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L-Arginine in Clinical Nutrition pp 85–94Cite as

l-Arginine, Pancreatic Beta Cell Function, and Diabetes: Mechanisms of Stimulated Insulin Release and Pathways of Metabolism

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Part of the book series: Nutrition and Health ((NH))

Abstract

Arginine (C6H14N4O2) is nutritionally classified as a conditional essential amino acid that can be commonly found in the protein component of both plants and animal foods. Over the past two decades, studies have described its role as a mediator of multiple biological processes including the release of several hormones, collagen synthesis during wound healing, antitumor activity, and immune cell responses. Typically endogenous synthesis accounts for approximately 20 % of the daily expenditure, and normal levels of arginine in the blood range from 40 to 100 μmol/L, which may decrease by up to 20 % in diabetes. Moreover, arginine is an amino acid that, through its metabolism, can impact blood flow and blood pressure, especially in relation to the production of nitric oxide (NO•). l-arginine has pronounced glucoregulatory and insulinotropic effects, stimulating insulin secretion acutely but reducing beta cell secretory function and proliferation following chronic exposure. The effect of reducing l-arginine concentration in vivo may have profoundly negative effects on the beta cell as discussed in this chapter. In addition, pigment epithelium-derived factor (PEDF) may be considered as a novel modulator of arginine metabolism and nitric oxide generation in the beta cell. Lastly, the effects of arginine supplementation in sport and exercise are considered.

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References

  1. Newsholme P, Abdulkader F, Rebelato E, et al. Amino acids and diabetes: implications for endocrine, metabolic and immune function. Front Biosci (Landmark Ed). 2011;16:315–39.

    Article  CAS  Google Scholar 

  2. Newsholme P, Cruzat V, Arfuso F, Keane KN. Nutrient regulation of insulin secretion and action. J Endocrinol. 2014;221:R105–20.

    Article  CAS  PubMed  Google Scholar 

  3. Newsholme P, Gaudel C, McClenaghan NH. Nutrient regulation of insulin secretion and beta-cell functional integrity. Adv Exp Med Biol. 2010;654:91–114.

    Article  CAS  PubMed  Google Scholar 

  4. Mullooly N, Vernon W, Smith DM, Newsholme P. Elevated levels of branched-chain amino acids have little effect on pancreatic islet cells, but l-arginine impairs function through activation of the endoplasmic reticulum stress response. Exp Physiol. 2014;99(3):538–51.

    Google Scholar 

  5. McCluskey JT, Hamid M, Guo-Parke H, McClenaghan NH, Gomis R, Flatt PR. Development and functional characterization of insulin-releasing human pancreatic beta cell lines produced by electrofusion. J Biol Chem. 2011;286(25):21982–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Smith PA, Sakura H, Coles B, Gummerson N, Proks P, Ashcroft FM. Electrogenic l-arginine transport mediates stimulus-secretion coupling in mouse pancreatic beta-cells. J Physiol. 1997;499(Pt 3):625–35.

    Google Scholar 

  7. Sener A, Best LC, Yates AP, et al. Stimulus-secretion coupling of l-arginine-induced insulin release: comparison between the cationic amino acid and its methyl ester. Endocrine. 2000;13(3):329–40.

    Google Scholar 

  8. Cheng K, Delghingaro-Augusto V, Nolan CJ, et al. High passage MIN6 cells have impaired insulin secretion with impaired glucose and lipid oxidation. PLoS One. 2012;7(7):e40868.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. McClenaghan NH, Barnett CR, O’Harte FP, Flatt PR. Mechanisms of amino acid-induced insulin secretion from the glucose-responsive BRIN-BD11 pancreatic B-cell line. J Endocrinol. 1996;151(3):349–57.

    Article  CAS  PubMed  Google Scholar 

  10. Thams P, Capito K. l-arginine stimulation of glucose-induced insulin secretion through membrane depolarization and independent of nitric oxide. Eur J Endocrinol. 1999;140(1):87–93.

