Glucagon receptor signaling is not required for N-carbamoyl glutamate- and l-citrulline-induced ureagenesis in mice

2020 ◽  
Vol 318 (5) ◽  
pp. G912-G927
Author(s):  
Katrine D. Galsgaard ◽  
Jens Pedersen ◽  
Sasha A. S. Kjeldsen ◽  
Marie Winther-Sørensen ◽  
Elena Stojanovska ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Urea Cycle ◽  
Receptor Signaling ◽  
Glucagon Receptor ◽  
Acetylglutamate Synthase

Hepatic ureagenesis is essential in amino acid metabolism and is importantly regulated by glucagon, but the exact mechanism is unclear. With the aim to identify the steps whereby glucagon both acutely and chronically regulates ureagenesis, we here show, contrary to our hypothesis, that glucagon receptor-mediated activation of ureagenesis is not required when N-acetylglutamate synthase activity and/or N-acetylglutamate levels are sufficient to activate the first step of the urea cycle in vivo.

scholarly journals Glucose and amino acid metabolism in mice depend mutually on glucagon and insulin receptor signaling

2019 ◽  
Vol 316 (4) ◽  
pp. E660-E673 ◽  
Author(s):  
Katrine D. Galsgaard ◽  
Marie Winther-Sørensen ◽  
Jens Pedersen ◽  
Sasha A. S. Kjeldsen ◽  
Mette M. Rosenkilde ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Insulin Receptor ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Receptor Signaling ◽  
Cell Secretion ◽  
Glucagon Receptor ◽  
Insulin Receptor Signaling ◽  
Glucagon And Insulin

Glucagon and insulin are important regulators of blood glucose. The importance of insulin receptor signaling for alpha-cell secretion and of glucagon receptor signaling for beta-cell secretion is widely discussed and of clinical interest. Amino acids are powerful secretagogues for both hormones, and glucagon controls amino acid metabolism through ureagenesis. The role of insulin in amino acid metabolism is less clear. Female C57BL/6JRj mice received an insulin receptor antagonist (IRA) (S961; 30 nmol/kg), a glucagon receptor antagonist (GRA) (25-2648; 100 mg/kg), or both GRA and IRA (GRA + IRA) 3 h before intravenous administration of similar volumes of saline, glucose (0.5 g/kg), or amino acids (1 µmol/g) while anesthetized with isoflurane. IRA caused basal hyperglycemia, hyperinsulinemia, and hyperglucagonemia. Unexpectedly, IRA lowered basal plasma concentrations of amino acids, whereas GRA increased amino acids, lowered glycemia, and increased glucagon but did not influence insulin concentrations. After administration of GRA + IRA, insulin secretion was significantly reduced compared with IRA administration alone. Blood glucose responses to a glucose and amino acid challenge were similar after vehicle and GRA + IRA administration but greater after IRA and lower after GRA. Anesthesia may have influenced the results, which otherwise strongly suggest that both hormones are essential for the maintenance of glucose homeostasis and that the secretion of both is regulated by powerful negative feedback mechanisms. In addition, insulin limits glucagon secretion, while endogenous glucagon stimulates insulin secretion, revealed during lack of insulin autocrine feedback. Finally, glucagon receptor signaling seems to be of greater importance for amino acid metabolism than insulin receptor signaling.

Amino Acid Metabolism Is Regulated by Glucagon Receptor Signaling in Mice

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 43-OR ◽  
Author(s):  
MARIE WINTHER-SOERENSEN ◽  
KATRINE D. GALSGAARD ◽  
RUNE E. KUHRE ◽  
JENS PEDERSEN ◽  
NICOLAI J. WEWER ALBRECHTSEN ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Receptor Signaling ◽  
Glucagon Receptor

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

2018 ◽  
Vol 314 (1) ◽  
pp. E93-E103 ◽  
Author(s):  
Katrine D. Galsgaard ◽  
Marie Winther-Sørensen ◽  
Cathrine Ørskov ◽  
Hannelouise Kissow ◽  
Steen S. Poulsen ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Alpha Cell ◽  
Alpha Cells ◽  
Receptor Signaling ◽  
Cell Hyperplasia ◽  
Glucagon Receptor ◽  
Pancreatic Alpha Cells

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, 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.

scholarly journals Glucagon Receptor Signaling and Glucagon Resistance

2019 ◽  
Vol 20 (13) ◽  
pp. 3314 ◽  
Author(s):  
Janah ◽  
Kjeldsen ◽  
Galsgaard ◽  
Winther-Sørensen ◽  
Stojanovska ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Metabolic Diseases ◽  
Physiological Role ◽  
Glucagon Receptor ◽  
Metabolomic Profiling ◽  
Hepatic Fat

Hundred years after the discovery of glucagon, its biology remains enigmatic. Accurate measurement of glucagon has been essential for uncovering its pathological hypersecretion that underlies various metabolic diseases including not only diabetes and liver diseases but also cancers (glucagonomas). The suggested key role of glucagon in the development of diabetes has been termed the bihormonal hypothesis. However, studying tissue-specific knockout of the glucagon receptor has revealed that the physiological role of glucagon may extend beyond blood-glucose regulation. Decades ago, animal and human studies reported an important role of glucagon in amino acid metabolism through ureagenesis. Using modern technologies such as metabolomic profiling, knowledge about the effects of glucagon on amino acid metabolism has been expanded and the mechanisms involved further delineated. Glucagon receptor antagonists have indirectly put focus on glucagon’s potential role in lipid metabolism, as individuals treated with these antagonists showed dyslipidemia and increased hepatic fat. One emerging field in glucagon biology now seems to include the concept of hepatic glucagon resistance. Here, we discuss the roles of glucagon in glucose homeostasis, amino acid metabolism, and lipid metabolism and present speculations on the molecular pathways causing and associating with postulated hepatic glucagon resistance.

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