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

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.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00198.2017 ◽

2018 ◽

Vol 314 (1) ◽

pp. E93-E103 ◽

Cited By ~ 33

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.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00294.2019 ◽

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.

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Amino Acid Metabolism Is Regulated by Glucagon Receptor Signaling in Mice

Diabetes ◽

10.2337/db18-43-or ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 43-OR ◽

Cited By ~ 1

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

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Biochemische Aspekte des Aminosäuren-Stoffwechsels bei Psoriasis vulgaris / Biochemical Aspects of Amino Acid Metabolism in Psoriasis vulgaris

Zeitschrift für Naturforschung C ◽

10.1515/znc-1973-7-816 ◽

1973 ◽

Vol 28 (7-8) ◽

pp. 449-451 ◽

Cited By ~ 2

Author(s):

G. Peter ◽

H. Angst ◽

U. Koch

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Free Amino Acids ◽

Free Amino ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Psoriasis Vulgaris ◽

Normal Subjects ◽

Pathological Process

Free and protein-bound amino acids in serum and scales were investigated. In serum the bound amino acids of psoriatics are significantly higher with exception of Pro, Met, Tyr and Phe in contrast to normal subjects. For free amino acids the differences between normal subjects and psoriatics found in serum and scales are not significant. Results are discussed in relation to the single amino acids and the biochemical correlations are outlined which takes the pathological process as a basis.

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The Diverse Functions of Non-Essential Amino Acids in Cancer

Cancers ◽

10.3390/cancers11050675 ◽

2019 ◽

Vol 11 (5) ◽

pp. 675 ◽

Cited By ~ 25

Author(s):

Bo-Hyun Choi ◽

Jonathan L. Coloff

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Cancer Therapy ◽

Metabolic Pathways ◽

Essential Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Essential Amino Acids ◽

Redox Status ◽

Antioxidant Systems

Far beyond simply being 11 of the 20 amino acids needed for protein synthesis, non-essential amino acids play numerous important roles in tumor metabolism. These diverse functions include providing precursors for the biosynthesis of macromolecules, controlling redox status and antioxidant systems, and serving as substrates for post-translational and epigenetic modifications. This functional diversity has sparked great interest in targeting non-essential amino acid metabolism for cancer therapy and has motivated the development of several therapies that are either already used in the clinic or are currently in clinical trials. In this review, we will discuss the important roles that each of the 11 non-essential amino acids play in cancer, how their metabolic pathways are linked, and how researchers are working to overcome the unique challenges of targeting non-essential amino acid metabolism for cancer therapy.

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Postharvest changes in ammonium, amino acids and enzymes of amino acid metabolism in asparagus spear tips

Journal of the Science of Food and Agriculture ◽

10.1002/jsfa.2740630414 ◽

1993 ◽

Vol 63 (4) ◽

pp. 465-471 ◽

Cited By ~ 36

Author(s):

Paul L. Hurst ◽

Christopher J. Clark

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism

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IDIOPATHIC HYPERGLYCINEMIA: A NEW DISORDER OF AMINO ACID METABOLISM

PEDIATRICS ◽

10.1542/peds.27.4.539 ◽

1961 ◽

Vol 27 (4) ◽

pp. 539-550 ◽

Cited By ~ 1

Author(s):

William L. Nyhan ◽

Margaret Borden ◽

Barton Childs

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Oral Administration ◽

Dietary Intake ◽

Urinary Excretion ◽

Cation Exchange ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Acute Illness ◽

Progressive Decrease

The amino acids of blood and urine have been investigated using chromatography on cation exchange columns in the study of a patient with idiopathic hyperglycinemia. Marked increases in concentrations of glycine, serine, alanine, isoleucine and valine were found in the plasma. These changes were not reflected in increased excretion of these amino acids in the urine (with the exception of glycine). Restriction of the dietary intake of protein resulted in a decrease in the concentrations of glycine and other amino acids in the blood and urine, and there was a concomitant decrease in the frequency and severity of episodes of acute illness. The oral administration of leucine was found to induce a decrease in the levels of a number of amino acids in the patient and in controls. Continued decrease during the 3 hours of observation was noted for serine, isoleucine and valine. A mild but progressive decrease in threonine concentration was observed in the controls, while in the patient the concentration increased after the administration of leucine. Decreased levels at 1½ hours, returning toward the fasting levels at 3 hours, were observed for alanine, taurine and glycine. These apparently normal responses to leucine loads were not mediated through increase in the urinary excretion of the amino acids involved, and the data are interpreted to indicate entry of these amino acids into cells.

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Glucagon Receptor Signaling and Glucagon Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms20133314 ◽

2019 ◽

Vol 20 (13) ◽

pp. 3314 ◽

Cited By ~ 18

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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Metabolic profile of in vitro derived human embryos is not affected by the mode of fertilization

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa015 ◽

2020 ◽

Vol 26 (4) ◽

pp. 277-287

Author(s):

Christine Leary ◽

Roger G Sturmey

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Metabolic Profile ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Human Embryos ◽

Embryo Morphology ◽

Male Factor ◽

Triglyceride Content

Abstract The pattern of metabolism by early embryos in vitro has been linked to a range of phenotypes, including viability. However, the extent to which metabolic function of embryos is modified by specific methods used during ART has yet to be fully described. This study has sought to determine if the mode of fertilization used to create embryos affects subsequent embryo metabolism of substrates. A metabolic profile, including consumption of key substrates and the endogenous triglyceride content of individual IVF and ICSI supernumerary embryos, was assessed and compared. Embryo development and quality was also recorded. All embryos were donated at a single clinical IVF center, on Day 5, from 36 patients aged 18–38 years, The data revealed that consumption of glucose and pyruvate, and production of lactate, did not differ between embryos created by IVF or ICSI. Similarly, the mode of insemination did not impact on the triglyceride content of embryos. However, ICSI-derived embryos displayed a more active turnover of amino acids (P = 0.023), compared to IVF embryos. The specific amino acids produced in higher quantities from ICSI compared to IVF embryos were aspartate (P = 0.016), asparagine (P = 0.04), histidine (P = 0.021) and threonine (P = 0.009) while leucine consumption was significantly lower (P = 0.04). However, importantly neither individual nor collective differences in amino acid metabolism were apparent for sibling oocytes subjected to either mode of fertilization. Embryo morphology (the number of top grade embryos) and development (proportion reaching the blastocyst stage) were comparable in patients undergoing IVF and ICSI. In conclusion, the microinjection of spermatozoa into oocytes does not appear to have an impact on subsequent metabolism and viability. Observed differences in amino acid metabolism may be attributed to male factor infertility of the patients rather than the ICSI procedure per se.

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