Experimental Animal Division

Proglucagon, which is encoded by the glucagon gene Gcg, is a precursor of several peptide hormones, including glucagon and glucagon-like peptide 1 (GLP-1). Glucagon is produced in pancreatic islet α-cells through the cleavage of proglucagon by prohormone convertase 2 (Pcsk2), and it stimulates hepatic glycogenolysis and gluconeogenesis in order to increase blood glucose levels. GLP-1 is produced mainly in intestinal L cells and stimulates insulin secretion to lower blood glucose levels.

Dr. Hayashi and colleagues have recently established mice lacking Gcg by replacing Gcg with cDNA for GFP (Gcg^gfp/+ mice) [1]. The serum concentration of insulin and the expression of enzymes involved in the conversion of amino acids to metabolites in the liver are reduced in Gcg^gfp/gfp mice [2]. Pregnant Gcg^gfp/gfp females show high blood glucose levels in late gestation, a decreased pregnancy rate, and smaller litter size [3]. Conversely, blood glucose levels in non-pregnant Gcg^gfp/gfp mice are not significantly different from those in wild-type mice. The metabolic impact of proglucagon deficiency may be ameliorated by lower plasma insulin levels and by glucagon-independent mechanisms that maintain gluconeogenesis. Indeed, Pcsk2 knockout mice and glucagon receptor knockout mice both exhibit increased production of GLP-1, which is absent in Gcg^gfp/gfp mice [4]. Gcg^gfp/gfp mice provide the opportunity to clarify the development, differentiation, and function of Gcg-expressing cells, as well as the physiological and pathological roles of glucagon in metabolism.