Triple Play: A Look at Agonists in Insulin Production

Type II diabetes is a condition where the body produces insulin at insufficient levels, causing undesirable raised glucose levels.  Left unchecked, these raised levels lead to a host of health problems. The incretin hormones, or gut peptides, play a role in insulin secretion called the incretin effect.   Of these incretins, glucose-dependent insulinotropic polypeptide or gastric inhibitory polypeptide (GIP) is found in the upper gut, while glucagon-like peptide 1 (GLP-1) is found in the lower gut.  A third player is also involved, glucagon. The glucagon receptor (GCGR) triggers the liver to convert stored glycogen to glucose, helping maintain glucose homeostasis.

An agonist works by binding to a receptor protein triggering a biological response and functions by stimulating the production of insulin following administration. Agonists are often peptides, but can also be small molecules. Peptide agonists are usually variations, or analogues, of the active part of the protein receptor targeted, sharing several similar amino acids.  In contrast, an antagonist would block a response.1

Single Agonists

Several glucagon-like peptide 1 (GLP-1) receptor agonists, or GLP-1Ras, have already been developed and approved for the treatment of type-2 diabetes (such as exenatide, lixisenatide, liraglutide, and semaglutide). These are single agonists since they only act on one protein receptor. 

Dual Agonists

Tirzepatide is considered a dual agonist because it is one molecule that is both a GIP and a GLP-1 receptor agonist.2  Mazdutide, currently in Phase III, is the first GLP-1R/GCGR dual agonist.3 These dual agonists are also sometimes called “twincretins”, since they act like two incretins in one.

Triple Agonists

Finally, a triple agonist binds to all three: GIP, GLP-1, and glucagon receptors.  These can also be referred to as triagonists. An example of a triagonist is retatrutide, currently in clinical trials.4


  1. Nauck MA, Meier JJ. Incretin hormones: Their role in health and disease. Diabetes Obes Metab. 2018 Feb; 20 Suppl 1:5-21. doi: 10.1111/dom.13129. PMID: 29364588. Retrieved May 2022:
  3. Knerr PJ, Mowery SA, Douros JD, Premdjee B, Hjøllund KR, He Y, Kruse Hansen AM, Olsen AK, Perez-Tilve D, DiMarchi RD, Finan B. Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice. Mol Metab. 2022 Sep;63:101533. doi: 10.1016/j.molmet.2022.101533. Epub 2022 Jul 7. PMID: 35809773; PMCID: PMC9305623. Retrieved June 2023:

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Content originally posted on the AmbioPharm website and shared with permission.