Understanding glucagon biology

The hormone everyone thinks they understand

Every medical student learns glucagon as the counter-regulatory hormone to insulin. Alpha cells in the pancreatic islets secrete glucagon in response to low blood glucose. Glucagon then acts on the liver to mobilise glucose from glycogen (glycogenolysis) and to synthesise new glucose from amino-acid precursors (gluconeogenesis). This raises blood glucose back toward normal. That description is entirely correct, and it captures the acute physiology of glucagon. But it also gave rise to a widely-held assumption: if glucagon raises blood glucose, then a glucagon receptor agonist would be a diabetes-worsening drug, so pharmacological glucagon activation must be a bad idea in metabolic disease. Retatrutide is now testing that assumption at phase-3 scale, and the early results suggest the story is considerably more interesting.

The other things glucagon does

Glucagon's acute glucose-raising effect is one part of its physiological profile, but it is not the whole profile. Glucagon receptor activation also increases hepatic fatty-acid oxidation (burning fat for energy), reduces hepatic lipogenesis (fat storage), increases energy expenditure through effects on brown adipose tissue and mitochondrial biogenesis, and has central effects on satiety and appetite regulation. In sustained pharmacological activation — as opposed to the brief pulses of native glucagon in hypoglycaemia — the net effect on body weight is loss rather than gain, and the net effect on hepatic lipid content is reduction rather than increase. This is why glucagon receptor agonism is being combined with GLP-1 and GIP agonism in retatrutide: the glucagon component contributes an energy-expenditure and hepatic-fat-clearance signal that GLP-1 and GIP do not deliver as strongly on their own.

How the diabetes concern gets managed

The glucose-raising effect of glucagon does not disappear in a multi-agonist context. It gets balanced by the glucose-lowering effect of GLP-1 (which augments insulin secretion in a glucose-dependent way, suppresses glucagon secretion from alpha cells, and slows gastric emptying) and by GIP's insulinotropic contribution. In the retatrutide phase-2 diabetes program (Rosenstock 2023 Lancet), glucose control improved substantially at all doses tested — the diabetes-worsening concern that would apply to a pure glucagon agonist did not materialise for the triple agonist. This is why the triple-agonist framing matters: no individual component of the combination is being used at doses that its native physiology would suggest are dangerous, but the net pharmacological signal at all three receptors together produces effects that exceed what any single component contributes.

What retatrutide's phase-2 data suggest about the glucagon contribution

The Jastreboff 2023 NEJM phase-2 obesity trial of retatrutide reported mean weight loss of approximately 24% at 48 weeks in the highest dose group — a number that is larger than what would be extrapolated from adding an incremental GLP-1 dose to tirzepatide. Weight loss curves in that trial did not appear to be plateauing at 48 weeks, which raised the possibility that the eventual weight-loss magnitude may be even larger with longer follow-up. Attribution of the weight loss between the three receptors is difficult without individual-agonist comparators at the same doses, but the glucagon contribution to hepatic fat oxidation and energy expenditure is a plausible driver of the incremental benefit over dual GLP-1/GIP agonism. The phase-3 program is ongoing; the actual clinical translation and safety profile at scale will settle these questions over the next few years.

Common questions

References

• Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial· Jastreboff AM, Kaplan LM, Frías JP, et al. · 2023
• Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial· Rosenstock J, Frías JP, Jastreboff AM, et al. · 2023

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