The past, present, and future physiology and pharmacology of glucagon

Abstract

The evolution of glucagon has seen the transition from an impurity in the preparation of insulin to the development of glucagon receptor agonists for use in type 1 diabetes. In type 2 diabetes, glucagon receptor antagonists have been explored to reduce glycemia thought to be induced by hyperglucagonemia. However, the catabolic actions of glucagon are currently being leveraged to target the rise in obesity that paralleled that of diabetes, bringing the pharmacology of glucagon full circle. During this evolution, the physiological importance of glucagon advanced beyond the control of hepatic glucose production, incorporating critical roles for glucagon to regulate both lipid and amino acid metabolism. Thus, it is unsurprising that the study of glucagon has left several paradoxes that make it difficult to distill this hormone down to a simplified action. Here, we describe the history of glucagon from the past to the present and suggest some direction to the future of this field.

Keywords: diabetes; glucagon; glucose; insulin; α cells.

Figure 1.. Mechanisms that increase glucagon secretion in response to hypoglycemia.

A decrease in glycemia leads to a rise in glucagon secretion through both direct and indirect mechanisms. (1) α-cells can directly respond to a decrease in glucose concentrations to increase glucagon secretion. (2) A decrease in glycemia reduces β-cell activity, which in turn relieves the inhibitory paracrine tone within the islet mediated by factors including insulin (Ins), amylin (Amy), zinc (Zn), and serotonin (5-HT) that directly inhibit α-cell function. In addition, reduced β-cell activity decreases urocortin 3 (Ucn3) secretion, which indirectly inhibits α-cell function by increasing somatostatin secretion from δ-cells. (3) The CNS responds to hypoglycemia by multiple autonomic systems, including direct input via the parasympathetic nervous system (PNS) and indirect actions via the sympathetic nervous system (SNS) mediated by epinephrine. The CNS also responds to hypoglycemia by increasing the production of arginine vasopressin (AVP) to stimulate glucagon secretion.

Figure 2.. The incretin actions of GIP on both β-cells and α-cells are required for optimal postprandial metabolism.

The nutrient composition and intake route determine the level of pancreatic islet activity and subsequently nutrient metabolism. A) parenteral delivery of a glucose-only stimulus stimulates β-cell production of insulin. Without incretin peptides, the amount of insulin production and subsequently glucose uptake is minimal. B) Enteral delivery of glucose stimulates the secretion of GIP, which potentiates glucose-stimulated insulin secretion in β-cells. The engagement of the incretin system provides a more robust stimulus of insulin secretion and more efficient glucose disposal. C) Enteral delivery of a protein rich meal stimulates GIP secretion. The lack of a glucose stimulus results in low-activity of β-cells and little to no insulin secretion. The amino acids (AAs) activate α-cells, upon which GIP can potentiate AA-stimulated glucagon secretion to enable the metabolism of proteins. D) Delivery of a mixed nutrient meal provides both glucose and AAs to activate β-cells and α-cells, respectively. The presence of GIP enables direct potentiation of insulin secretion in β-cells, but also enhances glucagon secretion to further enhance insulin secretion through α- to β-cell communication. This produces maximal insulin secretion and glucagon secretion to enable the optimate metabolism of nutrients.

Figure 3.. Glucagon receptor antagonism (GRA) can lower glycemia through both direct and indirect actions.

Blocking the hepatic glucagon receptor can directly reduce endogenous glucose production by decreasing both gluconeogenesis and glycogenolysis. The decrease in amino acid catabolism that results from GRA produces a dramatic rise in plasma amino acids levels that provide a stimulus for α-cell production of proglucagon peptides. The rise in both glucagon and GLP-1 levels enhances α- to β-cell communication via the GLP-1R to increase insulin secretion. Elevated insulin receptor activity in hepatocytes reduces endogenous glucose production and enhances peripheral glucose uptake. This indirect mechanism by which GRA lowers glucose is dependent upon the β-cell GLP-1R activity.

Figure 4.. Metabolic consequence of glucagon receptor agonism or antagonism.

In both preclinical models and humans, antagonism of the glucagon receptor decreases glycemia, reduces hepatic lipid oxidation, increases circulating concentrations of amino acids, and produces α-cell hyperplasia. There is also evidence in preclinical models that loss of glucagon activity can lead to cardioprotection and drive β-cell proliferation. Glucagon receptor agonism produces modest effects on satiety to reduce food intake, and enables the catabolism of carbohydrates, lipids and amino acids. Agonism also produces increases in energy expenditure through incompletely understood mechanisms. Glucagon receptor agonism is inotropic and can increase blood pressure, and in preclinical models has been shown to have deleterious effects in models of ischemic heart disease.