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

作者：Katrine D. Galsgaard, Marie Winther‐Sørensen, Cathrine Ørskov, Hannelouise Kissow, Steen Seier Poulsen, Hendrik Vilstrup, Cornelia Prehn, Jerzy Adamski, Sara L. Jepsen, Bolette Hartmann, Jenna Elizabeth Hunt, Maureen Charron, Jens Pedersen, Nicolai J. Wewer Albrechtsen, Jens J. Holst · 发表于：American Journal of Physiology-Endocrinology and Metabolism · 年份：2017 · DOI：10.1152/ajpendo.00198.2017 · 被引用次数：119 · 研究领域：Pancreatic function and diabetes、Diabetes Treatment and Management、Diabetes and associated disorders

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 α-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 (~6-fold) in the media and cell proliferation (~2-fold), respectively. In anesthetized mice, a glucagon receptor-specific antagonist (Novo Nordisk 25–2648, ...