Author information
1Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark. nicolai.albrechtsen@regionh.dk.
2Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. nicolai.albrechtsen@regionh.dk.
3Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
4Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
5Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.
6Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA.
7Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
8Gastro Unit, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.
9Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
10Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
11Department of Medicine, Endocrinology Division, Duke University Medical Center, Durham, NC, USA.
12Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
13Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
14Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.
15Steno Diabetes Center Copenhagen, Herlev, Denmark.
16Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany.
17German Center for Diabetes Research (DZD), München Neuherberg, Germany.
Abstract
The peptide hormone glucagon, discovered in late 1922, is secreted from pancreatic alpha cells and is an essential regulator of metabolic homeostasis. This review summarises experiences since the discovery of glucagon regarding basic and clinical aspects of this hormone and speculations on the future directions for glucagon biology and glucagon-based therapies. The review was based on the international glucagon conference, entitled 'A hundred years with glucagon and a hundred more', held in Copenhagen, Denmark, in November 2022. The scientific and therapeutic focus of glucagon biology has mainly been related to its role in diabetes. In type 1 diabetes, the glucose-raising properties of glucagon have been leveraged to therapeutically restore hypoglycaemia. The hyperglucagonaemia evident in type 2 diabetes has been proposed to contribute to hyperglycaemia, raising questions regarding underlying mechanism and the importance of this in the pathogenesis of diabetes. Mimicry experiments of glucagon signalling have fuelled the development of several pharmacological compounds including glucagon receptor (GCGR) antagonists, GCGR agonists and, more recently, dual and triple receptor agonists combining glucagon and incretin hormone receptor agonism. From these studies and from earlier observations in extreme cases of either glucagon deficiency or excess secretion, the physiological role of glucagon has expanded to also involve hepatic protein and lipid metabolism. The interplay between the pancreas and the liver, known as the liver-alpha cell axis, reflects the importance of glucagon for glucose, amino acid and lipid metabolism. In individuals with diabetes and fatty liver diseases, glucagon's hepatic actions may be partly impaired resulting in elevated levels of glucagonotropic amino acids, dyslipidaemia and hyperglucagonaemia, reflecting a new, so far largely unexplored pathophysiological phenomenon termed 'glucagon resistance'. Importantly, the hyperglucagonaemia as part of glucagon resistance may result in increased hepatic glucose production and hyperglycaemia. Emerging glucagon-based therapies show a beneficial impact on weight loss and fatty liver diseases and this has sparked a renewed interest in glucagon biology to enable further pharmacological pursuits.