    Google Scholar 

  11. Krause M, Rodrigues-Krause J, O’Hagan C, et al. Differential nitric oxide levels in the blood and skeletal muscle of type 2 diabetic subjects may be consequence of adiposity: a preliminary study. Metabolism. 2012;61(11):1528–37.

    Article  CAS  PubMed  Google Scholar 

  12. Krause MS, McClenaghan NH, Flatt PR, de Bittencourt PIH, Murphy C, Newsholme P. l-arginine is essential for pancreatic β-cell functional integrity, metabolism and defense from inflammatory challenge. J Endocrinol. 2011;211(21784771):87–97.

    Google Scholar 

  13. Smukler SR, Tang L, Wheeler MB, Salapatek AM. Exogenous nitric oxide and endogenous glucose-stimulated beta-cell nitric oxide augment insulin release. Diabetes. 2002;51(12):3450–60.

    Article  CAS  PubMed  Google Scholar 

  14. Lajoix AD, Reggio H, Chardes T, et al. A neuronal isoform of nitric oxide synthase expressed in pancreatic beta-cells controls insulin secretion. Diabetes. 2001;50(6):1311–23.

    Article  CAS  PubMed  Google Scholar 

  15. Beffy P, Lajoix AD, Masiello P, et al. A constitutive nitric oxide synthase modulates insulin secretion in the INS-1 cell line. Mol Cell Endocrinol. 2001;183(1–2):41–8.

    Article  CAS  PubMed  Google Scholar 

  16. Newsholme P, Homem De Bittencourt PI, O’Hagan C, De Vito G, Murphy C, Krause MS. Exercise and possible molecular mechanisms of protection from vascular disease and diabetes: the central role of ROS and nitric oxide. Clin Sci (Lond). 2009;118(5):341–9.

    Article  Google Scholar 

  17. Galal O, Podlogar J, Verspohl EJ. Impact of ADMA (asymmetric dimethylarginine) on physiology with respect to diabetes mellitus and respiratory system BEAS-2B cells (human bronchial epithelial cells). J Pharm Pharmacol. 2013;65(2):253–63.

    Article  CAS  PubMed  Google Scholar 

  18. Krause Mda S, de Bittencourt Jr PI. Type 1 diabetes: can exercise impair the autoimmune event? The l-arginine/glutamine coupling hypothesis. Cell Biochem Funct. 2008;26(4):406–33.

    Google Scholar 

  19. Crow JP, Beckman JS. The role of peroxynitrite in nitric oxide-mediated toxicity. Curr Top Microbiol Immunol. 1995;196(7634825):57–73.

    CAS  PubMed  Google Scholar 

  20. Broca C, Brennan L, Petit P, Newsholme P, Maechler P. Mitochondria-derived glutamate at the interplay between branched-chain amino acid and glucose-induced insulin secretion. FEBS Lett. 2003;545(12804769):167–72.

    Article  CAS  PubMed  Google Scholar 

  21. MacDonald MJ, Fahien LA. Glutamate is not a messenger in insulin secretion. J Biol Chem. 2000;275(10967090):34025–7.

    Article  CAS  PubMed  Google Scholar 

  22. Monti LD, Casiraghi MC, Setola E, et al. l-arginine enriched biscuits improve endothelial function and glucose metabolism: a pilot study in healthy subjects and a cross-over study in subjects with impaired glucose tolerance and metabolic syndrome. Metabolism. 2013;62(2):255–64.

    Google Scholar 

  23. Steele FR, Chader GJ, Johnson LV, Tombran-Tink J. Pigment epithelium-derived factor: neurotrophic activity and identification as a member of the serine protease inhibitor gene family. Proc Natl Acad Sci U S A. 1993;90(4):1526–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tombran-Tink J, Chader GG, Johnson LV. PEDF: a pigment epithelium-derived factor with potent neuronal differentiative activity. Exp Eye Res. 1991;53(3):411–4.

