Glucagon Agents

Pancreatic α cells cleave proglucagon (by prohormone convertase 2) into glucagon, a 29–amino acid peptide, and secrete it in response to hypoglycemia or raised amino acids. Rising glucose inhibits its release, and within the islet insulin, somatostatin and γ-aminobutyric acid inhibit it; GLP-1 also inhibits it, while GIP enhances it. Hypoglycemia releases glucagon together with the other counterregulatory hormones, epinephrine and cortisol.

Glucagon binds a 7-transmembrane G protein–coupled receptor coupled to Gs, expressed most in liver and kidney. Adenylyl cyclase raises cAMP and activates protein kinase A. PKA phosphorylates glycogen phosphorylase kinase, which activates glycogen phosphorylase — glycogenolysis — while phosphorylation inactivates glycogen synthase. PKA–CREB signaling increases transcription of PEPCK, the rate-limiting gluconeogenic enzyme, and glucagon inhibits glycolysis at phosphofructokinase-1. It also stimulates lipolysis and ketogenesis; the glucagon-to-insulin ratio tells the liver whether to turn fatty acids into ketone bodies.

Because glucagon works by releasing what the liver has stored, it is effective only if there is enough hepatic glycogen. In starvation, adrenal insufficiency or chronic hypoglycemia the stores may be too low, and those patients are treated with glucose. Alcohol sets up the same trap: it inhibits gluconeogenesis but not glycogenolysis, so hypoglycemia appears after several days of drinking, once glycogen is depleted.

The label adds two tumors. With an insulinoma, glucagon may first raise glucose and then, directly or through that rise, stimulate exaggerated insulin release and hypoglycemia — glucose is given orally or IV. With a pheochromocytoma, glucagon may stimulate catecholamine release and a substantial rise in blood pressure. Both are contraindications.

A patient with a decreased level of consciousness cannot safely take oral carbohydrate because of the risk of aspiration, and IV access can be hard to obtain; glucagon raises glucose without an IV. Severe hypoglycemia needs someone else to treat it, so the drug is given by a trained caregiver as soon as the low is recognized: by subcutaneous injection (prefilled autoinjector, syringe or kit) or as a nasal powder into one nostril, which does not need to be inhaled and still works with nasal congestion. Blood glucose starts to rise within about 10 minutes and peaks at around 30.

The rescuer calls for emergency help, gives a second dose from a new device if there is no response after 15 minutes, and turns the unconscious patient on their side, because nausea and vomiting are the commonest effects. Once the patient wakes and can swallow, oral carbohydrate restores liver glycogen and prevents a recurrence. (Insulin-induced hypoglycemia itself is on the Insulins page.) Dasiglucagon (Zegalogue), a 29–amino acid glucagon analog injected subcutaneously from age 6, is a glucagon receptor agonist that acts the same way, needs hepatic glycogen too, and shares the pheochromocytoma and insulinoma contraindications.

Glucagon relaxes the smooth muscle of the stomach, duodenum, small bowel and colon, so IV glucagon is used as a diagnostic aid to stop gut movement during radiologic examinations; the same mechanism helps pass esophageal food boluses. In that setting it can raise myocardial oxygen demand, blood pressure and pulse — cardiac monitoring is recommended in cardiac disease — and it can cause hyperglycemia in diabetes.

Its cardiac effects are also used off-label. Glucagon’s positive inotropic effect is mediated through adenylate cyclase, and high-dose glucagon infusion has been used, with β-agonists such as epinephrine, in β-blocker and calcium-channel-blocker overdose (Beta-Blockers and Calcium-Channel Blockers pages). Large amounts are hard to obtain, so high-dose insulin euglycemic therapy and catecholamines are optimized first, and in calcium-channel-blocker overdose glucagon is second-line after calcium, epinephrine, high-dose insulin and dextrose.