European Journal of Nutrition

, Volume 52, Issue 3, pp 975–983

Effects of l-arginine supplementation on blood flow, oxidative stress status and exercise responses in young adults with uncomplicated type I diabetes

  • Ana Paula Trussardi Fayh
  • Mauricio Krause
  • Josianne Rodrigues-Krause
  • Jerri Luiz Ribeiro
  • Jorge Pinto Ribeiro
  • Rogério Friedman
  • José Cláudio Fonseca Moreira
  • Alvaro Reischak-Oliveira
Original Contribution

Abstract

Background and aims

Vascular disease is the principal cause of death and disability in patients with diabetes, and endothelial dysfunction seems to be the major cause in its pathogenesis. Since l-arginine levels are diminished in conditions such as type 1 and type 2 diabetes, in this work we aimed to verify the effects of l-arginine supplementation (7 g/day) over the endothelial function and oxidative stress markers in young male adults with uncomplicated type 1 diabetes. We also investigated the influences of l-arginine administration on vascular/oxidative stress responses to an acute bout of exercise.

Methods

Ten young adult male subjects with uncomplicated type 1 diabetes and twenty matched controls volunteered for this study. We analysed the influence of l-arginine supplementation (7 g/day during 1 week) over lower limb blood flow (using a venous occlusion plethysmography technique), oxidative stress marker (TBARS, Carbonyls), anti-oxidant parameters (uric acid and TRAP) and total tNOx in rest conditions and after a single bout of submaximal exercise (VO2 at 10 % below the second ventilatory threshold). Data described as mean ± standard error (SE). Alpha level was P < 0.05.

Results

Glycaemic control parameters were altered in type 1 diabetic subjects, such as HbA1c (5.5 ± 0.03 vs. 8.3 ± 0.4 %) and fasted glycaemia (94.8 ± 1.4 vs. 183 ± 19 mg/dL). Oxidative stress/damage markers (carbonyls and TBARS) were increased in the diabetic group, while uric acid was decreased. Rest lower limb blood flow was lower in type 1 diabetic subjects than in healthy controls (3.53 ± 0.35 vs. 2.66 ± 0.3 ml 100 ml¹ min¹). l-Arginine supplementation completely recovered basal blood flow to normal levels in type 1 diabetics’ subjects (2.66 ± 0.3 to 4.74 ± 0.86 ml 100 ml¹ min¹) but did not interfere in any parameter of redox state or exercise.

Conclusion

Our findings highlight the importance of l-arginine for the improvement of vascular function in subjects with diabetes, indicating that l-arginine supplementation could be an essential tool for the treatment for the disease complications, at least in non-complicated diabetes. However, based on our data, it is not possible to draw conclusions regarding the mechanisms by which l-arginine therapy is inducing improvements on cardiovascular function, but this important issue requires further investigations.

Keywords

l-Arginine Type 1 diabetes Blood flow Oxidative stress 

Supplementary material

394_2012_404_MOESM1_ESM.ppt (248 kb)
Supplementary material 1 (PPT 248 kb)

