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Philip Newsholme - One of the best experts on this subject based on the ideXlab platform.

  • pro inflammatory cytokines increase glucose alanine and triacylglycerol utilization but inhibit insulin secretion in a clonal pancreatic beta cell line
    Journal of Endocrinology, 2007
    Co-Authors: A P Kiely, Neville H Mcclenaghan, Peter R Flatt, Philip Newsholme
    Abstract:

    We have investigated the effects of prolonged exposure (24 h) to pro-inflammatory cytokines on beta-cell metabolism and insulin secretion using clonal BRIN-BD11 beta cells. Addition of IL-1beta, tumour necrosis factor-alpha and IFN-gamma (at concentrations that did not induce apoptosis) inhibited chronic (24 h) and acute stimulated levels of insulin release (by 59 and 93% respectively), increased cellular glucose and alanine consumption, and also elevated lactate and glutamate release. However, ATP levels and cellular triacylglycerol were decreased while glutathione was increased. We conclude that sub-lethal concentrations of pro-inflammatory cytokines appear to shift beta-cell metabolism away from a key role in energy generation and stimulus-secretion coupling and towards a catabolic state which may be related to cell defence.

  • l alanine induces changes in metabolic and signal transduction gene expression in a clonal rat pancreatic β cell line and protects from pro inflammatory cytokine induced apoptosis
    Clinical Science, 2005
    Co-Authors: Grainne A Cunningham, Neville H Mcclenaghan, Peter R Flatt, Philip Newsholme
    Abstract:

    Acute effects of nutrient stimuli on pancreatic beta-cell function are widely reported; however, the chronic effects of insulinotropic amino acids, such as L-alanine, on pancreatic beta-cell function and integrity are unknown. In the present study, the effects of prolonged exposure (24 h) to the amino acid L-alanine on insulin secretory function, gene expression and pro-inflammatory cytokineinduced apoptosis were studied using clonal BRIN-BDII cells. Expression profiling of BRIN-BD I I cells chronically exposed to L-alanine was performed using oligonucleotide microarray analysis. The effect of alanine, the NOS (inducible nitric oxide synthase) inhibitor NMA (N-G -methyl-L-arginine acetate) or the NOS and NADPH oxidase inhibitor DPI (diphenylene iodonium) on apoptosis induced by a pro-inflammatory cytokine mix [IL- I beta (interleukin- I beta), TNF-alpha (tumour necrosis factor-a) and IFN-gamma (interferon-gamma)] was additionally assessed by flow cytometry. Culture for 24 h with 10 MM L-alanine resulted in desensitization to the subsequent acute insulin stimulatory effects Of L-alanine. This was accompanied by substantial changes in gene expression of BRIN-BD I I cells. Sixty-six genes were up-regulated; 1.8-fold, including many involved in cellular signalling, metabolism, gene regulation, protein synthesis, apoptosis and the cellular stress response. Subsequent functional experiments confirmed that L-alanine provided protection of BRIN-BD I I cells from pro-inflammatory cytokine-induced apoptosis. Protection from apoptosis was mimicked by NMA or DPI suggesting L-alanine enhances intracellular antioxidant generation. These observations indicate important long-term effects of L-alanine in regulating gene expression, secretory function and the integrity of insulin-secreting cells. Specific amino acids may therefore play a key role in beta-cell function in vivo.

  • a comparative study of amino acid consumption by rat islet cells and the clonal beta cell line brin bd11 the functional significance of l alanine
    Journal of Endocrinology, 2003
    Co-Authors: Gordon Dixon, Neville H Mcclenaghan, Peter R Flatt, John J Nolan, Philip Newsholme
    Abstract:

    Evidence has been published that -alanine may, under appropriate conditions, promote insulin secretion in normal rodent islets and various beta cell lines. Previous results utilising the clonal beta-cell line BRIN-BD11, demonstrated that alanine dramatically elevated insulin release by a mechanism requiring oxidative metabolism. We demonstrate in this paper that addition of -alanine had an insulinotropic effect in dispersed primary islet cells. Addition of -glucose increased -alanine consumption in both BRIN-BD11 cells and primary islet cells. -glutamine consumption in the BRIN-BD11 cell line and primary rat islets was also determined. The consumption rate was in line with that previously reported for cells of the immune system and other glutamine-utilising cells or tissues. However, -alanine consumption was at least an order of magnitude higher than -glutamine consumption. The metabolism of -alanine in the beta-cell may result in stimulation of insulin secretion via generation of metabolic stimulus secretion coupling factors such as -glutamate.

  • a nuclear magnetic resonance based demonstration of substantial oxidative l alanine metabolism and l alanine enhanced glucose metabolism in a clonal pancreatic beta cell line metabolism of l alanine is important to the regulation of insulin secretion
    Diabetes, 2002
    Co-Authors: Lorraine Brennan, A Shine, C M Hewage, J P G Malthouse, Kevin M Brindle, Neville H Mcclenaghan, Peter R Flatt, Philip Newsholme
    Abstract:

