What is the mechanism of action of glucagon (Glucagon) in increasing blood glucose levels?

Mechanism of Action of Glucagon in Increasing Blood Glucose Levels

Glucagon increases blood glucose concentration primarily by activating hepatic glucagon receptors, which stimulates glycogen breakdown and release of glucose from the liver. 1

Primary Mechanism

• Glucagon binds to glucagon receptors on hepatocytes (liver cells), initiating a signaling cascade that activates glycogen breakdown (glycogenolysis) and release of glucose into the bloodstream 1, 2
• The presence of adequate hepatic glycogen stores is necessary for glucagon to produce its antihypoglycemic effect 1
• Following administration, blood glucose concentration rises within 10 minutes of injection, with maximal concentrations attained at approximately 30 minutes 1
• The duration of hyperglycemic action after injection is typically 60 to 90 minutes 1

Physiological Role

• Glucagon is a primary regulator of hepatic glucose production during fasting, exercise, and hypoglycemia 2
• In the overnight fasted state, basal glucagon secretion is essential in countering the suppressive effects of basal insulin, maintaining appropriate levels of glycogenolysis and blood glucose 2
• The enhancement of glycogenolysis in response to elevated glucagon is critical in the life-preserving counterregulatory response to hypoglycemia 2, 3
• Glucagon also plays a key role in providing adequate circulating glucose for working muscle during exercise 2

Molecular Pathways

• When glucagon binds to its receptor, it activates a G-protein coupled receptor signaling pathway that increases intracellular cyclic AMP (cAMP) 3
• This increase in cAMP leads to activation of protein kinase A, which phosphorylates and activates enzymes involved in glycogen breakdown 2
• The rapid stimulation of hepatic glucose production is entirely attributable to an enhancement of glycogenolysis, with little to no acute effect on gluconeogenesis 2
• This dramatic rise in glycogenolysis in response to hyperglucagonemia wanes with time, showing a tachyphylaxis effect that is partially independent of hyperglycemia 2

Clinical Applications

• Glucagon is used therapeutically for the treatment of severe hypoglycemia in patients unable or unwilling to consume carbohydrates by mouth 4, 5
• Modern formulations include traditional reconstitution powder, intranasal glucagon, and ready-to-inject preparations for subcutaneous injection 4, 5
• An individual does not need to be a healthcare professional to safely administer glucagon 4
• After administration, glucagon is degraded in the liver, kidney, and plasma with a mean apparent half-life of about 42 minutes after subcutaneous administration and 26 minutes after intramuscular administration 1

Beyond Glucose Regulation

• Glucagon has extrahepatic effects including relaxation of smooth muscle in the stomach, duodenum, small bowel, and colon 1
• It also promotes lipolysis and lipid oxidation and has positive chronotropic and inotropic effects on the heart 6
• Glucagon decreases food intake and increases metabolic rate, contributing to weight management 6
• In type 1 diabetes, increased glucagon secretion contributes to elevated ketones and acidosis present in diabetic ketoacidosis 3

Clinical Implications

• In type 2 diabetes, inappropriate regulation of hepatic glucose production is due in part to an imbalance in the relationship between plasma levels of glucagon and insulin 7
• The glucagon response to insulin-induced hypoglycemia becomes impaired soon after the development of type 1 diabetes 3
• Glucagon receptor antagonists or inhibitors of glucagon secretion represent potential therapeutic targets for type 2 diabetes 2, 7
• For patients with recurrent hypoglycemia, glucagon should be readily available, and caregivers should be instructed on its proper use 4, 5