VIVO Pathophysiology

Endocrine Pancreas

Glucagon

Glucagon has a major role in maintaining normal concentrations of glucose in blood, and is often described as having the opposite effect of insulin because it has the effect of increasing blood glucose levels. This hormone was discovered as a contaminant in crude pancreatic extracts made for purification of insulin and, when purified, was found to induce a rapid increase in glucose concentrations; hence, it was named for being a "glucose agonist".

Glucagon is a linear peptide of 29 amino acids. Its primary sequence is almost perfectly conserved among vertebrates, and it is structurally related to the secretin family of peptide hormones. Glucagon is synthesized within alpha cells of the pancreatic islets by proteolytic cleavage of proglucagon which itself is a product of preproglucagon. Proglucagon is also expressed within the intestinal tract, where it is processed not into glucagon, but to a family of glucagon-like peptides or enteroglucagons.

Physiologic Effects of Glucagon

The major effect of glucagon is to stimulate an increase in blood concentration of glucose. As discussed previously, the brain in particular has an absolute dependence on glucose as a fuel, because neurons cannot utilize alternative energy sources like fatty acids to any significant extent. When blood levels of glucose begin to fall below the normal range, it is imperative to find and pump additional glucose into blood. Glucagon exerts control over two pivotal metabolic pathways within the liver, leading that organ to dispense glucose to the rest of the body:

• Glucagon stimulates breakdown of glycogen stored in the liver (glycogenolysis). When blood glucose levels are high, large amounts of glucose are taken up by the liver. Under the influence of insulin, much of this glucose is stored in the form of glycogen. Later, when blood glucose levels begin to fall, glucagon is secreted and acts on hepatocytes to activate the enzymes that depolymerize glycogen and release glucose.
• Glucagon activates hepatic gluconeogenesis. Gluconeogenesis is the pathway by which non-carbohydrate substrates such as amino acids and fatty acids are converted to glucose. As such, it provides another source of glucose for blood. This is especially important in animals like cats and sheep that don't normally have significant glucose in the intestine to absorb - in these species, activation of gluconeogenic enzymes is the chief mechanism by which glucagon does its job.

The glucagon receptor is expressed widely in the body, but as you might expect from these two effects, most prominently in liver.

Control of Glucagon Secretion

Knowing that glucagon's major effect is to increase blood glucose levels, it makes sense that glucagon is secreted in response to low blood concentrations of glucose, or hypoglycemia. Part of this effect is due to glucagon's ability to suppress secretion of insulin from islet beta cells. Additionally, several other factors are known to stimulate secretion of glucagon:

• Elevated blood levels of amino acids, as would be seen after consumption of a protein-rich meal. In this situation, glucagon would foster conversion of excess amino acids to glucose by enhancing gluconeogenesis. Since high blood levels of amino acids also stimulate insulin release, this would be a situation in which both insulin and glucagon are active.
• Epinephrine
• Exercise: In this case, it is not clear whether the actual stimulus is exercise per se, or the accompanying exercise-induced depletion of glucose.

In terms of negative control, glucagon secretion is inhibited by high levels of blood glucose. It is not clear whether this reflects a direct effect of glucose on the alpha cell, or perhaps an effect of insulin, which is known to dampen glucagon release. Another hormone well known to inhibit glucagon secretion is somatostatin.

Disease States

Diseases associated with excessively high or low secretion of glucagon are rare. Cancers of alpha cells (glucagonomas) are one situation known to cause excessive glucagon secretion. These tumors typically lead to a wasting syndrome and, interestingly, rash and other skin lesions.

Although insulin deficiency is clearly the major defect in type 1 diabetes mellitus, there is considerable evidence that aberrant secretion of glucagon contributes to the metabolic derangements seen in this important disease. For example, many diabetic patients with hyperglycemia also have elevated blood concentrations of glucagon, but glucagon secretion is normally suppressed by elevated levels of blood glucose. Several glucagon agonists and antagonists have been identified that may be useful in diabetic patients to normalize control of blood glucose concentrations.

References

• Capozzi ME, D'Alessio DA, Campbell JE. The past, present, and future physiology and pharmacology of glucagon. Cell Metab. 2022; 34:1654-1674.
• Lee SH, Park HY, Yun JH, Do EK. Glucagon in metabolic disease: a mini-review of emerging multi-organ roles beyond glycemic control. Front Endocrinol (Lausanne). 2025; 16:1645041.
• Robertson RP. Brief overview: glucagon history and physiology. J Endocrinol. 2023; 258:e220224.

Insulin

Endocrine Pancreas: Introduction and Index

Updated March 2026. Send comments to Richard.Bowen@colostate.edu