    Early experiments indicated that islet beta-cells substantially metabolized L-alanine but that insulin secretion was largely unaffected by the amino acid. It was subsequently demonstrated using more intricate studies that L-alanine is a. strong stimulus to insulin secretion in the presence of glucose in normal rodent islets and beta-cell lines. Using C-13 nuclear magnetic resonance (NMR), we have demonstrated substantial oxidative metabolism of L-alanine by the clonal beta-cell line BRIN-BD11, with time-dependent increases in production of cellular glutamate and aspartate. Stimulatory effects of L-alanine on insulin secretion were attenuated by the inhibition of beta-cell oxidative phosphorylation using oligomycin. Additionally, we detected substantial production of lactate, alanine, and glutamate from glucose (16.7 mmol/l) after 60 min. On addition of 10 mmol/l L-alanine to a stimulus of 16.7 mmol/l glucose, the utilization rate of glucose increased -2.4-fold. L-Alanine dramatically enhanced NMR-measurable aspects of glucose metabolism (both oxidative and nonoxidative). The enhanced rate of entry of glucose-derived pyruvate into the tricarboxylic acid (TCA) cycle in the presence of alanine may have stimulated rates of generation of key metabolites, including ATP, which affect the insulin secretory process. Thus L-alanine metabolism, in addition to the enhancing effect on glucose metabolism, contributes to the stimulatory effects of this amino acid on insulin secretion in vitro.

  • a nuclear magnetic resonance based demonstration of substantial oxidative l alanine metabolism and l alanine enhanced glucose metabolism in a clonal pancreatic beta cell line metabolism of l alanine is important to the regulation of insulin secretion
    Diabetes, 2002
    Co-Authors: Lorraine Brennan, A Shine, C M Hewage, J P G Malthouse, Kevin M Brindle, Neville H Mcclenaghan, Peter R Flatt, Philip Newsholme
    Abstract:

    Early experiments indicated that islet beta-cells substantially metabolized L-alanine but that insulin secretion was largely unaffected by the amino acid. It was subsequently demonstrated using more intricate studies that L-alanine is a strong stimulus to insulin secretion in the presence of glucose in normal rodent islets and beta-cell lines. Using (13)C nuclear magnetic resonance (NMR), we have demonstrated substantial oxidative metabolism of L-alanine by the clonal beta-cell line BRIN-BD11, with time-dependent increases in production of cellular glutamate and aspartate. Stimulatory effects of L-alanine on insulin secretion were attenuated by the inhibition of beta-cell oxidative phosphorylation using oligomycin. Additionally, we detected substantial production of lactate, alanine, and glutamate from glucose (16.7 mmol/l) after 60 min. On addition of 10 mmol/l L-alanine to a stimulus of 16.7 mmol/l glucose, the utilization rate of glucose increased approximately 2.4-fold. L-Alanine dramatically enhanced NMR-measurable aspects of glucose metabolism (both oxidative and nonoxidative). The enhanced rate of entry of glucose-derived pyruvate into the tricarboxylic acid (TCA) cycle in the presence of alanine may have stimulated rates of generation of key metabolites, including ATP, which affect the insulin secretory process. Thus L-alanine metabolism, in addition to the enhancing effect on glucose metabolism, contributes to the stimulatory effects of this amino acid on insulin secretion in vitro.

R C Harris - One of the best experts on this subject based on the ideXlab platform.

  • twenty four weeks of β alanine supplementation on carnosine content related genes and exercise
    Medicine and Science in Sports and Exercise, 2017
    Co-Authors: Bryan Saunders, Vitor De Salles Painelli, R C Harris, Luana Farias De Oliveira, Vinicius Da Eira Silva, Rafael Pires Da Silva, Luiz Riani, Mariana Franchi, Livia De Souza Goncalves, Hamilton Roschel
    Abstract:

    Introduction: Skeletal muscle carnosine content can be increased through [beta]-alanine supplementation, but the maximum increase achievable with supplementation is unknown. No study has investigated the effects of prolonged supplementation on carnosine-related genes or exercise capacity. Purpose: To investigate the effects of 24-weeks of [beta]-alanine supplementation on muscle carnosine content, gene expression and high-intensity cycling capacity (CCT110%). Methods: Twenty-five active males were supplemented with 6.4 g[middle dot]day-1 of sustained release [beta]-alanine (BA) or placebo (PL) over a 24-week period. Every 4 weeks participants provided a muscle biopsy and performed the CCT110%. Biopsies were analysed for muscle carnosine content and gene expression (CARNS, TauT, ABAT, CNDP2, PHT1, PEPT2 and PAT1). Results: Carnosine content was increased from baseline at every time point in BA (all P<0.0001; Week 4: +11.37+/-7.03 mmol[middle dot]kg-1dm, Week 8: +13.88+/-7.84 mmol[middle dot]kg-1dm, Week 12: +16.95+/-8.54 mmol[middle dot]kg-1dm, Week 16: +17.63+/-8.42 mmol[middle dot]kg-1dm, Week 20: +21.20+/-7.86 mmol[middle dot]kg-1dm, Week 24: +20.15+/-7.63 mmol[middle dot]kg-1dm), but not PL (all P=1.00). Maximal changes were +25.66+/-7.63 mmol[middle dot]kg-1dm (range: +17.13 to +41.32 mmol[middle dot]kg-1dm), and absolute maximal content was 48.03+/-8.97 mmol[middle dot]kg-1dm (range: 31.79 to 63.92 mmol[middle dot]kg-1dm). There was an effect of supplement (P=0.002) on TauT; no further differences in gene expression were shown. Exercise capacity was improved in BA (P=0.05) with possible to almost certain improvements across all weeks. Conclusions: Twenty-four weeks of [beta]-alanine supplementation increased muscle carnosine content and improved high-intensity cycling capacity. Downregulation of TauT suggests it plays an important role in muscle carnosine accumulation with [beta]-alanine supplementation, while the variability in changes in muscle carnosine content between individuals suggests that other determinants other than the availability of [beta]-alanine may also bear a major influence on muscle carnosine content.