References

  1. 1.
    Melendez-Ramirez LY, Richards RJ, Cefalu WT (2010) Complications of type 1 diabetes. Endocrinol Metab Clin North Am 39:625–640CrossRefGoogle Scholar
  2. 2.
    Huysman E, Mathieu C (2009) Diabetes and peripheral vascular disease. Acta Chir Belg 109:587–594Google Scholar
  3. 3.
    Krause Mda S, De Bittencourt PI Jr (2008) Type 1 diabetes: can exercise impair the autoimmune event? The l-arginine/glutamine coupling hypothesis. Cell Biochem Funct 26:406–433CrossRefGoogle Scholar
  4. 4.
    Poston L, Taylor PD (1995) Glaxo/MRS young investigator prize. Endothelium-mediated vascular function in insulin-dependent diabetes mellitus. Clin Sci (Lond) 88:245–255Google Scholar
  5. 5.
    Meeking DR, Browne DL, Allard S, Munday J, Chowienczyck PJ, Shaw KM, Cummings MH (2000) Effects of cyclo-oxygenase inhibition on vasodilatory response to acetylcholine in patients with type 1 diabetes and nondiabetic subjects. Diabetes Care 23:1840–1843CrossRefGoogle Scholar
  6. 6.
    Newsholme P, Homem De Bittencourt PI, C OH, De Vito G, Murphy C, Krause MS (2009) Exercise and possible molecular mechanisms of protection from vascular disease and diabetes: the central role of ROS and nitric oxide. Clin Sci (Lond) 118:341–349Google Scholar
  7. 7.
    Barbul A (1986) Arginine: biochemistry, physiology, and therapeutic implications. JPEN J Parenter Enteral Nutr 10:227–238CrossRefGoogle Scholar
  8. 8.
    Flynn NE, Meininger CJ, Haynes TE, Wu G (2002) The metabolic basis of arginine nutrition and pharmacotherapy. Biomed Pharmacother 56:427–438CrossRefGoogle Scholar
  9. 9.
    Maxwell AJ (2002) Mechanisms of dysfunction of the nitric oxide pathway in vascular diseases. Nitric Oxide 6:101–124CrossRefGoogle Scholar
  10. 10.
    El-Missiry MA, Othman AI, Amer MA (2004) l-Arginine ameliorates oxidative stress in alloxan-induced experimental diabetes mellitus. J Appl Toxicol 24:93–97CrossRefGoogle Scholar
  11. 11.
    Krause MS, McClenaghan NH, Flatt PR, de Bittencourt PI, Murphy C, Newsholme P (2011) l-arginine is essential for pancreatic beta-cell functional integrity, metabolism and defense from inflammatory challenge. J Endocrinol 211:87–97CrossRefGoogle Scholar
  12. 12.
    Fu WJ, Haynes TE, Kohli R, Hu J, Shi W, Spencer TE, Carroll RJ, Meininger CJ, Wu G (2005) Dietary l-arginine supplementation reduces fat mass in Zucker diabetic fatty rats. J Nutr 135:714–721Google Scholar
  13. 13.
    Vasilijevic A, Buzadzic B, Korac A, Petrovic V, Jankovic A, Korac B (2007) Beneficial effects of l-arginine nitric oxide-producing pathway in rats treated with alloxan. J Physiol 584:921–933CrossRefGoogle Scholar
  14. 14.
    Mendez JD, Balderas F (2001) Regulation of hyperglycemia and dyslipidemia by exogenous l-arginine in diabetic rats. Biochimie 83:453–458CrossRefGoogle Scholar
  15. 15.
    West MB, Ramana KV, Kaiserova K, Srivastava SK, Bhatnagar A (2008) l-Arginine prevents metabolic effects of high glucose in diabetic mice. FEBS Lett 582:2609–2614CrossRefGoogle Scholar
  16. 16.
    Mendez JD, Hernandez Rde H (2005) l-Arginine and polyamine administration protect beta-cells against alloxan diabetogenic effect in Sprague-Dawley rats. Biomed Pharmacother 59:283–289CrossRefGoogle Scholar
  17. 17.
    Wu G, Collins JK, Perkins-Veazie P, Siddiq M, Dolan KD, Kelly KA, Heaps CL, Meininger CJ (2007) Dietary supplementation with watermelon pomace juice enhances arginine availability and ameliorates the metabolic syndrome in Zucker diabetic fatty rats. J Nutr 137:2680–2685Google Scholar
  18. 18.
    Lucotti P, Monti L, Setola E, La Canna G, Castiglioni A, Rossodivita A, Pala MG, Formica F, Paolini G, Catapano AL, Bosi E, Alfieri O, Piatti P (2009) Oral l-arginine supplementation improves endothelial function and ameliorates insulin sensitivity and inflammation in cardiopathic nondiabetic patients after an aortocoronary bypass. Metabolism 58:1270–1276CrossRefGoogle Scholar
  19. 19.
