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 ml−¹ min−¹). 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 ml−¹ min−¹) 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.
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References
Melendez-Ramirez LY, Richards RJ, Cefalu WT (2010) Complications of type 1 diabetes. Endocrinol Metab Clin North Am 39:625–640
Huysman E, Mathieu C (2009) Diabetes and peripheral vascular disease. Acta Chir Belg 109:587–594
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 26:406–433
Poston L, Taylor PD (1995) Glaxo/MRS young investigator prize. Endothelium-mediated vascular function in insulin-dependent diabetes mellitus. Clin Sci (Lond) 88:245–255
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 23:1840–1843
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) 118:341–349
Barbul A (1986) Arginine: biochemistry, physiology, and therapeutic implications. JPEN J Parenter Enteral Nutr 10:227–238
Flynn NE, Meininger CJ, Haynes TE, Wu G (2002) The metabolic basis of arginine nutrition and pharmacotherapy. Biomed Pharmacother 56:427–438
Maxwell AJ (2002) Mechanisms of dysfunction of the nitric oxide pathway in vascular diseases. Nitric Oxide 6:101–124
El-Missiry MA, Othman AI, Amer MA (2004) l-Arginine ameliorates oxidative stress in alloxan-induced experimental diabetes mellitus. J Appl Toxicol 24:93–97
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 211:87–97
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 135:714–721
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 584:921–933
Mendez JD, Balderas F (2001) Regulation of hyperglycemia and dyslipidemia by exogenous l-arginine in diabetic rats. Biochimie 83:453–458
West MB, Ramana KV, Kaiserova K, Srivastava SK, Bhatnagar A (2008) l-Arginine prevents metabolic effects of high glucose in diabetic mice. FEBS Lett 582:2609–2614
Mendez JD, Hernandez Rde H (2005) l-Arginine and polyamine administration protect beta-cells against alloxan diabetogenic effect in Sprague-Dawley rats. Biomed Pharmacother 59:283–289
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 137:2680–2685
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 58:1270–1276
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 204:73–78
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 31:940–944
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–E912
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:CR131–137
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 43:1435–1438
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 27:690–695
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 119:3244–3262
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 93:933–935
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 80:331–333
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 75:205–210
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:E15
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 97:1989–1994
Pollack ML, Schmidt DH, Jackson AS (1980) Measurement of cardio-respiratory fitness and body composition in the clinical setting. Compr Ther 6:12–27
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 65:1127–1133
Duncan GE, Howley ET, Johnson BN (1997) Applicability of VO2max criteria: discontinuous versus continuous protocols. Med Sci Sports Exerc 29:273–278
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 89:281–288
Wasserman K, McIlroy MB (1964) Detecting the threshold of anaerobic metabolism in cardiac patients during exercise. Am J Cardiol 14:844–852
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 36:1716–1722
Copeland SR, Mills MC, Lerner JL, Crizer MF, Thompson CW, Sullivan JM (1996) Hemodynamic effects of aerobic vs resistance exercise. J Hum Hypertens 10:747–753
Miranda KM, Espey MG, Wink DA (2001) A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide 5:62–71
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Draper HH, Hadley M (1990) Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol 186:421–431
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 186:464–478
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 187:33–37
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 23:337–342
Huang EA, Gitelman SE (2008) The effect of oral alpha-lipoic acid on oxidative stress in adolescents with type 1 diabetes mellitus. Pediatr Diabetes 9:69–73
Harrison DG (1997) Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest 100:2153–2157
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 45:1515–1522
Wu G, Meininger CJ (2000) Arginine nutrition and cardiovascular function. J Nutr 130:2626–2629
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 80:2198–2202
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 257:109–121
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 19:177–180
Acknowledgments
This work was supported by the National Council for Scientific and Technological Development (CNPq, Brazil).
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The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
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Fayh, A.P.T., 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 52, 975–983 (2013). https://doi.org/10.1007/s00394-012-0404-7
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DOI: https://doi.org/10.1007/s00394-012-0404-7