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Wewer Albrechtsen, N.J.* ; Holst, J.J.* ; Cherrington, A.D.* ; Finan, B.* ; Gluud, L.L.* ; Dean, E.D.* ; Campbell, J.E.* ; Bloom, S.R.* ; Tan, T.M.M.* ; Knop, F.K.* ; Müller, T.D.

100 years of glucagon and 100 more.

Diabetologia 66, 1378-1394 (2023)
Verlagsversion DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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. Graphical Abstract: [Figure not available: see fulltext.]
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Review
Korrespondenzautor
Schlagwörter Amino Acids ; Co-agonists ; Diabetes ; Gcgr ; Glucagon ; Glucagon Receptor ; Gluconeogenesis ; Nafld ; Review; Alpha-cell-function; Dependent Insulinotropic Polypeptide; Sympathetic-nerve Activity; Fatty Liver-disease; Pancreatic Alpha; Blood-glucose; Induced Hypoglycemia; Receptor Agonist; Plasma-glucose; Knockout Mice
ISSN (print) / ISBN 0012-186X
e-ISSN 1432-0428
Zeitschrift Diabetologia
Quellenangaben Band: 66, Heft: 8, Seiten: 1378-1394 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort Berlin ; Heidelberg [u.a.]
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
Förderungen
European Research Council ERC-CoG Trusted
German Center for Diabetes Research (DZD e.V.)
German Research Foundation (DFG)
National Institute of Health
Independent Research Fund Denmark, Sapere Aude
European Foundation
Novo Nordic Foundation