Glucagon

Glucagon is a twenty-nine residue peptide cut from proglucagon by prohormone convertase 2 in the pancreatic alpha cell, the precursor intestinal L-cells process into GLP-1. It acts at a class B receptor concentrated in hepatocytes, raising cyclic AMP, activating protein kinase A and switching the liver to glucose release through glycogenolysis and gluconeogenesis. Its less-quoted actions matter for current drug design: raised resting energy expenditure, lipolysis and hepatic fatty acid oxidation.

Clinically it is first a rescue therapy for severe hypoglycaemia: a nasal powder approved by the FDA in 2019, the soluble analogue dasiglucagon in 2021. In type 2 diabetes the pathology runs the other way: alpha cells fail to suppress glucagon after a meal, and the resulting hepatic glucose output contributes as much to postprandial hyperglycaemia as the insulin deficit. Agonist pharmacology has now been added deliberately, in dual GLP-1 and glucagon agonists and in the triple agonist retatrutide, which reported roughly a quarter of body weight lost at forty-eight weeks in phase 2.

The engineering question is one of ratio. Glucagon agonism supplies energy expenditure and hepatic fat clearance that GLP-1 agonism does not, but it raises glucose, so it is usable only where enough GLP-1 activity is present to contain it. That is why these molecules are described by receptor potency ratios rather than by dose, and why a glucagon arm can be an asset in steatotic liver disease and a liability in poorly controlled diabetes.

The shorthand that glucagon is simply the opposite of insulin obscures this. It hides the thermogenic and hepatic lipid effects that make glucagon agonism attractive, and invites the assumption that any glucagon-containing molecule worsens glycaemic control, which the dual and triple agonist trials do not show.