Gcg, also known as the preproglucagon gene, is expressed in specific enteroendocrine cells (L-cells) of the intestinal mucosa, pancreatic islet α-cells, and certain neurons within the nucleus of the solitary tract. It encodes multiple peptides such as glucagon, glucagon-like peptide-1 (GLP-1), etc. Glucagon is mainly a counterregulatory hormone increasing glucose production to maintain euglycemia, while GLP-1 improves glucose homeostasis by stimulating insulin release and reducing glucagon secretion. There is cross-talk between these proglucagon-derived peptides [1].

In GcgGut-/-mice with genetic reduction of Gcg expression throughout the small and large bowel, the acute GLP-1 response to olive oil or arginine administration was markedly diminished, and the GLP-1 response to LPS was also attenuated. In GcgDistalGut-/-mice with selective reduction of Gcg expression in the distal gut, the increase in plasma GLP-1 levels following the administration of the GPR119 agonist AR231453 or the melanocortin-4 receptor (MC4R) agonist LY2112688 was markedly diminished, and the actions of metformin to increase plasma GLP-1 levels were substantially attenuated. These findings reveal the importance of different gut regions in the acute L cell response to various GLP-1 secretagogues [2].

In conclusion, Gcg is crucial for encoding key peptides involved in glucose and energy homeostasis. The study of Gcg knockout mouse models, like GcgGut-/-and GcgDistalGut-/ -, has provided insights into the role of Gcg in the regulation of GLP-1 secretion in different gut regions, which is relevant to understanding glucose metabolism-related diseases [2].