    Settergren M, Bohm F, Malmstrom RE, Channon KM, Pernow J (2009) l-arginine and tetrahydrobiopterin protects against ischemia/reperfusion-induced endothelial dysfunction in patients with type 2 diabetes mellitus and coronary artery disease. Atherosclerosis 204:73–78CrossRefGoogle Scholar
  20. 20.
    Martina V, Masha A, Gigliardi VR, Brocato L, Manzato E, Berchio A, Massarenti P, Settanni F, Della Casa L, Bergamini S, Iannone A (2008) Long-term N-acetylcysteine and l-arginine administration reduces endothelial activation and systolic blood pressure in hypertensive patients with type 2 diabetes. Diabetes Care 31:940–944CrossRefGoogle Scholar
  21. 21.
    Lucotti P, Setola E, Monti LD, Galluccio E, Costa S, Sandoli EP, Fermo I, Rabaiotti G, Gatti R, Piatti P (2006) Beneficial effects of a long-term oral l-arginine treatment added to a hypocaloric diet and exercise training program in obese, insulin-resistant type 2 diabetic patients. Am J Physiol Endocrinol Metab 291:E906–E912CrossRefGoogle Scholar
  22. 22.
    Natarajan Sulochana K, Lakshmi S, Punitham R, Arokiasamy T, Sukumar B, Ramakrishnan S (2002) Effect of oral supplementation of free amino acids in type 2 diabetic patients—a pilot clinical trial. Med Sci Monit 8:CR131–137Google Scholar
  23. 23.
    Heitzer T, Krohn K, Albers S, Meinertz T (2000) Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with type II diabetes mellitus. Diabetologia 43:1435–1438CrossRefGoogle Scholar
  24. 24.
    Wascher TC, Graier WF, Dittrich P, Hussain MA, Bahadori B, Wallner S, Toplak H (1997) Effects of low-dose l-arginine on insulin-mediated vasodilatation and insulin sensitivity. Eur J Clin Invest 27:690–695CrossRefGoogle Scholar
  25. 25.
    Marwick TH, Hordern MD, Miller T, Chyun DA, Bertoni AG, Blumenthal RS, Philippides G, Rocchini A (2009) Exercise training for type 2 diabetes mellitus: impact on cardiovascular risk: a scientific statement from the American Heart Association. Circulation 119:3244–3262CrossRefGoogle Scholar
  26. 26.
    Palloshi A, Fragasso G, Piatti P, Monti LD, Setola E, Valsecchi G, Galluccio E, Chierchia SL, Margonato A (2004) Effect of oral l-arginine on blood pressure and symptoms and endothelial function in patients with systemic hypertension, positive exercise tests, and normal coronary arteries. Am J Cardiol 93:933–935CrossRefGoogle Scholar
  27. 27.
    Ceremuzynski L, Chamiec T, Herbaczynska-Cedro K (1997) Effect of supplemental oral l-arginine on exercise capacity in patients with stable angina pectoris. Am J Cardiol 80:331–333CrossRefGoogle Scholar
  28. 28.
    Bednarz B, Wolk R, Chamiec T, Herbaczynska-Cedro K, Winek D, Ceremuzynski L (2000) Effects of oral l-arginine supplementation on exercise-induced QT dispersion and exercise tolerance in stable angina pectoris. Int J Cardiol 75:205–210CrossRefGoogle Scholar
  29. 29.
    Abdelhamed AI, Reis SE, Sane DC, Brosnihan KB, Preli RB, Herrington DM (2003) No effect of an l-arginine-enriched medical food (HeartBars) on endothelial function and platelet aggregation in subjects with hypercholesterolemia. Am Heart J 145:E15CrossRefGoogle Scholar
  30. 30.
    Clarkson P, Adams MR, Powe AJ, Donald AE, McCredie R, Robinson J, McCarthy SN, Keech A, Celermajer DS, Deanfield JE (1996) Oral l-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest 97:1989–1994CrossRefGoogle Scholar
  31. 31.
    Pollack ML, Schmidt DH, Jackson AS (1980) Measurement of cardio-respiratory fitness and body composition in the clinical setting. Compr Ther 6:12–27Google Scholar
  32. 32.
    Metra M, Raddino R, Dei Cas L, Visioli O (1990) Assessment of peak oxygen consumption, lactate and ventilatory thresholds and correlation with resting and exercise hemodynamic data in chronic congestive heart failure. Am J Cardiol 65:1127–1133CrossRefGoogle Scholar
  33. 33.
    Duncan GE, Howley ET, Johnson BN (1997) Applicability of VO2max criteria: discontinuous versus continuous protocols. Med Sci Sports Exerc 29:273–278Google Scholar
  34. 34.
    Dekerle J, Baron B, Dupont L, Vanvelcenaher J, Pelayo P (2003) Maximal lactate steady state, respiratory compensation threshold and critical power. Eur J Appl Physiol 89:281–288CrossRefGoogle Scholar
