Role of Glucagon and Its Receptor in the Pathogenesis of Diabetes

Abstract

Various theories for the hormonal basis of diabetes have been proposed and debated over the past few decades. Insulin insufficiency was previously regarded as the only hormone deficiency directly leading to metabolic disorders associated with diabetes. Although glucagon and its receptor are ignored in this framework, an increasing number of studies have shown that they play essential roles in the development and progression of diabetes. However, the molecular mechanisms underlying the effects of glucagon are still not clear. In this review, recent research on the mechanisms by which glucagon and its receptor contribute to the pathogenesis of diabetes as well as correlations between GCGR mutation rates in populations and the occurrence of diabetes are summarized. Furthermore, we summarize how recent research clearly establishes glucagon as a potential therapeutic target for diabetes.

Keywords: diabetes; glucagon; glucagon receptor; glucagon-like peptide 1; glucagonocentric hypothesis; pathogenesis.

Figure 1

Hormonal regulation of glucose homeostasis in the islet cells. This diagram illustrates the metabolic effects of glucagon and insulin. Blood glucose levels influence secretion of insulin and glucagon. Insulin deficiency leads to elevated lipolysis, increased proteolysis, and decreased glucose utilization, while excess glucagon leads to decreased glycogen synthesis, increased ketogenesis, elevated glycogenolysis, and gluconeogenesis. Red arrows refer to a stimulatory effect, while blue arrows refer to an inhibitory effect.

Figure 2

Activation of GCGR and GLP-1R to promote insulin secretion in islet β cells. Glucagon binds to GCGR and GLP-1R on β cells and the activated receptors engage the G protein Gαs. This results in adenylate cyclase activation and cAMP formation. Glucose binds to GLUT2, which increases ATP levels and intracellular calcium concentration, and enhances insulin exocytosis. The increase in intracellular cAMP levels activates PKA, which also promotes insulin exocytosis.