Advances in glucagon research ~ 100th anniversary: invitation to the new ‘glucagon-ology’

In 2023, glucagon celebrated the 100th anniversary of its discovery in 1923 [1]. However, progress in both basic and clinical research on glucagon in recent decades have been resulting in drastic transition of its pathophysiological position. For a long time, glucagon had been ‘simply’ considered as a ‘hyperglycemic factor’ that counteracts hypoglycemia and insulin. However, recent advances in research, particularly in the field of basic medicine, have shown that glucagon plays an important role as a comprehensive metabolic regulator in the control of systemic energy supply. As a result, glucagon has become one of the most attractive and highly anticipated therapeutic targets not only in diabetes, but also in other metabolic and nutritional diseases because of its therapeutic potential for ameliorating hyperglycemia in diabetes by glucagon receptor antagonism while treating obesity and metabolic liver diseases by glucagon receptor agonism.

Since the 2000s, glucagon research has rapidly resurfaced mainly led by basic medical research, undoubtedly triggered by the progress of research on glucagon-like peptide-1 (GLP-1), which shares its precursor proglucagon with ‘pancreatic’ glucagon, and the clinical application of incretin-based therapies for diabetes. With the expansion of incretin therapy, research on glucagon, one of the main therapeutic targets of incretin therapy, has been conducted extensively from basic science to clinical medicine, and a number of research results have been obtained. In addition, the development and application of a new sandwich enzyme-linked immunosorbent assay (ELISA) method for glucagon, which overcome the unresolved problems of the long-used glucagon radioimmunoassay (RIA) in clinical settings, made a significant contribution and promoted the explosion of clinical research. The new concepts and findings on glucagon discovered in basic medical research have been verified in clinical research, and the interaction of these two fields has greatly promoted the deeper understanding of glucagon. In addition, glucagon receptor agonists have become one of the most anticipated agents in recent receptor-targeting therapeutic strategies for various metabolic diseases [2].

Basic medical research on glucagon has progressed from physiological to pathological aspects, including the effects of glucagon on glucose metabolism in various organs, particularly the liver, the regulatory mechanism of glucagon secretion in pancreatic α-cells, and the mechanism of abnormal glucagon secretion in diabetes and therapeutic strategies against glucagon. In this context, recent studies have revealed new physiological functions of glucagon, hepatic amino acid metabolism, and amino acid-mediated cross talk between liver and α-cells [3], further emphasizing the physiological importance of glucagon (for more information, please see “Advances in basic research on glucagon and alpha cells” by Hayashi). Thus, the essential functions of glucagon are not limited to simply responding to hypoglycemia, but also include (1) promoting the metabolism and breakdown of nutrients in energy-storing organs such as the liver and adipose tissue, (2) releasing energy sources, primarily glucose, from these organs, and then (3) enhancing their delivery to energy-consuming organs such as the central nervous system and skeletal muscles. In effect, glucagon acts as a systemic energy mobilizer. In contrast, insulin, which ‘decreases’ blood glucose levels, essentially promotes glucose uptake in energy-consuming organs and inhibits excessive energy output from energy-releasing organs. In other words, insulin and glucagon do not simply counteract each other, but work together to facilitate the smooth flow of energy transfer in response to supply and demand. Thus, the function of glucagon is not simply to counteract hypoglycemia, but to actively regulate systemic energy status and nutrient metabolism more broadly.

The development and application of the new glucagon ELISA has also led to a number of clinical findings, some of which have confirmed and some of which have changed conventional clinical beliefs about glucagon. These findings provide important information for a comprehensive understanding of the pathophysiology of glucagon, which is more than just a biomarker in diabetes (for more information, please see “Advances in clinical research on glucagon” by Horie and Abiru). While the new assay has stimulated clinical research, we also conducted a clinical study of glucagon in subjects with type 1 diabetes and reported that glucagon secretion is dysregulated in response to plasma glucose levels [4] and this dysregulation persists in their annual checkups [5]. Although these findings confirmed previous knowledge from the 1970s, they also provided clinical evidence for the importance of pancreatic β-cells and intra-islet action in the regulation of glucagon secretion from α-cells. Interestingly, plasma glucagon levels did not correlate with HbA1c or other parameters of glucose metabolism, lipid metabolism, liver function, renal function, or diabetic complications, but only with serum urea nitrogen (BUN) levels [4]. This correlation between glucagon and BUN may indicate an association with amino acids, which are a source of nitrogen in the body. Indeed, characteristic changes in the plasma amino acid profile, such as a large decrease in plasma glutamate, have been observed in our subjects with type 1 diabetes [6], suggesting that dysregulated glucagon secretion induces abnormalities in amino acid metabolism and, ultimately, protein metabolism. Similarly, this study may provide clinical evidence for the relationship between glucagon and amino acid metabolism that has been proposed in basic research.

At the same time, these advances in both basic and clinical research on glucagon and α-cells have raised new clinical questions, unresolved methodological problems, and future perspectives. In particular, the technical problems of the glucagon ELISA, which is essential for the further development of clinical research on glucagon, have been improved by combining clinical and basic research strategies for its validation. These studies have also led to various future clinical aspects of recognizing glucagon as an important therapeutic indicator and target (please see “Advances in the clinical measurement of glucagon: From diagnosis to therapy” by Kitamura and Kobayashi). Thus, the multidirectional research achievements of glucagon have led to a drastic transition of its pathological and physiological position and expanded role, and also revealed complex but precise regulatory mechanisms of glucagon secretion and α-cell function, including by nutritional status, nervous system, incretin, and intra-islet action. These findings have also led to the development of new therapeutic strategies targeting these factors. In the clinical management of diabetes, it has been imperative to prevent the development of ‘classic’ microvascular and macrovascular complications by adequate glycemic management. Nowadays, the prevention of ‘new’ complications and comorbidities such as metabolic liver disease, malignancies, dementia, and sarcopenia/frailty must also be carefully considered. In addition, several nutrients other than glucose are implicated in the onset and pathogenesis of these diseases. Glucagon is now recognized as an important key player in the metabolism of multiple nutrients, including glucose, amino acids, and lipids, so it will definitely be necessary to establish a new ‘glucagon-ology’ that transcends the conventional glucose-centric aspect and comprehensively overlooks the systemic energy and nutritional status to develop future therapeutic approaches based on it.