Credit – Getty Images Sandy Huffaker for The Washington Post
The latest diabetes drug semaglutide, better known by the brand names Ozempic, Wegovy and Rybelsus, is attracting attention for its ability to both control blood sugar and cause weight loss. But doctors and patients alike predict that the most powerful of these drugs is yet to come, as the U.S. Food and Drug Administration is considering approving Eli Lilly’s drug tyrzepatide (trade name: Mounjaro) for the loss of weight by the end of the year.
In studies that Lilly has submitted to the FDA, the company has shown that Mounjaro, which is already approved to treat type 2 diabetes, can reduce body mass among users at its highest dose by up to 15%. While semaglutide targets one molecule, glucagon-like peptide-1 (GLP-1), involved in insulin secretion, tirzepatide is the first to target two: GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). ).
In a new study published in Metabolism of nature, an international group of researchers, in collaboration with scientists from Eli Lilly and Novo Nordisk (the creator of Ozempic and Wegovy), sought to understand how tyrzepatide produces its strong effects on blood sugar and weight. Working with both mice and cultures of human insulin-producing pancreatic cells, the team conducted a series of experiments to better understand the factors behind the drugs’ dual action.
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The historical narrative in the field has been that GIP is doing everything GLP-1 is doing, just not as well, says Jonathan Campbell, an associate professor of medicine at Duke University and the study’s senior author. Researchers have known that GLP-1 acts on cells in the pancreas and stimulates the production of insulin, which breaks down glucose in the body. It also works on the digestive system, suppressing hunger signals sent to the brain and curbing appetite. GIP has similar effects, but they are generally not as powerful.
The scientists therefore expected to find that tyrzepatide worked primarily by activating GLP-1 receptors in the body and wondered whether GIP would have an additional impact. Since the molecules are very similar, targeting both would not necessarily lead to an additive effect. Instead, the two entities could be competing to bind to the same cell receptors, both trying to go through the same door at the same time, Campbell says.
But to their surprise, the team found that tirzepatide actually triggers a potent GIP response. GIP was imperative, Campbell says. Indeed, in experiments on insulin-producing pancreatic cells donated by eight volunteers, the researchers found that if GIP was blocked in these cells, preventing the drug from binding to GIP receptors, the drug had no effect on stimulating insulin production. . When the GIP receptors weren’t blocked, the cells produced insulin.
This was surprising to us, and the opposite of what we thought, she says.
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The reason may have something to do with the differences between mice and humans. Scientists rely heavily on mouse models to understand how things like GIP and GLP-1 work in living organisms, but it turns out that GIP receptors are different in human cells. While the genetic sequences for GLP-1 receptors in mice and humans are identical, the sequences for GIP receptors in the two species are not. This is a problem, since the most efficient way to understand how GIP works is to study human versions of the receptors in mice. All of the data examining tyrzepatide mechanistically has been obtained primarily in mouse models, says Campbell. So we thought it was important for researchers to know that there are confounding variables.
The studies are an intriguing first step in answering questions about whether the latest class of GLP-1-based diabetes and weight-loss drugs might be more effective when combined with GIP-based drugs. More studies would be needed to explore whether targeting not just one, but several processes involved in insulin production and weight might be more effective. If that were the case, doctors would have different tools that would give them more options for treating people, Campbell says.
This study shows that for insulin secretion, which is an important biological action for glucose control, GIP appears to be very, very important, he says. Taking that scientific tip, Campbell hopes to build on these findings by studying GLP-1 and GIP in larger numbers of human cell samples. And since the volunteers in the current trial spanned a range of BMIs but didn’t have diabetes, he says it’s important to also include cells from people with the condition to better isolate the most efficient way to control blood sugar and weight.
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