    Article  CAS  PubMed  Google Scholar 

  25. Becerra SP. Focus on molecules: pigment epithelium-derived factor (PEDF). Exp Eye Res. 2006;82(5):739–40.

    Article  PubMed  Google Scholar 

  26. Filleur S, Nelius T, De Riese W, Kennedy RC. Characterization of pedf: a multi-functional serpin family protein. J Cell Biochem. 2009;106(5):769–75.

    Article  CAS  PubMed  Google Scholar 

  27. Silverman GA, Whisstock JC, Bottomley SP, et al. Serpins flex their muscle: I. Putting the clamps on proteolysis in diverse biological systems. J Biol Chem. 2010;285(32):24299–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Simonovic M, Gettins PGW, Volz K. Crystal structure of human PEDF, a potent anti-angiogenic and neurite growth-promoting factor. Proc Natl Acad Sci U S A. 2001;98(20):11131–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tombran-Tink J, Pawar H, Swaroop A, Rodriguez I, Chader GJ. Localization of the gene for pigment epithelium-derived factor (PEDF) to chromosome 17p13.1 and expression in cultured human retinoblastoma cells. Genomics. 1994;19(2):266–72.

    Article  CAS  PubMed  Google Scholar 

  30. Samkharadze T, Erkan M, Reiser-Erkan C, et al. Pigment epithelium-derived factor associates with neuropathy and fibrosis in pancreatic cancer. Am J Gastroenterol. 2011;106(5):968–80.

    Article  CAS  PubMed  Google Scholar 

  31. Broadhead ML, Becerra SP, Choong PFM, Dass CR. The applied biochemistry of PEDF and implications for tissue homeostasis. Growth Factors. 2010;28(4):280–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tombran-Tink J, Barnstable CJ. Osteoblasts and osteoclasts express PEDF, VEGF-A isoforms, and VEGF receptors: possible mediators of angiogenesis and matrix remodeling in the bone. Biochem Biophys Res Commun. 2004;316(2):573–9.

    Article  CAS  PubMed  Google Scholar 

  33. Elahy M, Baindur-Hudson S, Dass CR. The emerging role of PEDF in stem cell biology. J Biomed Biotechnol. 2012. doi:10.1155/2012/239091

  34. Sanchez A, Tripathy D, Yin X, Luo J, Martinez J, Grammas P. Pigment epithelium-derived factor (PEDF) protects cortical neurons in vitro from oxidant injury by activation of extracellular signal-regulated kinase (ERK) 1/2 and induction of Bcl-2. Neurosci Res. 2012;72(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  35. Wang Y, Subramanian P, Shen D, Tuo J, Becerra SP, Chan CC. Pigment epithelium-derived factor reduces apoptosis and pro-inflammatory cytokine gene expression in a murine model of focal retinal degeneration. ASN Neuro. 2013;5(5):e00126.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Nakashima S, Matsui T, Yamagishi S. Pigment epithelium-derived factor (PEDF) blocks high glucose-induced inflammatory reactions in endothelial cells through its anti-oxidative properties. Int J Cardiol. 2013;168(3):3004–6.

    Article  PubMed  Google Scholar 

  37. Dass CR, Choong PF. uPAR mediates anticancer activity of PEDF. Cancer Biol Ther. 2008;7(8):1262–70.

    Article  CAS  PubMed  Google Scholar 

  38. Broadhead ML, Dass CR, Choong PF. In vitro and in vivo biological activity of PEDF against a range of tumors. Expert Opin Ther Targets. 2009;13(12):1429–38.

    Article  CAS  PubMed  Google Scholar 

  39. Yasui N, Mori T, Morito D, et al. Dual-site recognition of different extracellular matrix components by anti-angiogenic/neurotrophic serpin, PEDF. Biochemistry. 2003;42(11):3160–7.

    Article  CAS  PubMed  Google Scholar 

  40. Sánchez-Sánchez F, Aroca-Aguilar JD, Segura I, et al. Expression and purification of functional recombinant human pigment epithelium-derived factor (PEDF) secreted by the yeast Pichia pastoris. J Biotechnol. 2008;134(1–2):193–201.

