Unraveling the mode of action of tirzepatide

Tirzepatide is a recently approved treatment for type-2 diabetes. Treatment with tirzepatide decreases body weight while improving glucose metabolism in patients with obesity and type-2 diabetes. Although the drug is designed to activate receptors for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the contribution of activating the GIP receptor in the overall efficacy of tirzepatide is not fully understood. A team of researchers demonstrated for the first time that tirzepatide stimulates insulin secretion in the human pancreas via the GIP receptor. These results contrast with findings in mice, where Tirzepatide primarily stimulated insulin secretion via the GLP-1 receptor. This study is now published in Nature Metabolism.

Globally, type-2 diabetes and obesity are on the rise, with prevalence rates having tripled since the 1980’s, according to the WHO. Both diseases are associated with an impaired insulin action and treatment options are explored extensively, including those that target relevant hormone receptors. Two clinically validated targets are the receptors for glucagon-like peptide-1 (GLP-1) and for glucose-dependent insulinotropic polypeptide (GIP). Both receptors increase insulin secretion upon activation. Tirzepatide is a once-weekly GIP receptor and GLP-1 receptor agonist. It is a single molecule that activates the body's receptors for GIP and GLP-1, which are natural incretin hormones. Both GIP and GLP-1 receptors are found in areas of the human brain important for appetite regulation. Tirzepatide has been shown to decrease food intake and modulate fat utilization. It is in phase 3 development for adults with obesity, or overweight with weight-related comorbidity. It is also being studied as a potential treatment for people with obesity and/or overweight with heart failure with preserved ejection fraction (HFpEF), obstructive sleep apnea (OSA), and non-alcoholic steatohepatitis (NASH). Studies of tirzepatide in chronic kidney disease (CKD) and in morbidity/mortality in obesity (MMO) are also ongoing.

Activation of The Human GIP Receptor Tirzepatide Enhances Insulin Secretion

While the co-agonist tirzepatide improves glucose control in patients with type-2 diabetes with superior efficacy compared with selective GLP-1 receptor agonists, the role of the GIP receptor in mediating these effects was unknown until now. Scientists from Helmholtz Munich, the German Center for Diabetes Research, Eli Lilly and Company, Novo Nordisk and the Duke University discovered that signaling via the GIP receptor in human pancreatic islets is crucial to stimulate insulin secretion. They were able to show that pharmacologically blocking the GIP receptor reduces the effectiveness of tirzepatide to stimulate insulin secretion from human islets. At the same time, blockade of the GLP-1 receptor had relatively marginally effects. These findings affirm the importance of GIP receptor signaling in the mechanism of action of tirzepatide. “These data are very interesting and demonstrate the importance of the GIP receptor in the metabolic action of tirzepatide”, summarizes Dr Jon Campbell, group leader at Duke University and senior author of the study. 

Furthermore, the scientists evaluated the pharmacology of tirzepatide at the human and mouse receptors and compared its mode of action in isolated pancreatic islets from mice and human donors. “Similar to human GIP, tirzepatide shows weaker potency on the mouse GIP receptor, indicating that tirzepatide seems to work differently in mice and man”, notes Dr Timo Müller, Director of the Institute for Diabetes and Obesity at Helmholtz Munich and one of the corresponding authors. “While tirzepatide favors in the mouse the GLP-1 receptor to stimulate islet insulin secretion, it primarily acts via the GIP receptor in humans to boost insulin secretion”, adds Müller. “In subsequent studies, we will now assess how important the GIP receptor is for the body weight lowering effect of the drug”, says Kyle Sloop, a scientist at Eli Lilly and Company and corresponding author of the study.

Original publication 

El and Douros et al. (2023): The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets. Nature Metabolism. DOI: 10.1038/s42255-023-00811-0.