  • effects of beta alanine supplementation on brain homocarnosine carnosine signal and cognitive function an exploratory study
    PLOS ONE, 2015
    Co-Authors: Marina Yazigi Solis, Ruth M. Hobson, Daniel Martin, Vitor De Salles Painelli, Guilherme Giannini Artioli, Simon B Cooper, Maria Concepcion Garcia Otaduy, Hamilton Roschel, Jacques Robertson, R C Harris
    Abstract:

    Objectives Two independent studies were conducted to examine the effects of 28 d of Beta-Alanine supplementation at 6.4 g d-1 on brain homocarnosine/carnosine signal in omnivores and vegetarians (Study 1) and on cognitive function before and after exercise in trained cyclists (Study 2). Methods In Study 1, seven healthy vegetarians (3 women and 4 men) and seven age- and sexmatched omnivores undertook a brain 1H-MRS exam at baseline and after Beta-Alanine supplementation. In study 2, nineteen trained male cyclists completed four 20-Km cycling time trials (two pre supplementation and two post supplementation), with a battery of cognitive function tests (Stroop test, Sternberg paradigm, Rapid Visual Information Processing task) being performed before and after exercise on each occasion. Results In Study 1, there were no within-group effects of Beta-Alanine supplementation on brain homocarnosine/carnosine signal in either vegetarians (p = 0.99) or omnivores (p = 0.27); nor was there any effect when data from both groups were pooled (p = 0.19). Similarly, there was no group by time interaction for brain homocarnosine/carnosine signal (p = 0.27). In study 2, exercise improved cognitive function across all tests (P<0.05), although there was no effect (P>0.05) of Beta-Alanine supplementation on response times or accuracy for the Stroop test, Sternberg paradigm or RVIP task at rest or after exercise. Conclusion 28 d of Beta-Alanine supplementation at 6.4g d-1 appeared not to influence brain homocarnosine/carnosine signal in either omnivores or vegetarians; nor did it influence cognitive function before or after exercise in trained cyclists.

  • Effects of Beta-Alanine Supplementation on Brain Homocarnosine/Carnosine Signal and Cognitive Function: An Exploratory Study
    PloS one, 2015
    Co-Authors: Marina Yazigi Solis, Ruth M. Hobson, Daniel Martin, Vitor De Salles Painelli, Guilherme Giannini Artioli, Simon B Cooper, Maria Concepcion Garcia Otaduy, Hamilton Roschel, Jacques Robertson, R C Harris
    Abstract:

    Objectives Two independent studies were conducted to examine the effects of 28 d of Beta-Alanine supplementation at 6.4 g d-1 on brain homocarnosine/carnosine signal in omnivores and vegetarians (Study 1) and on cognitive function before and after exercise in trained cyclists (Study 2). Methods In Study 1, seven healthy vegetarians (3 women and 4 men) and seven age- and sexmatched omnivores undertook a brain 1H-MRS exam at baseline and after Beta-Alanine supplementation. In study 2, nineteen trained male cyclists completed four 20-Km cycling time trials (two pre supplementation and two post supplementation), with a battery of cognitive function tests (Stroop test, Sternberg paradigm, Rapid Visual Information Processing task) being performed before and after exercise on each occasion. Results In Study 1, there were no within-group effects of Beta-Alanine supplementation on brain homocarnosine/carnosine signal in either vegetarians (p = 0.99) or omnivores (p = 0.27); nor was there any effect when data from both groups were pooled (p = 0.19). Similarly, there was no group by time interaction for brain homocarnosine/carnosine signal (p = 0.27). In study 2, exercise improved cognitive function across all tests (P0.05) of Beta-Alanine supplementation on response times or accuracy for the Stroop test, Sternberg paradigm or RVIP task at rest or after exercise. Conclusion 28 d of Beta-Alanine supplementation at 6.4g d-1 appeared not to influence brain homocarnosine/carnosine signal in either omnivores or vegetarians; nor did it influence cognitive function before or after exercise in trained cyclists.

  • Homocarnosine/carnosine signal in vegetarians and omnivores before and after Beta-Alanine supplementation.
    2015
    Co-Authors: Marina Yazigi Solis, Ruth M. Hobson, Daniel Martin, Guilherme Giannini Artioli, Maria Concepcion Garcia Otaduy, Hamilton Roschel, Jacques Robertson, Simon Cooper, Vitor S. Painelli, R C Harris
    Abstract:

    Panel A: Homocarnosine/carnosine signal in vegetarians versus omnivores. Panel B: Effects of Beta-Alanine supplementation on brain homocarnosine/carnosine signal in all the subjects irrespective of their diet. Panel C: Effects of Beta-Alanine supplementation on homocarnosine/carnosine signal in vegetarians. Panel D: Effects of Beta-Alanine supplementation on homocarnosine/carnosine signal in omnivores. Data are expressed as individual data (circles), mean (central line) ± 95% confidence interval (lower and upper lines). Neither diet nor beta-supplementation significantly affected homocarnosine/carnosine signal.

