.”
This study is the first detailed look at GLP-1 resistance, but researchers have not yet determined the mechanism.
“That’s the million-dollar question,” Guinn said. “We ticked off this huge list of all the ways we thought GLP-1 resistance could occur. No matter what we did, we couldn’t figure out exactly why GLP-1 resistance occurred.”
unexpected resistance
The researchers focused on two genetic mutations that impair an enzyme known as PAM (peptidylglycine alpha amidation monooxygenase), which has the unique ability to activate many hormones in the body, including GLP-1.
“PAM is a really attractive enzyme because it is the only enzyme that can perform a chemical process called amidation, which increases the half-life and potency of biologically active peptides,” Groin said.
“We thought that if there was a problem with this enzyme, there might be different aspects of biology that weren’t working properly.”
In fact, PAM variants are known to be more prevalent in diabetic patients. Dr. Groen has shown that they impair insulin release from the pancreas. The researchers suspected that this genetic defect might also affect GLP-1, a gut hormone that plays a key role in regulating blood sugar levels after meals, by stimulating insulin release, slowing stomach emptying, and reducing appetite. GLP-1 receptor agonists work by mimicking this hormone.
They recruited adult participants with and without the PAM variant known as p.S539W, gave them a sugary solution, and then measured their blood every five minutes over the next four hours. (They studied participants without diabetes, as diabetes introduces an additional confounding variable.)
The researchers thought that people with the PAM mutation might have lower levels of GLP-1 in their blood, perhaps because the non-amidated form is less stable.
“What we actually observed was that their GLP-1 levels were increasing,” Groin said. “This was the exact opposite of what we imagined we would find.”
“Even though people with the PAM mutation had higher circulating levels of GLP-1, we saw no evidence of higher biological activity. They did not lower blood sugar levels faster; they needed more GLP-1 to achieve the same biological effect, meaning they were resistant to GLP-1.”
asking for confirmation
The results were so surprising that Gwinn’s team spent the next several years confirming them.
“We couldn’t figure this out, so we looked at as many different methods as we could to see if this was really a solid observation,” she said.
They collaborated with researchers in Zurich who were working on a mouse model in which the PAM gene was knocked out. The mice also showed signs of GLP-1 resistance, increased levels of GLP-1 that don’t help regulate blood sugar.
An important function of GLP-1 and drugs that mimic it is to slow the passage of food through the stomach, known as gastric emptying, which helps with both glucose regulation and weight loss. Researchers found that mice lacking the PAM gene had faster gastric emptying. Treatment of mice with a GLP-1 receptor agonist did not slow gastric emptying.
We also observed a reduced response to GLP-1 in the pancreas and intestines of these mice, indicating GLP-1 resistance, although there was no change in GLP-1 receptor expression in these tissues.
Working with researchers in Copenhagen, they showed that loss of PAM does not change the GLP-1 receptor’s ability to bind GLP-1 or the way the hormone signals through the receptor. This suggests that GLP-1 resistance emerges further downstream.
Results may vary
To see whether GLP-1 resistance reflected therapeutic differences, researchers looked at data from several clinical trials of GLP-1 receptor agonists in diabetic patients. A meta-analysis of three trials with a total of 1,119 participants found that people with PAM mutations were less responsive to drugs and less successful in lowering their HbA1c, a measure of average blood sugar levels. About a quarter of noncarriers reached the recommended HbA1c target after 6 months of treatment, compared with 11.5% of participants with the p.S539W variant and 18.5% of participants with the p.D563G variant.
Participants with the mutation did not respond differently to other common diabetes treatments such as sulfonylureas, metformin, and DPP-4i.
“What was really impressive was that having the mutation had no effect on response to other types of diabetes drugs,” Groin said. “We can see very clearly that this is unique to drugs that work through the pharmacology of the GLP-1 receptor.”
In two other drug company-funded clinical trials that were not included in the meta-analysis due to methodological differences, drug responses were similar between carriers and non-carriers. These trials used longer-acting GLP-1 receptor agonists, which may help counter GLP-1 resistance, Groin said.
complex puzzle
Gloyn’s team first observed GLP-1 resistance nearly a decade ago, before there was an explosion of interest in GLP-1 receptor agonists as weight-loss drugs. Only two of the clinical trials analyzed in the study provided weight data, and while there was no difference in weight loss between patients with and without PAM mutations, Groin said the data were too limited to be conclusive.
There is likely a wealth of clinical trial data on how genetics influence various responses to GLP-1 receptor agonists, including weight loss, but that data is difficult to obtain.
“It’s very common for pharmaceutical companies to collect genetic data on participants,” she says. “For new GLP-1 therapeutics, testing whether genetic mutations, such as PAM variants, exist may help explain poor response to the drug.”
For now, Groin said, the mechanisms that cause GLP-1 resistance remain unresolved, but are likely complex and multifactorial. She likens this phenomenon to insulin resistance, which is still not fully understood decades after its discovery. Nevertheless, scientists have discovered a way to treat insulin resistance.
“There are many drugs that improve insulin resistance, so we may be able to develop drugs that sensitize people to GLP-1, or find formulations of GLP-1, such as long-acting forms, that circumvent GLP-1 resistance,” she said.
Researchers from the University of Oxford, University of Dundee, University of Copenhagen, University of British Columbia, Churchill Hospital, University of Newcastle, University of Bath and University of Exeter also contributed to the study.
This research received funding from Wellcome, the Medical Research Council, the European Union Horizon 2020 program, the National Institutes of Health (grants U01-DK105535, U01-DK085545 and UM-1DK126185), the National Institutes of Health Oxford Biomedical Research Centre, the Canadian Institutes of Health Research, the Novo Nordisk Foundation, Boehringer Ingelheim and Diabetes. Australia.
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Reference magazines:
Umapathishivam, MM, others. (2026). Type 2 diabetes risk alleles of peptidylglycine alpha amidation monooxygenase influence GLP-1 levels and response to GLP-1 receptor agonists. genomic medicine. DOI: 10.1186/s13073-026-01630-0. https://link.springer.com/article/10.1186/s13073-026-01630-0
