NEW YEAR'S RESOLUTION: EAT LIKE A LIZARD

Imagine eating a huge holiday feast and feeling so satisfied that you wouldn’t have to eat for days, maybe even a week. The blueprint for that scenario can be found in the venom of a lizard native to the southwestern United States. This venom is the unlikely model for a medication that suppresses our appetite—a glucagon-like peptide-1 (GLP-1) receptor agonist. The orange-and-black desert reptile, the Gila monster (Heloderma suspectum), produces a unique peptide called exendin-4 (Ex-4). Ex-4 resembles GLP-1 found in humans but is more potent and has inspired drugs such as semaglutide and tirzepatide.

In humans, GLP-1 is produced primarily by the intestinal endocrine L-cells and in specific neurons in the brain in response to eating. It stimulates the pancreas to increase insulin release and decrease glucagon release, thereby regulating blood sugar (glucose) concentration. After a meal, insulin moves sugar from the blood into surrounding cells. Glucagon stimulates the liver to release stored glucose, but GLP-1 blunts that response, thus, along with insulin, helping maintain a perfect balance of how much sugar should be in the blood. GLP-1 also slows stomach emptying and signals the brain to reduce hunger and food cravings. However, GLP-1 is rapidly degraded by the enzyme DPP-4. In theory, creating a GLP-1 receptor agonist that binds longer than the original would be a game-changer for people with type 2 diabetes, by helping regulate blood sugar levels.

Enter the Gila monster.

In the Gila monster, exendin-4 is found in the venom produced by modified salivary glands in the lower jaw. It slows digestion and prolongs the blood glucose-lowering effects, similar to GLP-1 found in humans. However, Gila monsters do not eat regular meals. Instead, they consume sporadic, large meals. They can eat prey weighing one-third of their body mass at a time and sometimes go for months without feeding. Such an unusual diet requires extraordinary physiological control. Thus, Ex-4 is more stable, longer-lasting than GLP-1, and produces longer satiety. That makes sense if the Gila monster doesn’t know when its next meal is coming.

By studying GLP-1 and Ex-4, scientists discovered that their structures were similar and that Ex-4 lacks the specific site where the enzyme DPP-4 cleaves GLP-1, thereby prolonging its presence in the body. Scientists also found that these peptides were more effective when injected than if taken by mouth. Understanding the mechanism by which these peptides worked enabled scientists to exploit Ex-4  as a template for the development of the GLP-1 agonist drugs. Today, GLP-1 drugs such as Ozempic, Wegovy, and Mounjaro are used to treat diabetes, suppress appetite, and promote weight loss.

Leave it to a poisonous lizard to provide the blueprint for a medication that makes you feel so full after a meal, you think you just ate a rabbit, a squirrel, and two snakes.

Happy New Year!