Repositioning Glucagon Action in the Physiology and Pharmacology of Diabetes

Abstract

Glucagon is historically described as the counterregulatory hormone to insulin, induced by fasting/hypoglycemia to raise blood glucose through action mediated in the liver. However, it is becoming clear that the biology of glucagon is much more complex and extends beyond hepatic actions to exert control on glucose metabolism. We discuss the inconsistencies with the canonical view that glucagon is primarily a hyperglycemic agent driven by fasting/hypoglycemia and highlight the recent advances that have reshaped the metabolic role of glucagon. These concepts are placed within the context of both normal physiology and the pathophysiology of disease and then extended to discuss emerging strategies that incorporate glucagon agonism in the pharmacology of treating diabetes.

Figure 1

Effects of glucose versus amino acids on glucagon secretion in isolated perifused islets. Glucagon secretion was measured in perifused islets, calculated as the incremental area under the curve, and expressed as fold change relative to the values collected at high glucose (10 mmol/L). Low glucose conditions were at 2.7 mmol/L glucose, while the glucagon responses to both glutamine and arginine were collected under high-glucose conditions (10 mmol/L).

Figure 2

Impact of glucose concentration on amino acid–stimulated glucagon secretion. Glucagon secretion was measured in perifused human islets from donors with T2D and calculated as the incremental area under the curve. The schematic illustrates the hypothesis that high-glucose conditions result in more inhibitory tone on the α-cell through paracrine interactions that originate from either β- or δ-cells, with the net effect of decreased α-cell tone and decrease glucagon secretion in response to the same amino acid stimulus.

Figure 3

Proglucagon processing and the impact on β-cell function. A: Proglucagon is posttranslationally modified by PC enzymes to produce glucagon and GLP-1 (1). α-Cells express high levels of PC2 to produce glucagon, a primary product of proglucagon (2). GLP-1 production by PC1/3 in α-cells is low in healthy states but can be induced by metabolic stress to increase the secretion of islet GLP-1 (3). Glucagon production and PC2 expression in enteroendocrine L-cells are low or absent in healthy states. Interventions such as bariatric surgery or pancreatectomy may induce PC2 expression and subsequent glucagon production in the gut (4). GLP-1 is the primary product of proglucagon in the gut under most conditions. B: α-Cells can use both glucagon and GLP-1 to stimulate insulin secretion in β-cells. In healthy islets, glucagon is the major product that mediates α- to β-cell communication but can do so through both the glucagon receptor (GCGR) and GLP-1R. Metabolic stress and T2D increase proglucagon production and the expression of PC1/3 in α-cells. Under these conditions, both glucagon and GLP-1 mediate α- to β-cell communication predominantly through the GLP-1R. Treatment with a GCGR antagonist substantially increases both glucagon and GLP-1. It is anticipated that α- to β-cell communication is enhanced through GLP-1R activity as long as the antagonist remains engaged with the GCGR.

Figure 4

Estimation of islet interstitial glucagon levels. Gcg^−/− islets have impaired GSIS that has been attributed to lack of proglucagon input from paracrine interactions with α-cells (16). Titration of glucagon to rescue insulin secretion to WT levels provides an estimation of the interstitial glucagon levels in WT islets. Glucagon concentration at −300 pmol/L rescued insulin secretion, although Gcg^−/− islets were more sensitive to glucagon, making this an imprecise and likely underestimation of interstitial glucagon concentrations. G, glucose.