Diabetes mellitus is predominantly characterized by impaired glucose regulation, traditionally attributed to insulin deficiency or resistance.

However, recent advances reveal glucagon's pivotal role in diabetes pathophysiology.

Glucagon’s Physiological Function

Glucagon is a 29-amino-acid peptide primarily secreted in response to hypoglycemia. Its main target is the liver, where it binds to glucagon receptors (GCGR) to stimulate glycogenolysis and gluconeogenesis, effectively increasing blood glucose levels. This counter-regulatory action to insulin maintains glucose homeostasis during fasting or increased energy demands. Additionally, glucagon influences lipid metabolism and modulates insulin secretion through complex intra-islet signaling networks.

Dysregulation of Glucagon in Diabetes

In both type 1 and type 2 diabetes, abnormal glucagon secretion—hyperglucagonemia—contributes to aggravated hyperglycemia. In type 2 diabetes specifically, fasting glucagon levels are often elevated and its suppression after glucose intake may be impaired or even paradoxically increased.

This dysregulation stems in part from defects in paracrine inhibition of α‑cells by insulin—so‑called α‑cell insulin resistance—resulting in inappropriate glucagon release. Emerging research also suggests the possibility of extrapancreatic glucagon sources, complicating the control of glucagon in diabetes and highlighting the need for ongoing investigation.

The elevated glucagon stimulates excessive hepatic glucose production, worsening hyperglycemia despite available insulin, creating a vicious cycle. This glucagon-driven hepatic glucose output partly explains why insulin supplementation does not entirely normalize blood glucose in diabetic patients. Furthermore, glucagon receptor expression and signaling appear altered in diabetes, with hepatic glucagon resistance paradoxically coexisting with hyperglucagonemia, highlighting complex receptor dynamics and metabolic regulation failures.

Interplay Between Glucagon and Insulin

Glucagon exerts insulinotropic effects by promoting insulin secretion via both glucagon and glucagon-like peptide-1 receptors in beta cells. This intra-islet paracrine signaling is vital for balanced glucose regulation. Research shows that blocking glucagon receptor signaling decreases insulin secretion and disrupts glucose homeostasis, emphasizing the hormone’s dualistic nature: antagonizing insulin during fasting but cooperating to regulate postprandial glucose levels. Insulin deficiency alone cannot entirely explain the metabolic disturbances in diabetes without considering glucagon’s influence.

Dr. Y.H. Lee, University of California and diabetes researcher, states in a 2016 peer-reviewed review article: "Glucagon plays important roles in normal glucose homeostasis and in metabolic abnormalities, particularly diabetes. Glucagon excess, rather than insulin deficiency, is essential for the development of diabetes for several reasons. Glucagon increases hepatic glucose and ketone production, the catabolic features of insulin deficiency. Hyperglucagonaemia is present in every form of diabetes."

Therapeutic Implications

Understanding glucagon’s contribution has shifted therapeutic paradigms. Besides conventional insulin therapy, agents targeting glucagon signaling are under development and clinical evaluation. Glucagon receptor antagonists and dual agonists modulating glucagon and GLP-1 receptors offer promising avenues to correct hyperglucagonemia and improve glycemic control.

Moreover, glucagon-like peptide-1 receptor agonists, already established in diabetes therapy, capitalize on overlapping pathways with glucagon to enhance insulin secretion and regulate glucose metabolism effectively. Strategies aiming to restore balanced alpha-beta cell communication and mitigate glucagon excess may offer superior metabolic outcomes and reduce diabetes complications.

Glucagon's involvement in diabetes pathology extends far beyond its earlier characterization as merely the insulin counter-regulatory hormone. Its dysregulation significantly contributes to sustained hyperglycemia and impaired metabolic control in both type 1 and type 2 diabetes.

A nuanced understanding of glucagon biology opens new therapeutic possibilities targeting glucagon signaling pathways alongside traditional insulin-centered approaches. The evolving landscape underscores glucagon as a key player in diabetes, crucial for advancing precision treatment strategies.