{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T19:24:04Z","timestamp":1793647444986,"version":"4.5.1"},"reference-count":62,"publisher":"American Diabetes Association","issue":"9","license":[{"start":{"date-parts":[[2022,6,3]],"date-time":"2022-06-03T00:00:00Z","timestamp":1654214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,9,1]]},"abstract":"<jats:p>Glucagon and insulin are the main regulators of blood glucose. While the actions of insulin are extensively mapped, less is known about glucagon. Besides glucagon\u2019s role in glucose homeostasis, there are additional links between the pancreatic \u03b1-cells and the hepatocytes, often collectively referred to as the liver\u2013\u03b1-cell axis, that may be of importance for health and disease. Thus, glucagon receptor antagonism (pharmacological or genetic), which disrupts the liver\u2013\u03b1-cell axis, results not only in lower fasting glucose but also in reduced amino acid turnover and dyslipidemia. Here, we review the actions of glucagon on glucose homeostasis, amino acid catabolism, and lipid metabolism in the context of the liver\u2013\u03b1-cell axis. The concept of glucagon resistance is also discussed, and we argue that the various elements of the liver\u2013\u03b1-cell axis may be differentially affected in metabolic diseases such as diabetes, obesity, and nonalcoholic fatty liver disease (NAFLD). This conceptual rethinking of glucagon biology may explain why patients with type 2 diabetes have hyperglucagonemia and how NAFLD disrupts the liver\u2013\u03b1-cell axis, compromising the normal glucagon-mediated enhancement of substrate-induced amino acid turnover and possibly fatty acid \u03b2-oxidation. In contrast to amino acid catabolism, glucagon-induced glucose production may not be affected by NAFLD, explaining the diabetogenic effect of NAFLD-associated hyperglucagonemia. Consideration of the liver\u2013\u03b1-cell axis is essential to understanding the complex pathophysiology underlying diabetes and other metabolic diseases.<\/jats:p>","DOI":"10.2337\/dbi22-0004","type":"journal-article","created":{"date-parts":[[2022,6,3]],"date-time":"2022-06-03T12:02:44Z","timestamp":1654257764000},"page":"1852-1861","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":87,"title":["The Liver\u2013\u03b1-Cell Axis in Health and in Disease"],"prefix":"10.2337","volume":"71","author":[{"given":"Michael M.","family":"Richter","sequence":"first","affiliation":[{"name":"1Department of Clinical Biochemistry, Diagnostic Center, Copenhagen University Hospital\u2014Rigshospitalet, Copenhagen, Denmark"},{"name":"2Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrine D.","family":"Galsgaard","sequence":"additional","affiliation":[{"name":"3Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Elmelund","sequence":"additional","affiliation":[{"name":"3Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2495-5034","authenticated-orcid":false,"given":"Filip K.","family":"Knop","sequence":"additional","affiliation":[{"name":"4Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark"},{"name":"5Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"},{"name":"6Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"},{"name":"7Steno Diabetes Center Copenhagen, Herlev, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte P.","family":"Suppli","sequence":"additional","affiliation":[{"name":"4Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6853-3805","authenticated-orcid":false,"given":"Jens J.","family":"Holst","sequence":"additional","affiliation":[{"name":"3Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"},{"name":"5Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Winther-S\u00f8rensen","sequence":"additional","affiliation":[{"name":"2Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"},{"name":"3Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sasha A.S.","family":"Kjeldsen","sequence":"additional","affiliation":[{"name":"2Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"},{"name":"3Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4230-5753","authenticated-orcid":false,"given":"Nicolai J.","family":"Wewer Albrechtsen","sequence":"additional","affiliation":[{"name":"1Department of Clinical Biochemistry, Diagnostic Center, Copenhagen University Hospital\u2014Rigshospitalet, Copenhagen, Denmark"},{"name":"2Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"},{"name":"3Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"},{"name":"8Department of Clinical Biochemistry, Copenhagen University Hospital\u2014Bispebjerg and Frederiksberg Hospital, Bispebjerg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2022,6,3]]},"reference":[{"key":"2023052414204717800_B1","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1152\/physrev.00025.2016","article-title":"The new biology and pharmacology of glucagon","volume":"97","author":"M\u00fcller","year":"2017","journal-title":"Physiol Rev"},{"key":"2023052414204717800_B2","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1210\/en.2016-1748","article-title":"Insulin and glucagon: partners for life","volume":"158","author":"Holst","year":"2017","journal-title":"Endocrinology"},{"key":"2023052414204717800_B3","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.2217\/bmm-2016-0090","article-title":"The biology of glucagon and the consequences of hyperglucagonemia","volume":"10","author":"Wewer Albrechtsen","year":"2016","journal-title":"Biomarkers 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