Metabolic Impact of Glucagon Deficiency

Multiple bioactive peptides are produced from proglucagon encoded by glucagon gene (Gcg). Glucagon is produced in islet α-cells through processing by prohormone convertase 2 (Pcsk2) and exerts its action through the glucagon receptor (Gcgr). Although it is difficult to produce a genetic model that harbours isolated glucagon deficiency without affecting the production of other peptides derived from proglucagon, three different animal models that harbour deficiencies in glucagon signalling have been generated by gene targeting strategy. Although both Pcsk2(-/-) and Gcgr(-/-) mice display lower blood glucose levels, homozygous glucagon-GFP knock-in mice (Gcg(gfp/gfp) ) display normoglycaemia despite complete glucagon deficiency. In Gcg(gfp/gfp) mice, the metabolic impact of glucagon deficiency is probably ameliorated by lower plasma insulin levels and glucagon-independent mechanisms that maintain gluconeogenesis. As both Pcsk2(-/-) and Gcgr(-/-) mice exhibit increased production of glucagon-like peptide-1 (GLP-1), which is absent in Gcg(gfp/gfp), GLP-1 is the likely cause of the difference in metabolic impact of glucagon deficiency in these animal models. Although all the three models display islet 'α'-cell hyperplasia, the mechanisms involved remain to be elucidated. Studies using Pcsk2(-/-), Gcgr(-/-) and Gcg(gfp/gfp) mice, especially in combination with α-cell ablation models such as pancreas-specific aristaless-related homeobox (ARX) knockout mice, should further clarify the physiological and pathological roles of glucagon in the regulation of metabolism and the control of islet cell differentiation and proliferation.