title: Glucagon and Amino Acids Are Linked in a Mutual Feedback Cycle: The Liver-α-Cell Axis.
abstract: Glucagon is usually viewed as an important counterregulatory hormone in glucose metabolism, with actions opposing those of insulin. Evidence exists that shows glucagon is important for minute-to-minute regulation of postprandial hepatic glucose production, although conditions of glucagon excess or deficiency do not cause changes compatible with this view. In patients with glucagon-producing tumors (glucagonomas), the most conspicuous signs are skin lesions (necrolytic migratory erythema), while in subjects with inactivating mutations of the glucagon receptor, pancreatic swelling may be the first sign; neither condition is necessarily associated with disturbed glucose metabolism. In glucagonoma patients, amino acid turnover and ureagenesis are greatly accelerated, and low plasma amino acid levels are probably at least partly responsible for the necrolytic migratory erythema, which resolves after amino acid administration. In patients with receptor mutations (and in knockout mice), pancreatic swelling is due to α-cell hyperplasia with gross hypersecretion of glucagon, which according to recent groundbreaking research may result from elevated amino acid levels. Additionally, solid evidence indicates that ureagenesis, and thereby amino acid levels, is critically controlled by glucagon. Together, this constitutes a complete endocrine system; feedback regulation involving amino acids regulates α-cell function and secretion, while glucagon, in turn, regulates amino acid turnover.
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark jjholst@sund.ku.dk.|Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens J
authors.identifier: 0000-0001-6853-3805
authors.initials: JJ
authors.lastname: Holst
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Nicolai J
authors.identifier: 0000-0003-4230-5753
authors.initials: NJ
authors.lastname: Wewer Albrechtsen
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Pedersen
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.
authors.forename: Filip K
authors.initials: FK
authors.lastname: Knop
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D005246:Feedback; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D005935:Glucagonoma / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000378:metabolism; D018027:Receptors, Glucagon / Q000235:genetics; D014508:Urea / Q000378:metabolism
chemical_list: D000596:Amino Acids; D018027:Receptors, Glucagon; D014508:Urea; D005934:Glucagon; D005947:Glucose