American Journal of Physiology - Endocrinology and Metabolism
American Journal of Physiology - Endocrinology and Metabolism
5 years ago

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

Hunt, Prehn, Vilstrup, Poulsen, Ørskov, Winther-Sørensen, Hartmann, Galsgaard, Charron, Kissow, Holst, Wewer Albrechtsen, Adamski, Pedersen, Jepsen
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 to WT littermates. Incubating cultured α-TC1.9 cells with a mixture of amino acids (Vamin 1%) for 30 minutes and for up to 48 hours led to increased glucagon concentrations (~six-fold) in the media and cell proliferation (~two-fold), respectively. In anesthetized mice, a glucagon receptor specific antagonist (Novo Nordisk 25-2648, 100 mg/kg) reduced amino acid clearance. Our data supports 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.

Publisher URL: http://doi.org/10.1152/ajpendo.00198.2017

DOI: 10.1152/ajpendo.00198.2017

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.