Postprandial Suppression of Glucagon Secretion: A Puzzlement.

Abstract

Pancreatic glucagon is a 29–amino acid hormone processed from proglucagon by prohormone convertase 2 in the pancreatic α-cells (1). Glucagon’s best-established function is to defend against decreases in glucose availability during fasting, stress, and exercise by stimulating hepatic glycogenolysis phasically and hepatic gluconeogenesis tonically (1–5). Glucagon also increases phasically during mixed-nutrient meals (6,7). Although many individual controls of glucagon secretion have been identified (Fig. 1), their interaction under physiological conditions is poorly understood. Figure 1 Some controls of glucagon secretion that may be involved in glucagon nonsuppression or tonically increased fasting glucagon levels in insulin resistance or diabetes (note that receptor mechanisms are not shown). As reviewed in detail elsewhere (1–5,26–28), nutrient, neural, endocrine, paracrine, and autocrine effects control glucagon secretion. The dynamic interactions among these controls are poorly understood. As the figure indicates, there are many possibilities for positive- and negative-feedback loops (e.g., glucagon stimulates both hepatic glucose production and insulin secretion, and both glucose and insulin inhibit glucagon secretion), for indirect effects (e.g., the incretin hormone glucagon-like peptide 1 [GLP-1] stimulates insulin and amylin secretion, both of which inhibit glucagon secretion, both by acting directly on the α-cells and by reducing gastric emptying), and for antagonistic effects (one example is that the incretin hormone GLP-1 inhibits glucagon secretion but the incretin hormone glucose-dependent insulinotropic polypeptide [GIP] stimulates it; another example is that mixed-nutrient meals increase both plasma glucose, which inhibits glucagon secretion, and plasma amino acids, which stimulates glucagon secretion, with the net result a brief stimulation of glucagon secretion). Somatostatin may contribute in situations in which insulin and glucagon …