Glucagon

Glucagon

Glucagon is a 29-amino-acid peptide hormone made by the alpha cells of the pancreatic islets of Langerhans. Its best-known job is to raise blood sugar. It makes the liver break down stored glycogen into glucose (glycogenolysis) and make new glucose from other sources (gluconeogenesis). In this role glucagon balances insulin, preventing low blood sugar during fasting and between meals.

Glucagon also has major effects on energy use and fat metabolism, and these are central to how retatrutide works. Activating the glucagon receptor in the liver promotes fat burning and reduces fat build-up, which is especially relevant to the drop in liver fat seen in retatrutide trials. Glucagon also raises resting energy use, possibly through heat production in brown fat and wasteful “futile” metabolic cycles. These calorie-burning effects are thought to help explain why retatrutide produces more weight loss than drugs that target only GLP-1 or GLP-1/GIP.

Adding glucagon receptor activity to retatrutide first seemed odd, since glucagon raises blood sugar. But clinical data show that retatrutide’s GLP-1 and GIP receptor activity provides enough insulin release and glucose lowering to cancel out glucagon’s effect on blood sugar. The overall result is better blood sugar control plus the metabolic benefits of glucagon, including higher energy use and less liver fat.

Glucagon receptor activity is the defining feature that sets retatrutide apart from dual agonists like tirzepatide (GIP/GLP-1) and places it in a new class of triple-acting metabolic drugs.