  • beta alanine carnosyn supplementation in elderly subjects 60 80 years effects on muscle carnosine content and physical capacity
    Amino Acids, 2012
    Co-Authors: Serena Del Favero, Guilherme Giannini Artioli, Marina Yazigi Solis, Maria Concepcion Garcia Otaduy, Hamilton Roschel, R C Harris, Ana P Hayashi, Fabiana Braga Benatti, John A Wise, Claudia Da Costa Leite
    Abstract:

    The aim of this study was to investigate the effects of Beta-Alanine supplementation on exercise capacity and the muscle carnosine content in elderly subjects. Eighteen healthy elderly subjects (60–80 years, 10 female and 4 male) were randomly assigned to receive either Beta-Alanine (BA, n = 12) or placebo (PL, n = 6) for 12 weeks. The BA group received 3.2 g of Beta-Alanine per day (2 × 800 mg sustained-release Carnosyn™ tablets, given 2 times per day). The PL group received 2 × (2 × 800 mg) of a matched placebo. At baseline (PRE) and after 12 weeks (POST-12) of supplementation, assessments were made of the muscle carnosine content, anaerobic exercise capacity, muscle function, quality of life, physical activity and food intake. A significant increase in the muscle carnosine content of the gastrocnemius muscle was shown in the BA group (+85.4%) when compared with the PL group (+7.2%) (p = 0.004; ES: 1.21). The time-to-exhaustion in the constant-load submaximal test (i.e., TLIM) was significantly improved (p = 0.05; ES: 1.71) in the BA group (+36.5%) versus the PL group (+8.6%). Similarly, time-to-exhaustion in the incremental test was also significantly increased (p = 0.04; ES 1.03) following Beta-Alanine supplementation (+12.2%) when compared with placebo (+0.1%). Significant positive correlations were also shown between the relative change in the muscle carnosine content and the relative change in the time-to-exhaustion in the TLIM test (r = 0.62; p = 0.01) and in the incremental test (r = 0.48; p = 0.02). In summary, the current data indicate for the first time, that Beta-Alanine supplementation is effective in increasing the muscle carnosine content in healthy elderly subjects, with subsequent improvement in their exercise capacity.

Neville H Mcclenaghan - One of the best experts on this subject based on the ideXlab platform.

  • pro inflammatory cytokines increase glucose alanine and triacylglycerol utilization but inhibit insulin secretion in a clonal pancreatic beta cell line
    Journal of Endocrinology, 2007
    Co-Authors: A P Kiely, Neville H Mcclenaghan, Peter R Flatt, Philip Newsholme
    Abstract:

    We have investigated the effects of prolonged exposure (24 h) to pro-inflammatory cytokines on beta-cell metabolism and insulin secretion using clonal BRIN-BD11 beta cells. Addition of IL-1beta, tumour necrosis factor-alpha and IFN-gamma (at concentrations that did not induce apoptosis) inhibited chronic (24 h) and acute stimulated levels of insulin release (by 59 and 93% respectively), increased cellular glucose and alanine consumption, and also elevated lactate and glutamate release. However, ATP levels and cellular triacylglycerol were decreased while glutathione was increased. We conclude that sub-lethal concentrations of pro-inflammatory cytokines appear to shift beta-cell metabolism away from a key role in energy generation and stimulus-secretion coupling and towards a catabolic state which may be related to cell defence.

  • l alanine induces changes in metabolic and signal transduction gene expression in a clonal rat pancreatic β cell line and protects from pro inflammatory cytokine induced apoptosis
    Clinical Science, 2005
    Co-Authors: Grainne A Cunningham, Neville H Mcclenaghan, Peter R Flatt, Philip Newsholme
    Abstract:

    Acute effects of nutrient stimuli on pancreatic beta-cell function are widely reported; however, the chronic effects of insulinotropic amino acids, such as L-alanine, on pancreatic beta-cell function and integrity are unknown. In the present study, the effects of prolonged exposure (24 h) to the amino acid L-alanine on insulin secretory function, gene expression and pro-inflammatory cytokineinduced apoptosis were studied using clonal BRIN-BDII cells. Expression profiling of BRIN-BD I I cells chronically exposed to L-alanine was performed using oligonucleotide microarray analysis. The effect of alanine, the NOS (inducible nitric oxide synthase) inhibitor NMA (N-G -methyl-L-arginine acetate) or the NOS and NADPH oxidase inhibitor DPI (diphenylene iodonium) on apoptosis induced by a pro-inflammatory cytokine mix [IL- I beta (interleukin- I beta), TNF-alpha (tumour necrosis factor-a) and IFN-gamma (interferon-gamma)] was additionally assessed by flow cytometry. Culture for 24 h with 10 MM L-alanine resulted in desensitization to the subsequent acute insulin stimulatory effects Of L-alanine. This was accompanied by substantial changes in gene expression of BRIN-BD I I cells. Sixty-six genes were up-regulated; 1.8-fold, including many involved in cellular signalling, metabolism, gene regulation, protein synthesis, apoptosis and the cellular stress response. Subsequent functional experiments confirmed that L-alanine provided protection of BRIN-BD I I cells from pro-inflammatory cytokine-induced apoptosis. Protection from apoptosis was mimicked by NMA or DPI suggesting L-alanine enhances intracellular antioxidant generation. These observations indicate important long-term effects of L-alanine in regulating gene expression, secretory function and the integrity of insulin-secreting cells. Specific amino acids may therefore play a key role in beta-cell function in vivo.