  35. 35.
    Wasserman K, McIlroy MB (1964) Detecting the threshold of anaerobic metabolism in cardiac patients during exercise. Am J Cardiol 14:844–852CrossRefGoogle Scholar
  36. 36.
    Amann M, Subudhi AW, Walker J, Eisenman P, Shultz B, Foster C (2004) An evaluation of the predictive validity and reliability of ventilatory threshold. Med Sci Sports Exerc 36:1716–1722CrossRefGoogle Scholar
  37. 37.
    Copeland SR, Mills MC, Lerner JL, Crizer MF, Thompson CW, Sullivan JM (1996) Hemodynamic effects of aerobic vs resistance exercise. J Hum Hypertens 10:747–753Google Scholar
  38. 38.
    Miranda KM, Espey MG, Wink DA (2001) A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide 5:62–71CrossRefGoogle Scholar
  39. 39.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
  40. 40.
    Draper HH, Hadley M (1990) Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol 186:421–431CrossRefGoogle Scholar
  41. 41.
    Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG, Ahn BW, Shaltiel S, Stadtman ER (1990) Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol 186:464–478CrossRefGoogle Scholar
  42. 42.
    Wayner DD, Burton GW, Ingold KU, Locke S (1985) Quantitative measurement of the total, peroxyl radical-trapping antioxidant capability of human blood plasma by controlled peroxidation. The important contribution made by plasma proteins. FEBS Lett 187:33–37CrossRefGoogle Scholar
  43. 43.
    Cvetkovic T, Mitic B, Lazarevic G, Vlahovic P, Antic S, Stefanovic V (2009) Oxidative stress parameters as possible urine markers in patients with diabetic nephropathy. J Diabetes Complications 23:337–342CrossRefGoogle Scholar
  44. 44.
    Huang EA, Gitelman SE (2008) The effect of oral alpha-lipoic acid on oxidative stress in adolescents with type 1 diabetes mellitus. Pediatr Diabetes 9:69–73CrossRefGoogle Scholar
  45. 45.
    Harrison DG (1997) Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest 100:2153–2157CrossRefGoogle Scholar
  46. 46.
    Milsom AB, Jones CJ, Goodfellow J, Frenneaux MP, Peters JR, James PE (2002) Abnormal metabolic fate of nitric oxide in type I diabetes mellitus. Diabetologia 45:1515–1522CrossRefGoogle Scholar
  47. 47.
    Wu G, Meininger CJ (2000) Arginine nutrition and cardiovascular function. J Nutr 130:2626–2629Google Scholar
  48. 48.
    Higashi Y, Oshima T, Ono N, Hiraga H, Yoshimura M, Watanabe M, Matsuura H, Kambe M, Kajiyama G (1995) Intravenous administration of l-arginine inhibits angiotensin-converting enzyme in humans. J Clin Endocrinol Metab 80:2198–2202CrossRefGoogle Scholar
  49. 49.
    Kilbom A, Wennmalm A (1976) Endogenous prostaglandins as local regulators of blood flow in man: effect of indomethacin on reactive and functional hyperaemia. J Physiol 257:109–121Google Scholar
  50. 50.
    Cowley AJ, Stainer K, Rowley JM, Wilcox RG (1985) Effect of aspirin and indomethacin on exercise-induced changes in blood pressure and limb blood flow in normal volunteers. Cardiovasc Res 19:177–180CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Ana Paula Trussardi Fayh
    • 1
  • Mauricio Krause
    • 2
    • 3
  • Josianne Rodrigues-Krause
    • 2
    • 3
  • Jerri Luiz Ribeiro
    • 4
  • Jorge Pinto Ribeiro
    • 5
  • Rogério Friedman
    • 5
  • José Cláudio Fonseca Moreira
    • 6
  • Alvaro Reischak-Oliveira
    • 1
  1. 1.Laboratório de Pesquisa do Exercício, Escola de Educação FísicaUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Department of Science, Biomedical Research GroupInstitute of Technology TallaghtDublinIreland
  3. 3.UCD School of Biomolecular and Biomedical Science, UCD Conway InstituteUniversity College DublinDublinIreland
  4. 4.Instituto Metodista Porto AlegrePorto AlegreBrazil
  5. 5.Hospital de Clínicas de Porto AlegrePorto AlegreBrazil
  6. 6.Departamento de Bioquímica, Centro de Estudos em Estresse OxidativoUniversidade Federal do Rio Grande do SulPorto AlegreBrazil

Personalised recommendations