scholarly journals Alanine, arginine, and proline but not glutamine are the feed-back regulators in the liver-alpha cell axis in mice

2019 ◽  
Author(s):  
Katrine D. Galsgaard ◽  
Sara Lind Jepsen ◽  
Sasha A.S. Kjeldsen ◽  
Jens Pedersen ◽  
Nicolai J. Wewer Albrechtsen ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Statistical Significance ◽  
Plasma Concentrations ◽  
Glucagon Secretion ◽  
Alpha Cell ◽  
Cell Axis ◽  
Glucagon Receptor ◽  
Significant Difference ◽  
Amino Acid Mixtures

AbstractAimTo identify the amino acids that stimulate glucagon secretion in mice and whether the metabolism of these relies on glucagon receptor signaling.MethodsPancreata of female C57BL/6JRj mice were perfused with 19 individual amino acids (1 mM) and secretion of glucagon was assessed using a specific glucagon radioimmunoassay. Separately, a glucagon receptor antagonist (GRA; 25-2648, 100 mg/kg) or vehicle was administered to female C57BL/6JRj mice three hours prior to an intraperitoneal injection of four different isomolar (in total 7 µmol/g body weight) amino acid mixtures; mixture 1: alanine, arginine, cysteine, and proline; mixture 2: asparatate, glutamate, histidine, and lysine; mixture 3: citrulline, methionine, serine, and threonine; and mixture 4: glutamine, leucine, isoleucine, and valine. Blood glucose, plasma glucagon, amino acid, and insulin concentrations were measured using well characterized methodologies.ResultsAlanine (P=0.03), arginine (P<0.001), and proline (P=0.03) but not glutamine (P=0.2) stimulated glucagon secretion from the perfused mouse pancreas. Cysteine had the numerically largest effect on glucagon secretion but did not reach statistical significance (P=0.08). However, when the four isomolar amino acid mixtures were administered there were no significant difference (P>0.5) in plasma concentrations of glucagon across mixture 1-4. Plasma concentrations of total amino acids were higher after administration of GRA when mixture 1 (P=0.004) or mixture 3 (P=0.04) were injected.ConclusionOur data suggest that alanine, arginine, and proline but not glutamine are involved in the liver-alpha cell axis in mice as they all increased glucagon secretion and their disappearance rate was altered by GRA.Graphical abstract

Alanine, arginine, cysteine, and proline, but not glutamine, are substrates for, and acute mediators of, the liver-α-cell axis in female mice

2020 ◽  
Vol 318 (6) ◽  
pp. E920-E929 ◽  
Author(s):  
Katrine D. Galsgaard ◽  
Sara L. Jepsen ◽  
Sasha A. S. Kjeldsen ◽  
Jens Pedersen ◽  
Nicolai J. Wewer Albrechtsen ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Plasma Concentrations ◽  
Glucagon Secretion ◽  
Cell Axis ◽  
Glucagon Receptor ◽  
Female Mice ◽  
Glucagon Receptor Antagonist ◽  
Amino Acid Mixtures

The aim of this study was to identify the amino acids that stimulate glucagon secretion in mice and whose metabolism depends on glucagon receptor signaling. Pancreata of female C57BL/6JRj mice were perfused with 19 individual amino acids and pyruvate (at 10 mM), and secretion of glucagon was assessed using a specific glucagon radioimmunoassay. Separately, a glucagon receptor antagonist (GRA; 25–2648, 100 mg/kg) or vehicle was administered to female C57BL/6JRj mice 3 h before an intraperitoneal injection of four different isomolar amino acid mixtures (in total 7 µmol/g body wt) as follows: mixture 1 contained alanine, arginine, cysteine, and proline; mixture 2 contained aspartate, glutamate, histidine, and lysine; mixture 3 contained citrulline, methionine, serine, and threonine; and mixture 4 contained glutamine, leucine, isoleucine, and valine. Blood glucose, plasma glucagon, amino acid, and insulin concentrations were measured using well-characterized methodologies. Alanine ( P = 0.03), arginine ( P < 0.0001), cysteine ( P = 0.01), glycine ( P = 0.02), lysine ( P = 0.02), and proline ( P = 0.03), but not glutamine ( P = 0.9), stimulated glucagon secretion from the perfused mouse pancreas. However, when the four isomolar amino acid mixtures were administered in vivo, the four mixtures elicited similar glucagon responses ( P > 0.5). Plasma concentrations of total amino acids in vivo were higher after administration of GRA when mixture 1 ( P = 0.004) or mixture 3 ( P = 0.04) were injected. Our data suggest that alanine, arginine, cysteine, and proline, but not glutamine, are involved in the acute regulation of the liver-α-cell axis in female mice, as they all increased glucagon secretion and their disappearance rate was altered by GRA.

