Advances in basic research on glucagon and alpha cells

The regulation of plasma amino acid levels by glucagon in humans first attracted the attention of researchers in the 1980s. Recent basic research using animal models of glucagon deficiency suggested that a major physiological role of glucagon is the regulation of amino acid metabolism rather than to increase blood glucose levels. In this regard, novel feedback regulatory mechanisms that are mediated by glucagon and amino acids have recently been described between islet alpha cells and the liver. Increasingly, hyperglucagonemia in humans with diabetes and/or nonalcoholic fatty liver diseases is reported to likely be a compensatory response to hepatic glucagon resistance. Severe glucagon resistance due to a glucagon receptor mutation in humans causes hyperaminoacidemia and islet alpha cell expansion combined with pancreatic hypertrophy. Notably, a recent report showed that the restoration of glucagon resistance by liver transplantation resolved not only hyperglucagonemia, but also pancreatic hypertrophy and other metabolic disorders. The mechanisms that regulate islet cell proliferation by amino acids largely remain unelucidated. Clarification of such mechanisms will increase our understanding of the pathophysiology of diseases related to glucagon.