    Article  PubMed  Google Scholar 

  41. Orgaz JL, Ladhani O, Hoek KS, et al. Loss of pigment epithelium-derived factor enables migration, invasion and metastatic spread of human melanoma. Oncogene. 2009;28(47):4147–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yabe T, Wilson D, Schwartz JP. NFκB activation is required for the neuroprotective effects of pigment epithelium-derived factor (PEDF) on cerebellar granule neurons. J Biol Chem. 2001;276(46):43313–9.

    Article  CAS  PubMed  Google Scholar 

  43. Zaichuk TA, Shroff EH, Emmanuel R, Filleur S, Nelius T, Volpert OV. Nuclear factor of activated T cells balances angiogenesis activation and inhibition. J Exp Med. 2004;199(11):1513–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ho TC, Chen SL, Yang YC, Liao CL, Cheng HC, Tsao YP. PEDF induces p53-mediated apoptosis through PPAR gamma signaling in human umbilical vein endothelial cells. Cardiovasc Res. 2007;76(2):213–23.

    Article  CAS  PubMed  Google Scholar 

  45. Yamagishi S, Adachi H, Abe A, et al. Elevated serum levels of pigment epithelium-derived factor in the metabolic syndrome. J Clin Endocrinol Metab. 2006;91(6):2447–50.

    Article  CAS  PubMed  Google Scholar 

  46. Wang P, Smit E, Brouwers MC, et al. Plasma pigment epithelium-derived factor is positively associated with obesity in Caucasian subjects, in particular with the visceral fat depot. Eur J Endocrinol. 2008;159(6):713–8.

    Article  CAS  PubMed  Google Scholar 

  47. Ogata N, Matsuoka M, Matsuyama K, et al. Plasma concentration of pigment epithelium-derived factor in patients with diabetic retinopathy. J Clin Endocrinol Metab. 2007;92(3):1176–9.

    Article  CAS  PubMed  Google Scholar 

  48. Jenkins A, Zhang SX, Gosmanova A, et al. Increased serum pigment epithelium derived factor levels in type 2 diabetes patients. Diabetes Res Clin Pract. 2008;82(1):e5–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Crowe S, Wu LE, Economou C, et al. Pigment epithelium-derived factor contributes to insulin resistance in obesity. Cell Metab. 2009;10(1):40–7.

    Article  CAS  PubMed  Google Scholar 

  50. Famulla S, Lamers D, Hartwig S, et al. Pigment epithelium-derived factor (PEDF) is one of the most abundant proteins secreted by human adipocytes and induces insulin resistance and inflammatory signaling in muscle and fat cells. Int J Obes (Lond). 2011;35(6):762–72.

    Article  CAS  Google Scholar 

  51. Notari L, Baladron V, Aroca-Aguilar JD, et al. Identification of a lipase-linked cell membrane receptor for pigment epithelium-derived factor. J Biol Chem. 2006;281(49):38022–37.

    Article  CAS  PubMed  Google Scholar 

  52. Becerra SP, Notario V. The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential. Nat Rev Cancer. 2013;13(4):258–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chung C, Doll JA, Gattu AK, et al. Anti-angiogenic pigment epithelium-derived factor regulates hepatocyte triglyceride content through adipose triglyceride lipase (ATGL). J Hepatol. 2008;48(3):471–8.

    Article  CAS  PubMed  Google Scholar 

  54. Barbul A. l-Arginine: biochemistry, physiology, and therapeutic implications. JPEN J Parenter Enteral Nutr. 1986;10(2):227–38.

    Google Scholar 

  55. Wax B, Kavazis AN, Webb HE, Brown SP. Acute l-arginine alpha ketoglutarate supplementation fails to improve muscular performance in resistance trained and untrained men. J Int Soc Sports Nutr. 2012;9(1):17.

    Google Scholar 

  56. Fayh AP, Krause M, Rodrigues-Krause J, et al. Effects of l-arginine supplementation on blood flow, oxidative stress status and exercise responses in young adults with uncomplicated type I diabetes. Eur J Nutr. 2013;52(3):975–83.

