What is glucagon and why is it in retatrutide?

Glucagon is a 29-amino-acid peptide hormone secreted by alpha cells in the pancreatic islets. Its most-taught physiological function is counter-regulation of hypoglycaemia: when blood glucose falls, alpha cells release glucagon, which acts on the liver to mobilise glucose from glycogen and to synthesise new glucose from amino-acid precursors.

But glucagon has other, less-taught functions that become important under sustained pharmacological activation. Glucagon receptor activation increases hepatic fatty-acid oxidation (burning fat for energy), reduces hepatic lipogenesis, increases energy expenditure through effects on brown adipose tissue, and has central effects on satiety. These effects favour weight loss and hepatic fat clearance rather than weight gain.

Retatrutide is a triple agonist that combines GLP-1, GIP, and glucagon receptor agonism in a single molecule. The pharmacological logic is that the three receptor systems contribute complementary effects: GLP-1's insulin-secretion enhancement and appetite suppression, GIP's contribution to the appetite/energy axis, and glucagon's energy-expenditure and hepatic-fat-clearance signal. Phase-2 data (Jastreboff 2023 NEJM) reported ~24% mean weight loss at 48 weeks with signs the curve was not yet plateauing. Phase-3 confirmation is ongoing.

The glucose-raising effect of native glucagon does not disappear in this context but is balanced by the strong glucose-lowering effects of GLP-1 and GIP — phase-2 diabetes evidence (Rosenstock 2023 Lancet) showed glucose control improved at all tested doses.