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Diabetes affects an estimated 37 million Americans. The disease affects the body’s control of circulating sugar, usually through changes in tissue responses to insulin.

Incretins, peptide hormones that influence insulin secretion, have emerged in recent decades as drug targets for diabetes. Glucagon-like peptide 1 receptor agonists, peptide drugs that mimic the incretin GLP-1, improve glycemic control among diabetic patients. But they are less effective than the much more invasive treatment of bariatric surgery, which leaves pharmaceutical researchers wondering whether these drugs can be improved.

Scientists have looked to other incretins, beginning with glucose-dependent insulinotropic polypeptide, or GIP. GLP-1 and GIP have a similar alpha-helical structure and significant sequence overlap, and both are released from the gastrointestinal tract to reduce circulating glucose by stimulating insulin secretion.

3D structural renderings show the backbone structures of GLP-1, glucagon and GIP. Researchers are exploring ways to combine the three peptides, which are very similar in structure but rarely released into the bloodstream at the same time, into a drug that combines the signaling effects of all three.

This year, the U.S. Food and Drug Administration the first peptide drug that works as a bifunctional agonist of both GLP-1 and GIP receptors. The drug, tirzepatide, causes weight loss and improves cardiometabolic and glycemic outcomes in diabetic patients. Its amino acid sequence, based on GIP, is engineered to bind both GIP and GLP-1 receptors, with modifications to boost its half-life by reducing its susceptibility to proteases and improving its binding to albumin.

Meanwhile, industrial research labs are looking to expand from bifunctional to trifunctional peptide drugs that target GLP-1, GIP and also glucagon receptors. Adding glucagon to the mix is expected to have complementary effects on glycemic control, obesity and diabetes. Researchers at Eli Lilly and Company wrote in a statement to ASBMB Today, “Our hypothesis considers that GLP-1 reduces appetite and GIP enhances GLP-1-induced reduction of appetite and glucagon enhances energy expenditure and combination of all those effects may produce more weight loss.”

This year, two papers published in the journal Cell Metabolism reported on trifunctional agonists that can activate all three receptors. Both drugs’ sequences use insights from alignment and 3D structural examination to merge the features of each peptide that are important for receptor binding and balance potency against all three receptors. In obese mice and monkeys, the triple agonists reduced body weight even in animals that lacked the GLP-1 receptor.

Both drugs were tested in humans in small preliminary trials. Sanofi discontinued work on its drug in 2019 after ; Eli Lilly to develop its drug, with two effectiveness and safety trials set to begin this year. These may be the first of many; in their , the Lilly scientists observed that “targeting all 3 of these receptors has evolved into the next generation of drug development for treatment of T2D and obesity.”