scholarly journals The liver-alpha-cell axis after a mixed meal and during weight loss in type 2 diabetes

2021 ◽  
Author(s):  
Julia Otten ◽  
Andreas Stomby ◽  
Maria Waling ◽  
Elin Chorell ◽  
Mats Ryberg ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Amino Acids ◽  
Weight Loss ◽  
Insulin Sensitivity ◽  
Glucagon Secretion ◽  
Alpha Cell ◽  
Cell Axis ◽  
Hepatic Insulin Sensitivity ◽  
Protein Rich

Objective: Glucagon and amino acids may be regulated in a feedback loop called the liver-alpha-cell axis with alanine or glutamine as suggested signal molecules. We assessed this concept in individuals with type 2 diabetes in the fasting state, after ingestion of a protein rich meal and during weight loss. Moreover, we investigated if postprandial glucagon secretion and hepatic insulin sensitivity were related. Methods: This is a secondary analysis of a 12-week weight loss trial (Paleolithic diet ± exercise) in 29 individuals with type 2 diabetes. Before and after the intervention, plasma glucagon and amino acids were measured in the fasting state and during 180 min after a protein-rich mixed meal. Hepatic insulin sensitivity was measured using the hyperinsulinemic euglycemic clamp with [6,6-2H2]glucose as tracer. Results: The postprandial increase of plasma glucagon was associated with the postprandial increase of alanine and several other amino acids but not glutamine. In the fasted state and after the meal, glucagon levels were negatively correlated with hepatic insulin sensitivity (rS = -0.51 / r = -0.58 respectively; both P<0.05). Improved hepatic insulin sensitivity with weight loss was correlated with decreased postprandial glucagon response (r = -0.78; P<0.001). Conclusions: Several amino acids, notably alanine, but not glutamine could be key signals to the alpha cell to increase glucagon secretion. Amino acids may be part of a feedback mechanism as glucagon increases endogenous glucose production and ureagenesis in the liver. Moreover, postprandial glucagon secretion seems to be tightly related to hepatic insulin sensitivity.

scholarly journals EJE PRIZE 2018: A gut feeling about glucagon

2018 ◽  
Vol 178 (6) ◽  
pp. R267-R280 ◽  
Author(s):  
Filip K Knop
Keyword(s):  
Amino Acids ◽  
Glucagon Secretion ◽  
Feedback System ◽  
Alpha Cell ◽  
Liver Fat ◽  
Oral Glucose ◽  
Cell Axis ◽  
Intravenous Glucose ◽  
New Findings ◽  
Clinical Experiments

Hyperglucagonaemia (in the fasting as well as in the postprandial state) is considered a core pathophysiological component of diabetes and is found to contribute substantially to the hyperglycaemic state of diabetes. Hyperglucagonaemia is usually viewed upon as a consequence of pancreatic alpha cell insensitivity to the glucagon-suppressive effects of glucose and insulin. Since we observed that the well-known hyperglucagonaemic response to oral glucose in patients with type 2 diabetes is exchanged by normal suppression of plasma glucagon levels following isoglycaemic intravenous glucose administration in these patients, we have been focusing on the gut and gut-derived factors as potential mediators of diabetic hyperglucagonaemia. In a series of clinical experiments, we have elucidated the role of gut-derived factors in diabetic hyperglucagonaemia and shown that glucose-dependent insulinotropic polypeptide promotes hyperglucagonaemia and that glucagon, hitherto considered a pancreas-specific hormone, may also be secreted from extrapancreatic tissues – most likely from proglucagon-producing enteroendocrine cells. Furthermore, our observation that fasting hyperglucagonaemia is unrelated to the diabetic state, but strongly correlates with obesity, liver fat content and circulating amino acids, has made us question the common ‘pancreacentric’ and ‘glucocentric’ understanding of hyperglucagonaemia and led to the hypothesis that steatosis-induced hepatic glucagon resistance (and reduced amino acid turnover) and compensatory glucagon secretion mediated by increased circulating amino acids constitute a complete endocrine feedback system: the liver–alpha cell axis. This article summarises the physiological regulation of glucagon secretion in humans and considers new findings suggesting that the liver and the gut play key roles in determining fasting and postabsorptive circulating glucagon levels.