  • a comparative study of amino acid consumption by rat islet cells and the clonal beta cell line brin bd11 the functional significance of l alanine
    Journal of Endocrinology, 2003
    Co-Authors: Gordon Dixon, Neville H Mcclenaghan, Peter R Flatt, John J Nolan, Philip Newsholme
    Abstract:

    Evidence has been published that -alanine may, under appropriate conditions, promote insulin secretion in normal rodent islets and various beta cell lines. Previous results utilising the clonal beta-cell line BRIN-BD11, demonstrated that alanine dramatically elevated insulin release by a mechanism requiring oxidative metabolism. We demonstrate in this paper that addition of -alanine had an insulinotropic effect in dispersed primary islet cells. Addition of -glucose increased -alanine consumption in both BRIN-BD11 cells and primary islet cells. -glutamine consumption in the BRIN-BD11 cell line and primary rat islets was also determined. The consumption rate was in line with that previously reported for cells of the immune system and other glutamine-utilising cells or tissues. However, -alanine consumption was at least an order of magnitude higher than -glutamine consumption. The metabolism of -alanine in the beta-cell may result in stimulation of insulin secretion via generation of metabolic stimulus secretion coupling factors such as -glutamate.

  • a nuclear magnetic resonance based demonstration of substantial oxidative l alanine metabolism and l alanine enhanced glucose metabolism in a clonal pancreatic beta cell line metabolism of l alanine is important to the regulation of insulin secretion
    Diabetes, 2002
    Co-Authors: Lorraine Brennan, A Shine, C M Hewage, J P G Malthouse, Kevin M Brindle, Neville H Mcclenaghan, Peter R Flatt, Philip Newsholme
    Abstract:

    Early experiments indicated that islet beta-cells substantially metabolized L-alanine but that insulin secretion was largely unaffected by the amino acid. It was subsequently demonstrated using more intricate studies that L-alanine is a. strong stimulus to insulin secretion in the presence of glucose in normal rodent islets and beta-cell lines. Using C-13 nuclear magnetic resonance (NMR), we have demonstrated substantial oxidative metabolism of L-alanine by the clonal beta-cell line BRIN-BD11, with time-dependent increases in production of cellular glutamate and aspartate. Stimulatory effects of L-alanine on insulin secretion were attenuated by the inhibition of beta-cell oxidative phosphorylation using oligomycin. Additionally, we detected substantial production of lactate, alanine, and glutamate from glucose (16.7 mmol/l) after 60 min. On addition of 10 mmol/l L-alanine to a stimulus of 16.7 mmol/l glucose, the utilization rate of glucose increased -2.4-fold. L-Alanine dramatically enhanced NMR-measurable aspects of glucose metabolism (both oxidative and nonoxidative). The enhanced rate of entry of glucose-derived pyruvate into the tricarboxylic acid (TCA) cycle in the presence of alanine may have stimulated rates of generation of key metabolites, including ATP, which affect the insulin secretory process. Thus L-alanine metabolism, in addition to the enhancing effect on glucose metabolism, contributes to the stimulatory effects of this amino acid on insulin secretion in vitro.

  • a nuclear magnetic resonance based demonstration of substantial oxidative l alanine metabolism and l alanine enhanced glucose metabolism in a clonal pancreatic beta cell line metabolism of l alanine is important to the regulation of insulin secretion
    Diabetes, 2002
    Co-Authors: Lorraine Brennan, A Shine, C M Hewage, J P G Malthouse, Kevin M Brindle, Neville H Mcclenaghan, Peter R Flatt, Philip Newsholme
    Abstract:

    Early experiments indicated that islet beta-cells substantially metabolized L-alanine but that insulin secretion was largely unaffected by the amino acid. It was subsequently demonstrated using more intricate studies that L-alanine is a strong stimulus to insulin secretion in the presence of glucose in normal rodent islets and beta-cell lines. Using (13)C nuclear magnetic resonance (NMR), we have demonstrated substantial oxidative metabolism of L-alanine by the clonal beta-cell line BRIN-BD11, with time-dependent increases in production of cellular glutamate and aspartate. Stimulatory effects of L-alanine on insulin secretion were attenuated by the inhibition of beta-cell oxidative phosphorylation using oligomycin. Additionally, we detected substantial production of lactate, alanine, and glutamate from glucose (16.7 mmol/l) after 60 min. On addition of 10 mmol/l L-alanine to a stimulus of 16.7 mmol/l glucose, the utilization rate of glucose increased approximately 2.4-fold. L-Alanine dramatically enhanced NMR-measurable aspects of glucose metabolism (both oxidative and nonoxidative). The enhanced rate of entry of glucose-derived pyruvate into the tricarboxylic acid (TCA) cycle in the presence of alanine may have stimulated rates of generation of key metabolites, including ATP, which affect the insulin secretory process. Thus L-alanine metabolism, in addition to the enhancing effect on glucose metabolism, contributes to the stimulatory effects of this amino acid on insulin secretion in vitro.

Peter R Flatt - One of the best experts on this subject based on the ideXlab platform.

  • pro inflammatory cytokines increase glucose alanine and triacylglycerol utilization but inhibit insulin secretion in a clonal pancreatic beta cell line
    Journal of Endocrinology, 2007
    Co-Authors: A P Kiely, Neville H Mcclenaghan, Peter R Flatt, Philip Newsholme
    Abstract:

    We have investigated the effects of prolonged exposure (24 h) to pro-inflammatory cytokines on beta-cell metabolism and insulin secretion using clonal BRIN-BD11 beta cells. Addition of IL-1beta, tumour necrosis factor-alpha and IFN-gamma (at concentrations that did not induce apoptosis) inhibited chronic (24 h) and acute stimulated levels of insulin release (by 59 and 93% respectively), increased cellular glucose and alanine consumption, and also elevated lactate and glutamate release. However, ATP levels and cellular triacylglycerol were decreased while glutathione was increased. We conclude that sub-lethal concentrations of pro-inflammatory cytokines appear to shift beta-cell metabolism away from a key role in energy generation and stimulus-secretion coupling and towards a catabolic state which may be related to cell defence.