    Google Scholar 

  57. Willoughby DS, Boucher T, Reid J, Skelton G, Clark M. Effects of 7 days of l-arginine-alpha-ketoglutarate supplementation on blood flow, plasma l-arginine, nitric oxide metabolites, and asymmetric dimethyl l-arginine after resistance exercise. Int J Sport Nutr Exerc Metab. 2011;21(4):291–9.

    Google Scholar 

  58. Liu TH, Wu CL, Chiang CW, Lo YW, Tseng HF, Chang CK. No effect of short-term l-arginine supplementation on nitric oxide production, metabolism and performance in intermittent exercise in athletes. J Nutr Biochem. 2009;20(6):462–8.

    Google Scholar 

  59. Castell LM, Burke LM, Stear SJ. A-Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance Part 2. Br J Sports Med. 2009;43(11):807–10.

    Article  CAS  PubMed  Google Scholar 

  60. Kanaley JA. Growth hormone, l-arginine and exercise. Curr Opin Clin Nutr Metab Care. 2008;11(1):50–4.

    Google Scholar 

  61. Cruzat VF, Pantaleao LC, Donato Jr J, de Bittencourt Jr PI, Tirapegui J. Oral supplementations with free and dipeptide forms of L-glutamine in endotoxemic mice: effects on muscle glutamine-glutathione axis and heat shock proteins. J Nutr Biochem. 2014;25(3):345–52.

    Article  CAS  PubMed  Google Scholar 

  62. Cruzat VF, Rogero MM, Tirapegui J. Effects of supplementation with free glutamine and the dipeptide alanyl-glutamine on parameters of muscle damage and inflammation in rats submitted to prolonged exercise. Cell Biochem Funct. 2010;28(1):24–30.

    Article  CAS  PubMed  Google Scholar 

  63. Basu HN, Liepa GU. l-Arginine: a clinical perspective. Nutr Clin Pract. 2002;17(4):218–25.

    Google Scholar 

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Acknowledgements

We thank the School of Biomedical Sciences and Faculty of Health Sciences, Curtin University, Perth, Western Australia, for provision of excellent research facilities and support.

Author declaration

All authors contributed to the writing of this manuscript and have no conflicts of interest with respect to publication. VC and PN were responsible for generation of Fig. 7.1.

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Authors and Affiliations

  1. School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Curtin University, Kent Street, Bentley, Perth, WA, 6102, Australia

    Philip Newsholme BSc (Hons), DPhil (PhD), Kevin N. Keane BSc, PhD & Vinicius Fernandes Cruzat

  2. School of Public Health, CHIRI Biosciences Research Precinct, Curtin University, Kent Street, Bentley, Perth, WA, 6102, Australia

    Mina Elahy BSc, MSc, PhD

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  1. Philip Newsholme BSc (Hons), DPhil (PhD)
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  3. Mina Elahy BSc, MSc, PhD
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Correspondence to Philip Newsholme BSc (Hons), DPhil (PhD) .

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Editors and Affiliations

  1. Faculty of Science & Technology Department of Biomedical Sciences, University of Westminster, London, United Kingdom

    Vinood B. Patel

  2. Department Nutrition and Dietetics Nutritional Sciences Division School of Biomedical & Health Sciences, King’s College London, London, United Kingdom

    Victor R. Preedy

  3. Nutritional Sciences Research Division Faculty of Life Science and Medicine, King’s College London, London, United Kingdom

    Rajkumar Rajendram

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Newsholme, P., Keane, K.N., Elahy, M., Cruzat, V.F. (2017). l-Arginine, Pancreatic Beta Cell Function, and Diabetes: Mechanisms of Stimulated Insulin Release and Pathways of Metabolism. In: Patel, V., Preedy, V., Rajendram, R. (eds) L-Arginine in Clinical Nutrition. Nutrition and Health. Humana Press, Cham. https://doi.org/10.1007/978-3-319-26009-9_7

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  • DOI: https://doi.org/10.1007/978-3-319-26009-9_7

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