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 Deleterious mutation V369M in the mouse GCGR gene causes abnormal plasma amino acid levels indicative of a possible liver-α-cell axis

2021 ◽  
Author(s):  
Qiaofeng Liu ◽  
Guangyao Lin ◽  
Yan Chen ◽  
Wenbo Feng ◽  
Yingna Xu ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Glucagon Secretion ◽  
Plasma Amino Acid ◽  
Cell Hyperplasia ◽  
Cell Axis ◽  
Glucagon Receptor ◽  
A Cell ◽  
Amino Acid Levels

Glucagon plays an important role in glucose homeostasis and amino acid metabolism. It regulates plasma amino acid levels which in turn modulate glucagon secretion from the pancreatic a-cell, thereby establishing a liver-α-cell axis described recently. We reported previously that the knock-in mice bearing homozygous V369M substitution (equivalent to a naturally occurring mutation V368M in the human glucagon receptor, GCGR) led to hypoglycemia with improved glucose tolerance. They also exhibited hyperglucagonemia, pancreas enlargement and α-cell hyperplasia. Here, we investigated the effect of V369M/V368M mutation on glucagon-mediated amino acid metabolism. It was found that GcgrV369M+/+ mice displayed increased plasma amino acid levels in general, but significant accumulation of the ketogenic/glucogenic amino acids was observed in animals fed with a high fat diet, resulting in deleterious metabolic consequence characteristic of α-cell proliferation and hyperglucagonemia.

scholarly journals Progress towards reduced-crude protein diets for broiler chickens and sustainable chicken-meat production

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sonia Yun Liu ◽  
Shemil P. Macelline ◽  
Peter V. Chrystal ◽  
Peter H. Selle
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Broiler Chickens ◽  
Crude Protein ◽  
Plasma Concentrations ◽  
Essential Amino Acids ◽  
Chicken Meat ◽  
Meat Production ◽  
Accurate Identification ◽  
Reduced Crude Protein

AbstractThe prime purpose of this review is to explore the pathways whereby progress towards reduced-crude protein (CP) diets and sustainable chicken-meat production may be best achieved. Reduced-CP broiler diets have the potential to attenuate environmental pollution from nitrogen and ammonia emissions; moreover, they have the capacity to diminish the global chicken-meat industry’s dependence on soybean meal to tangible extents. The variable impacts of reduced-CP broiler diets on apparent amino acid digestibility coefficients are addressed. The more accurate identification of amino acid requirements for broiler chickens offered reduced-CP diets is essential as this would diminish amino acid imbalances and the deamination of surplus amino acids. Deamination of amino acids increases the synthesis and excretion of uric acid for which there is a requirement for glycine, this emphasises the value of so-called “non-essential” amino acids. Starch digestive dynamics and their possible impact of glucose on pancreatic secretions of insulin are discussed, although the functions of insulin in avian species require clarification. Maize is probably a superior feed grain to wheat as the basis of reduced-CP diets; if so, the identification of the underlying reasons for this difference should be instructive. Moderating increases in starch concentrations and condensing dietary starch:protein ratios in reduced-CP diets may prove to be advantageous as expanding ratios appear to be aligned to inferior broiler performance. Threonine is specifically examined because elevated free threonine plasma concentrations in birds offered reduced-CP diets may be indicative of compromised performance. If progress in these directions can be realised, then the prospects of reduced-CP diets contributing to sustainable chicken-meat production are promising.

scholarly journals Effect of co-ingestion of amino acids with rice on glycaemic and insulinaemic response

2015 ◽  
Vol 114 (11) ◽  
pp. 1845-1851 ◽  
Author(s):  
Yean Yean Soong ◽  
Joseph Lim ◽  
Lijuan Sun ◽  
Christiani Jeyakumar Henry
Keyword(s):  
Amino Acids ◽  
Blood Glucose ◽  
Amino Acid ◽  
Glycaemic Index ◽  
Amino Acid Mixture ◽  
Postprandial Blood Glucose ◽  
Acid Mixture ◽  
White Rice ◽  
Amino Acid Mixtures