  • l alanine induces changes in metabolic and signal transduction gene expression in a clonal rat pancreatic β cell line and protects from pro inflammatory cytokine induced apoptosis
    Clinical Science, 2005
    Co-Authors: Grainne A Cunningham, Neville H Mcclenaghan, Peter R Flatt, Philip Newsholme
    Abstract:

    Acute effects of nutrient stimuli on pancreatic beta-cell function are widely reported; however, the chronic effects of insulinotropic amino acids, such as L-alanine, on pancreatic beta-cell function and integrity are unknown. In the present study, the effects of prolonged exposure (24 h) to the amino acid L-alanine on insulin secretory function, gene expression and pro-inflammatory cytokineinduced apoptosis were studied using clonal BRIN-BDII cells. Expression profiling of BRIN-BD I I cells chronically exposed to L-alanine was performed using oligonucleotide microarray analysis. The effect of alanine, the NOS (inducible nitric oxide synthase) inhibitor NMA (N-G -methyl-L-arginine acetate) or the NOS and NADPH oxidase inhibitor DPI (diphenylene iodonium) on apoptosis induced by a pro-inflammatory cytokine mix [IL- I beta (interleukin- I beta), TNF-alpha (tumour necrosis factor-a) and IFN-gamma (interferon-gamma)] was additionally assessed by flow cytometry. Culture for 24 h with 10 MM L-alanine resulted in desensitization to the subsequent acute insulin stimulatory effects Of L-alanine. This was accompanied by substantial changes in gene expression of BRIN-BD I I cells. Sixty-six genes were up-regulated; 1.8-fold, including many involved in cellular signalling, metabolism, gene regulation, protein synthesis, apoptosis and the cellular stress response. Subsequent functional experiments confirmed that L-alanine provided protection of BRIN-BD I I cells from pro-inflammatory cytokine-induced apoptosis. Protection from apoptosis was mimicked by NMA or DPI suggesting L-alanine enhances intracellular antioxidant generation. These observations indicate important long-term effects of L-alanine in regulating gene expression, secretory function and the integrity of insulin-secreting cells. Specific amino acids may therefore play a key role in beta-cell function in vivo.

  • a comparative study of amino acid consumption by rat islet cells and the clonal beta cell line brin bd11 the functional significance of l alanine
    Journal of Endocrinology, 2003
    Co-Authors: Gordon Dixon, Neville H Mcclenaghan, Peter R Flatt, John J Nolan, Philip Newsholme
    Abstract:

    Evidence has been published that -alanine may, under appropriate conditions, promote insulin secretion in normal rodent islets and various beta cell lines. Previous results utilising the clonal beta-cell line BRIN-BD11, demonstrated that alanine dramatically elevated insulin release by a mechanism requiring oxidative metabolism. We demonstrate in this paper that addition of -alanine had an insulinotropic effect in dispersed primary islet cells. Addition of -glucose increased -alanine consumption in both BRIN-BD11 cells and primary islet cells. -glutamine consumption in the BRIN-BD11 cell line and primary rat islets was also determined. The consumption rate was in line with that previously reported for cells of the immune system and other glutamine-utilising cells or tissues. However, -alanine consumption was at least an order of magnitude higher than -glutamine consumption. The metabolism of -alanine in the beta-cell may result in stimulation of insulin secretion via generation of metabolic stimulus secretion coupling factors such as -glutamate.

  • a nuclear magnetic resonance based demonstration of substantial oxidative l alanine metabolism and l alanine enhanced glucose metabolism in a clonal pancreatic beta cell line metabolism of l alanine is important to the regulation of insulin secretion
    Diabetes, 2002
    Co-Authors: Lorraine Brennan, A Shine, C M Hewage, J P G Malthouse, Kevin M Brindle, Neville H Mcclenaghan, Peter R Flatt, Philip Newsholme
    Abstract:

    Early experiments indicated that islet beta-cells substantially metabolized L-alanine but that insulin secretion was largely unaffected by the amino acid. It was subsequently demonstrated using more intricate studies that L-alanine is a. strong stimulus to insulin secretion in the presence of glucose in normal rodent islets and beta-cell lines. Using C-13 nuclear magnetic resonance (NMR), we have demonstrated substantial oxidative metabolism of L-alanine by the clonal beta-cell line BRIN-BD11, with time-dependent increases in production of cellular glutamate and aspartate. Stimulatory effects of L-alanine on insulin secretion were attenuated by the inhibition of beta-cell oxidative phosphorylation using oligomycin. Additionally, we detected substantial production of lactate, alanine, and glutamate from glucose (16.7 mmol/l) after 60 min. On addition of 10 mmol/l L-alanine to a stimulus of 16.7 mmol/l glucose, the utilization rate of glucose increased -2.4-fold. L-Alanine dramatically enhanced NMR-measurable aspects of glucose metabolism (both oxidative and nonoxidative). The enhanced rate of entry of glucose-derived pyruvate into the tricarboxylic acid (TCA) cycle in the presence of alanine may have stimulated rates of generation of key metabolites, including ATP, which affect the insulin secretory process. Thus L-alanine metabolism, in addition to the enhancing effect on glucose metabolism, contributes to the stimulatory effects of this amino acid on insulin secretion in vitro.

