GLP-1 medications aren’t effective for everyone. According to new research published in Genome Medicine, around 1 in 10 people carry a genetic variant that makes them resistant to the popular diabetes medications, but researchers aren’t sure why.
An enzyme called PAM is responsible for helping to synthesize GLP-1 and increasing its longevity by adding an amide group in a process known as amidation. But for the unlucky 10 percent with one of the two defective variants, this process is stalled, and the carriers show higher rates of diabetes.
“PAM is a truly fascinating enzyme because it’s the only enzyme we have that’s capable of a chemical process called amidation, which increases the half-life or the potency of biologically active peptides,” study author Anna Gloyn of Stanford University said in a statement. “We thought, if you have a problem with this enzyme, there’s going to be multiple aspects of your biology that are not working properly.”
To find out, researchers recruited healthy adults with and without a flawed PAM variant, fed them a sugary drink, and took blood samples at five-minute increments for four hours. Because they believed the unamidated form of GLP-1 would be less stable, researchers expected to find lower levels of the hormone. What they discovered surprised them. “What we actually saw was they had increased levels of GLP-1,” Gloyn said. “This was the opposite of what we imagined we would find.”
In another mystery, the higher levels of GLP-1 weren’t translating into lower blood sugar. “Despite people with the PAM variant having higher circulating levels of GLP-1, we saw no evidence of higher biological activity,” Gloyn said. “They were not reducing their blood sugar levels more quickly. More GLP-1 was needed to have the same biological effect, meaning they were resistant to GLP-1.”
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The researchers then looked at differences in people with diabetes. A review of three clinical trials of GLP-1 medications in people with diabetes revealed that those with PAM defects struggled to lower their average blood sugar levels as well. Interestingly, there was no difference in how they responded to other common diabetes treatments.
“What was really striking was that we saw no effect from whether you have a variant on your response to other types of diabetes medications,” Gloyn said. “We can see very clearly that this is specific to medications that are working through GLP-1 receptor pharmacology.”
So what’s going on?
That answer remains a mystery. Research in mice with no PAM activity showed similar signs of GLP-1 resistance—high GLP-1 levels paired with high blood sugar levels. But an investigation into the possible mechanism discovered no issues with GLP-1 binding to its receptor, indicating a cryptic problem somewhere downstream.
What’s also unclear is whether the weight loss effects of GLP-1s are attenuated in otherwise healthy people with the deficient PAM variant. Only two of the trials in the study tracked weight, and although they showed no differences in weight loss among the groups, researchers believe the data is too limited to draw conclusions.
Despite the puzzle of GLP-1 resistance, there’s still hope for those with faulty PAM variants. Comparing the phenomenon to insulin insensitivity—another metabolic issue we don’t fully understand—Gloyn says it could be possible to find treatments.
“There are a whole class of medications that are insulin sensitizers, so perhaps we can develop medications that will allow people to be sensitized to GLP-1s or find formulations of GLP-1, like the longer-acting versions, that avoid the GLP-1 resistance,” she explained.
By shedding light on what happens when GLP-1s don’t work, this new research can help ensure they do work—for everyone. 
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Lead image: robsonphoto / Adobe Stock
