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Galsgaard, K.D.* ; Winther-Sørensen, M.* ; Ørskov, C.* ; Kissow, J.* ; Poulsen, S.S.* ; Vilstrup, H.* ; Prehn, C. ; Adamski, J. ; Jepsen, S.L.* ; Hartmann, B.* ; Hunt, J.* ; Charron, M.J.* ; Pedersen, J.H.* ; Wewer Albrechtsen, N.J.* ; Holst, J.J.*

Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver-alpha-cell axis.

Am. J. Physiol. Endocrinol. Metab. 314, E93-E103 (2017)
Verlagsversion Postprint DOI
Open Access Green
Glucagon secreted from the pancreatic alpha-cells is essential for regulation of blood glucose levels. However, glucagon may play an equally important role in the regulation of amino acid metabolism by promoting ureagenesis. We hypothesized that disruption of glucagon receptor signaling would lead to an increased plasma concentration of amino acids, which in a feedback manner stimulates the secretion of glucagon, eventually associated with compensatory proliferation of the pancreatic alpha-cells. To address this, we performed plasma profiling of glucagon receptor knockout (Gcgr(-/-)) mice and wild-type (WT) littermates using liquid chromatography-mass spectrometry (LC-MS)based metabolomics, and tissue biopsies from the pancreas were analyzed for islet hormones and by histology. A principal component analysis of the plasma metabolome from Gcgr(-/-) and WT littermates indicated amino acids as the primary metabolic component distinguishing the two groups of mice. Apart from their hyperaminoacidemia, Gcgr(-/-) mice display hyperglucagonemia, increased pancreatic content of glucagon and somatostatin (but not insulin), and alpha-cell hyperplasia and hypertrophy compared with WT littermates. Incubating cultured alpha-TC1.9 cells with a mixture of amino acids (Vamin 1%) for 30 min and for up to 48 h led to increased glucagon concentrations (similar to 6-fold) in the media and cell proliferation (similar to 2-fold), respectively. In anesthetized mice, a glucagon receptor-specific antagonist (Novo Nordisk 25-2648, 100 mg/kg) reduced amino acid clearance. Our data support the notion that glucagon secretion and hepatic amino acid metabolism are linked in a close feedback loop, which operates independently of normal variations in glucose metabolism.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Alpha-cell ; Amino Acids ; Glucagon ; Glucagon Receptor ; Hyperglucagonemia; Amino-acid-metabolism; Diet-induced Obesity; Glucose-homeostasis; Glp-1 Receptor; Sandwich Elisa; Blood-glucose; Knockout Mice; Beta-cells; Secretion; Insulin
ISSN (print) / ISBN 0193-1849
e-ISSN 1522-1555
Quellenangaben Band: 314, Heft: 1, Seiten: E93-E103 Artikelnummer: , Supplement: ,
Verlag American Physiological Society
Verlagsort Bethesda
Begutachtungsstatus Peer reviewed
Institut(e) Molekulare Endokrinologie und Metabolismus (MEM)