  • a nuclear magnetic resonance based demonstration of substantial oxidative l alanine metabolism and l alanine enhanced glucose metabolism in a clonal pancreatic beta cell line metabolism of l alanine is important to the regulation of insulin secretion
    Diabetes, 2002
    Co-Authors: Lorraine Brennan, A Shine, C M Hewage, J P G Malthouse, Kevin M Brindle, Neville H Mcclenaghan, Peter R Flatt, Philip Newsholme
    Abstract:

    Early experiments indicated that islet beta-cells substantially metabolized L-alanine but that insulin secretion was largely unaffected by the amino acid. It was subsequently demonstrated using more intricate studies that L-alanine is a strong stimulus to insulin secretion in the presence of glucose in normal rodent islets and beta-cell lines. Using (13)C nuclear magnetic resonance (NMR), we have demonstrated substantial oxidative metabolism of L-alanine by the clonal beta-cell line BRIN-BD11, with time-dependent increases in production of cellular glutamate and aspartate. Stimulatory effects of L-alanine on insulin secretion were attenuated by the inhibition of beta-cell oxidative phosphorylation using oligomycin. Additionally, we detected substantial production of lactate, alanine, and glutamate from glucose (16.7 mmol/l) after 60 min. On addition of 10 mmol/l L-alanine to a stimulus of 16.7 mmol/l glucose, the utilization rate of glucose increased approximately 2.4-fold. L-Alanine dramatically enhanced NMR-measurable aspects of glucose metabolism (both oxidative and nonoxidative). The enhanced rate of entry of glucose-derived pyruvate into the tricarboxylic acid (TCA) cycle in the presence of alanine may have stimulated rates of generation of key metabolites, including ATP, which affect the insulin secretory process. Thus L-alanine metabolism, in addition to the enhancing effect on glucose metabolism, contributes to the stimulatory effects of this amino acid on insulin secretion in vitro.

Guilherme Giannini Artioli - One of the best experts on this subject based on the ideXlab platform.

  • nutritional strategies to modulate intracellular and extracellular buffering capacity during high intensity exercise
    Sports Medicine, 2015
    Co-Authors: Antonio Herbert Lancha, Vitor De Salles Painelli, Bryan Saunders, Guilherme Giannini Artioli
    Abstract:

    Intramuscular acidosis is a contributing factor to fatigue during high-intensity exercise. Many nutritional strategies aiming to increase intra- and extracellular buffering capacity have been investigated. Among these, supplementation of Beta-Alanine (~3–6.4 g/day for 4 weeks or longer), the rate-limiting factor to the intramuscular synthesis of carnosine (i.e. an intracellular buffer), has been shown to result in positive effects on exercise performance in which acidosis is a contributing factor to fatigue. Furthermore, sodium bicarbonate, sodium citrate and sodium/calcium lactate supplementation have been employed in an attempt to increase the extracellular buffering capacity. Although all attempts have increased blood bicarbonate concentrations, evidence indicates that sodium bicarbonate (0.3 g/kg body mass) is the most effective in improving high-intensity exercise performance. The evidence supporting the ergogenic effects of sodium citrate and lactate remain weak. These nutritional strategies are not without side effects, as gastrointestinal distress is often associated with the effective doses of sodium bicarbonate, sodium citrate and calcium lactate. Similarly, paresthesia (i.e. tingling sensation of the skin) is currently the only known side effect associated with Beta-Alanine supplementation, and it is caused by the acute elevation in plasma Beta-Alanine concentration after a single dose of Beta-Alanine. Finally, the co-supplementation of Beta-Alanine and sodium bicarbonate may result in additive ergogenic gains during high-intensity exercise, although studies are required to investigate this combination in a wide range of sports.

  • effects of beta alanine supplementation on brain homocarnosine carnosine signal and cognitive function an exploratory study
    PLOS ONE, 2015
    Co-Authors: Marina Yazigi Solis, Ruth M. Hobson, Daniel Martin, Vitor De Salles Painelli, Guilherme Giannini Artioli, Simon B Cooper, Maria Concepcion Garcia Otaduy, Hamilton Roschel, Jacques Robertson, R C Harris
    Abstract:

    Objectives Two independent studies were conducted to examine the effects of 28 d of Beta-Alanine supplementation at 6.4 g d-1 on brain homocarnosine/carnosine signal in omnivores and vegetarians (Study 1) and on cognitive function before and after exercise in trained cyclists (Study 2). Methods In Study 1, seven healthy vegetarians (3 women and 4 men) and seven age- and sexmatched omnivores undertook a brain 1H-MRS exam at baseline and after Beta-Alanine supplementation. In study 2, nineteen trained male cyclists completed four 20-Km cycling time trials (two pre supplementation and two post supplementation), with a battery of cognitive function tests (Stroop test, Sternberg paradigm, Rapid Visual Information Processing task) being performed before and after exercise on each occasion. Results In Study 1, there were no within-group effects of Beta-Alanine supplementation on brain homocarnosine/carnosine signal in either vegetarians (p = 0.99) or omnivores (p = 0.27); nor was there any effect when data from both groups were pooled (p = 0.19). Similarly, there was no group by time interaction for brain homocarnosine/carnosine signal (p = 0.27). In study 2, exercise improved cognitive function across all tests (P<0.05), although there was no effect (P>0.05) of Beta-Alanine supplementation on response times or accuracy for the Stroop test, Sternberg paradigm or RVIP task at rest or after exercise. Conclusion 28 d of Beta-Alanine supplementation at 6.4g d-1 appeared not to influence brain homocarnosine/carnosine signal in either omnivores or vegetarians; nor did it influence cognitive function before or after exercise in trained cyclists.