AbstractConsumption of high glycaemic index (GI) and glycaemic response (GR) food such as white rice has been implicated in the development of type 2 diabetes. Previous studies have reported the ability of individual amino acids to reduce GR of carbohydrate-rich foods. Because of the bitter flavour of amino acids, they have rarely been used to reduce GR. We now report the use of a palatable, preformed amino acid mixture in the form of essence of chicken. In all, sixteen healthy male Chinese were served 68 or 136 ml amino acid mixture together with rice, or 15 or 30 min before consumption of white rice. Postprandial blood glucose and plasma insulin concentrations were measured at fasting and every 15 min after consumption of the meal until 60 min after the consumption of the white rice. Subsequent blood samples were taken at 30-min intervals until 210 min. The co-ingestion of 68 ml of amino acid mixture with white rice produced the best results in reducing the peak blood glucose and GR of white rice without increasing the insulinaemic response. It is postulated that amino acid mixtures prime β-cell insulin secretion and peripheral tissue uptake of glucose. The use of ready-to-drink amino acid mixtures may be a useful strategy for lowering the high-GI rice diets consumed in Asia.

scholarly journals Effect of Different Edaphic Crop Conditions on the Free Amino Acid Profile of PH-16 Dry Cacao Beans

Agronomy ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1637
Author(s):  
Quintino Reis de Araujo ◽  
Guilherme Amorim Homem de Abreu Loureiro ◽  
Cid Edson Mendonça Póvoas ◽  
Douglas Steinmacher ◽  
Stephane Sacramento de Almeida ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Glutamic Acid ◽  
Free Amino Acid ◽  
Free Amino Acids ◽  
Free Amino ◽  
Principal Component ◽  
Amino Acid Profile ◽  
Gamma Aminobutyric Acid ◽  
Significant Difference

Free amino acids in cacao beans are important precursors to the aroma and flavor of chocolate. In this research, we used inferential and explanatory statistical techniques to verify the effect of different edaphic crop conditions on the free amino acid profile of PH-16 dry cacao beans. The decreasing order of free amino acids in PH-16 dry cacao beans is leucine, phenylalanine, glutamic acid, alanine, asparagine, tyrosine, gamma-aminobutyric acid, valine, isoleucine, glutamine, lysine, aspartic acid, serine, tryptophan, threonine, glycine. With the exception of lysine, no other free amino acid showed a significant difference between means of different edaphic conditions under the ANOVA F-test. The hydrophobic free amino acids provided the largest contribution to the explained variance with 58.01% of the first dimension of the principal component analysis. Glutamic acid stands out in the second dimension with 13.09%. Due to the stability of the biochemical profile of free amino acids in this clonal variety, it is recommended that cacao producers consider the genotype as the primary source of variation in the quality of cacao beans and ultimately the chocolate to be produced.

Application of FT-IR Spectrometry to Determine the Global Metabolic Adaptations to Physical Conditioning in Sportsmen

2002 ◽  
Vol 56 (10) ◽  
pp. 1259-1267 ◽  
Author(s):  
Cyril Petibois ◽  
Georges Cazorla ◽  
André Cassaigne ◽  
Gérard Déléris
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Ir Spectra ◽  
Plasma Concentrations ◽  
Physical Conditioning ◽  
Ir Spectrometry ◽  
Metabolic Adaptations ◽  
Spectral Area ◽  
Ft Ir

Global metabolic adaptations to physical conditioning were described in 15 subjects by FT-IR spectrometry as the method allowed determination of glucose (Glc), lactate (La), glycerol, triglycerides (TG), fatty acyl moieties (FAM), and total amino acids plasma concentrations. Subtraction of plasma FT-IR spectra obtained at resting state from the exercise spectra also allowed determination of the biomolecular response to exercise. On week 1, exercise induced a transient hypoglycemia, a lactatemia increase of 153%, a FAM depletion of 27%, and a TG concentration decrease of 28%. Protein contents increased by 2%, but these were partly catabolized for amino acid supply (+27%), suggesting an important metabolic stress during exercise. On week 3, exercise hypoglycemia had disappeared, lactate increase was diminished by 91%, TG contents were decreased by 14%, and proteins and amino acids exhibited higher absorption increases. On week 5, TG and FAM concentrations were markedly increased during exercise, protein absorption was still increased (+9%), but amino acid blood release was diminished by 81%. These results described positive adaptations to training. Furthermore, FAM concentration could be determined from plasma FT-IR spectra by using the 2996–2819 cm−1 spectral area [ νas(CH3), νas(CH2), νs(CH3), and νs(CH2) absorbance; 0.82 mMol·L−1, a.u. cm−1], as well as for amino acid concentration by using the ν(COO−) spectral area (1430–1360 cm−1; 0.062 g·L−1, a.u. × cm−1). FT-IR spectrometry was useful to determine simultaneously various plasma concentrations and most of the biomolecular changes through successive samples.

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.

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