Glucagon

Glucagon is a 29-amino acid peptide hormone synthesized and secreted by alpha cells of the pancreatic islets of Langerhans. It is the primary counter-regulatory hormone to insulin, and its fundamental physiological role is to prevent and reverse hypoglycemia by mobilizing glucose from hepatic glycogen stores and stimulating gluconeogenesis.

Glucagon is encoded by the proglucagon gene — the same gene that encodes GLP-1, GLP-2, GIP-2, and oxyntomodulin, which are differentially produced by tissue-specific post-translational processing. In the pancreas, proglucagon is cleaved primarily to produce glucagon. In the intestinal L-cells, the same proglucagon precursor is cleaved to GLP-1 and GLP-2.

**Core mechanisms:** 1. **GCGR (glucagon receptor) activation in liver** → cAMP → PKA → phosphorylase kinase → glycogen phosphorylase activation → glycogenolysis 2. **GCGR in liver** → gluconeogenesis from lactate, alanine, glutamine 3. **GCGR in adipocytes** → lipolysis → free fatty acid release → hepatic ketogenesis 4. **GCGR in CNS/hypothalamus** → satiety signaling, thermogenesis

The relationship between glucagon and the GLP-1/GIP incretin system is complex and bidirectional. Normally, insulin/glucagon are secreted in inverse ratios to maintain euglycemia. GLP-1 receptor agonists suppress glucagon, while glucagon receptor agonism increases energy expenditure.

This creates an interesting therapeutic window: the energy expenditure benefits of glucagon receptor agonism can be harnessed if glucagon-induced hyperglycemia is simultaneously prevented by co-agonism at GLP-1R (insulinotropic). This is the rationale for dual (cotadutide) and triple (retatrutide) agonists that include GCGR agonism as a component.

Glucagon also has therapeutic applications beyond hypoglycemia: beta-blocker overdose (GCGR in the heart increases heart rate and contractility), bowel relaxation for radiology procedures, growth hormone stimulation testing, and diagnostic evaluation of glucagonomas.