  • Effects of Beta-Alanine Supplementation on Brain Homocarnosine/Carnosine Signal and Cognitive Function: An Exploratory Study
    PloS one, 2015
    Co-Authors: Marina Yazigi Solis, Ruth M. Hobson, Daniel Martin, Vitor De Salles Painelli, Guilherme Giannini Artioli, Simon B Cooper, Maria Concepcion Garcia Otaduy, Hamilton Roschel, Jacques Robertson, R C Harris
    Abstract:

    Objectives Two independent studies were conducted to examine the effects of 28 d of Beta-Alanine supplementation at 6.4 g d-1 on brain homocarnosine/carnosine signal in omnivores and vegetarians (Study 1) and on cognitive function before and after exercise in trained cyclists (Study 2). Methods In Study 1, seven healthy vegetarians (3 women and 4 men) and seven age- and sexmatched omnivores undertook a brain 1H-MRS exam at baseline and after Beta-Alanine supplementation. In study 2, nineteen trained male cyclists completed four 20-Km cycling time trials (two pre supplementation and two post supplementation), with a battery of cognitive function tests (Stroop test, Sternberg paradigm, Rapid Visual Information Processing task) being performed before and after exercise on each occasion. Results In Study 1, there were no within-group effects of Beta-Alanine supplementation on brain homocarnosine/carnosine signal in either vegetarians (p = 0.99) or omnivores (p = 0.27); nor was there any effect when data from both groups were pooled (p = 0.19). Similarly, there was no group by time interaction for brain homocarnosine/carnosine signal (p = 0.27). In study 2, exercise improved cognitive function across all tests (P0.05) of Beta-Alanine supplementation on response times or accuracy for the Stroop test, Sternberg paradigm or RVIP task at rest or after exercise. Conclusion 28 d of Beta-Alanine supplementation at 6.4g d-1 appeared not to influence brain homocarnosine/carnosine signal in either omnivores or vegetarians; nor did it influence cognitive function before or after exercise in trained cyclists.

  • Homocarnosine/carnosine signal in vegetarians and omnivores before and after Beta-Alanine supplementation.
    2015
    Co-Authors: Marina Yazigi Solis, Ruth M. Hobson, Daniel Martin, Guilherme Giannini Artioli, Maria Concepcion Garcia Otaduy, Hamilton Roschel, Jacques Robertson, Simon Cooper, Vitor S. Painelli, R C Harris
    Abstract:

    Panel A: Homocarnosine/carnosine signal in vegetarians versus omnivores. Panel B: Effects of Beta-Alanine supplementation on brain homocarnosine/carnosine signal in all the subjects irrespective of their diet. Panel C: Effects of Beta-Alanine supplementation on homocarnosine/carnosine signal in vegetarians. Panel D: Effects of Beta-Alanine supplementation on homocarnosine/carnosine signal in omnivores. Data are expressed as individual data (circles), mean (central line) ± 95% confidence interval (lower and upper lines). Neither diet nor beta-supplementation significantly affected homocarnosine/carnosine signal.

  • beta alanine carnosyn supplementation in elderly subjects 60 80 years effects on muscle carnosine content and physical capacity
    Amino Acids, 2012
    Co-Authors: Serena Del Favero, Guilherme Giannini Artioli, Marina Yazigi Solis, Maria Concepcion Garcia Otaduy, Hamilton Roschel, R C Harris, Ana P Hayashi, Fabiana Braga Benatti, John A Wise, Claudia Da Costa Leite
    Abstract:

    The aim of this study was to investigate the effects of Beta-Alanine supplementation on exercise capacity and the muscle carnosine content in elderly subjects. Eighteen healthy elderly subjects (60–80 years, 10 female and 4 male) were randomly assigned to receive either Beta-Alanine (BA, n = 12) or placebo (PL, n = 6) for 12 weeks. The BA group received 3.2 g of Beta-Alanine per day (2 × 800 mg sustained-release Carnosyn™ tablets, given 2 times per day). The PL group received 2 × (2 × 800 mg) of a matched placebo. At baseline (PRE) and after 12 weeks (POST-12) of supplementation, assessments were made of the muscle carnosine content, anaerobic exercise capacity, muscle function, quality of life, physical activity and food intake. A significant increase in the muscle carnosine content of the gastrocnemius muscle was shown in the BA group (+85.4%) when compared with the PL group (+7.2%) (p = 0.004; ES: 1.21). The time-to-exhaustion in the constant-load submaximal test (i.e., TLIM) was significantly improved (p = 0.05; ES: 1.71) in the BA group (+36.5%) versus the PL group (+8.6%). Similarly, time-to-exhaustion in the incremental test was also significantly increased (p = 0.04; ES 1.03) following Beta-Alanine supplementation (+12.2%) when compared with placebo (+0.1%). Significant positive correlations were also shown between the relative change in the muscle carnosine content and the relative change in the time-to-exhaustion in the TLIM test (r = 0.62; p = 0.01) and in the incremental test (r = 0.48; p = 0.02). In summary, the current data indicate for the first time, that Beta-Alanine supplementation is effective in increasing the muscle carnosine content in healthy elderly subjects, with subsequent improvement in their exercise capacity.