Acute Hyperhomocysteinemia Impairs Endothelium Function in Subjects with Type 2 Diabetes Mellitus

Abstract

The objective of the present study was to examine the effect of acute, methionine-induced hyperhomocysteinemia (HHCY) on endothelial function and indices of arterial stiffness in subjects with type 2 diabetes mellitus (T2DM). A total of 30 subjects with T2DM, free of macrovascular disease were examined in a crossover study. L-methionine (M) (0.1 g/kg) and water (W) load were given in random order with an interval of about 1 week in between. Endothelial function was assessed by flow-mediated vasodilation (FMD). Arterial stiffness was assessed by determination of augmentation index (AI). Measurements were performed in the fasting state, 1, 2 and 3 h after the M or the W load. Total plasma homocysteine (HCY) levels did not change after W administration, while M administration resulted in a significant increase in HCY concentrations at 3 h. FMD throughout the experiment expressed as area under the curve (AUC) was significantly lower after the M than after the W load. Consistent with impairment in endothelial function, the AUC of AI was significantly higher after the M than after the W administration. Acute HHCY impairs endothelial function and increases arterial stiffness in patients with T2DM. This effect is probably mediated by a reduction of nitric oxide bioavailability in endothelium.

Key words

homocysteine - type 2 diabetes mellitus - flow-mediated vasodilation - augmentation index - arterial stiffness

References

• 1 Avogaro A, Kreutzenberg SV, Fadini G. Endothelial dysfunction: Causes and consequences in patients with diabetes mellitus.  Diabetes research and clinical practice. 2008; 
• 2 B-Vitamin Treatment Trialists' Collaboration. . Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials.  American heart journal. 2006;  151 282-287
• 3 Bloomgarden ZT. American Diabetes Association annual meeting, 1999: dyslipidemia, endothelial dysfunction, and glycosylation.  Diabetes care. 2000;  23 690-698
• 4 Boger RH, Lentz SR, Bode-Boger SM. et al . Elevation of asymmetrical dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst(e)inaemia in humans.  Clin Sci (Lond). 2001;  100 161-167
• 5 Bots ML, Westerink J, Rabelink TJ. et al . Assessment of flow-mediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of the FMD measurement on the FMD response.  European heart journal. 2005;  26 363-368
• 6 Bowman L, Armitage J, Bulbulia R. et al . Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors.  American heart journal. 2007;  154 815-823 823 e811-e816
• 7 Chambers JC, McGregor A, Jean-Marie J. et al . Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia: an effect reversible with vitamin C therapy.  Circulation. 1999;  99 1156-1160
• 8 Chen P, Poddar R, Tipa EV. et al . Homocysteine metabolism in cardiovascular cells and tissues: implications for hyperhomocysteinemia and cardiovascular disease.  Advances in enzyme regulation. 1999;  39 93-109
• 9 Corretti MC, Anderson TJ, Benjamin EJ. et al . Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force.  Journal of the American College of Cardiology. 2002;  39 257-265
• 10 Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis.  Circulation. 2004;  109 III27-III32
• 11 de Groot PG, Willems C, Boers GH. et al . Endothelial cell dysfunction in homocystinuria.  European journal of clinical investigation. 1983;  13 405-410
• 12 Fowler B. Homocysteine: overview of biochemistry, molecular biology, and role in disease processes.  Seminars in vascular medicine. 2005;  5 77-86
• 13 Guthikonda S, Haynes WG. Homocysteine: role and implications in atherosclerosis.  Current atherosclerosis reports. 2006;  8 100-106
• 14 Herrmann W, Herrmann M, Obeid R. Hyperhomocysteinaemia: a critical review of old and new aspects.  Current drug metabolism. 2007;  8 17-31
• 15 Hoogeveen EK, Kostense PJ, Jakobs C. et al . Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes : 5-year follow-up of the Hoorn Study.  Circulation. 2000;  101 1506-1511
• 16 Loscalzo J. The oxidant stress of hyperhomocyst(e)inemia.  The Journal of clinical investigation. 1996;  98 5-7
• 17 Mayer O, Filipovsky J, Dolejsova M. et al . Mild hyperhomocysteinaemia is associated with increased aortic stiffness in general population.  Journal of human hypertension. 2006;  20 267-271
• 18 Nappo F, De Rosa N, Marfella R. et al . Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins.  Jama. 1999;  281 2113-2118
• 19 Nestel PJ, Chronopoulos A, Cehun M. Arterial stiffness is rapidly induced by raising the plasma homocysteine concentration with methionine.  Atherosclerosis. 2003;  171 83-86
• 20 Neves MF, Endemann D, Amiri F. et al . Small artery mechanics in hyperhomocysteinemic mice: effects of angiotensin II.  Journal of hypertension. 2004;  22 959-966
• 21 O'Rourke MF, Mancia G. Arterial stiffness.  Journal of hypertension. 1999;  17 1-4
• 22 Rasouli ML, Nasir K, Blumenthal RS. et al . Plasma homocysteine predicts progression of atherosclerosis.  Atherosclerosis. 2005;  181 159-165
• 23 Romerio SC, Linder L, Nyfeler J. et al . Acute hyperhomocysteinemia decreases NO bioavailability in healthy adults.  Atherosclerosis. 2004;  176 337-344
• 24 Shukla N, Thompson CS, Angelini GD. et al . Homocysteine enhances impairment of endothelium-dependent relaxation and guanosine cyclic monophosphate formation in aortae from diabetic rabbits.  Diabetologia. 2002;  45 1325-1331
• 25 Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease: an update.  Hypertension. 2001;  37 1053-1059
• 26 Stuhlinger MC, Oka RK, Graf EE. et al . Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine.  Circulation. 2003;  108 933-938
• 27 Tawakol A, Omland T, Gerhard M. et al . Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans.  Circulation. 1997;  95 1119-1121
• 28 Tentolouris N, Christodoulakos G, Lambrinoudaki I. et al . Effect of hormone therapy on the elastic properties of the arteries in healthy postmenopausal women.  Journal of endocrinological investigation. 2005;  28 305-311
• 29 Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis.  BMJ Clinical research ed. 2002;  325 1202
• 30 Wilkinson IB, Franklin SS, Cockcroft JR. Nitric oxide and the regulation of large artery stiffness: from physiology to pharmacology.  Hypertension. 2004;  44 112-116
• 31 Wilkinson IB, Qasem A, McEniery CM. et al . Nitric oxide regulates local arterial distensibility in vivo.  Circulation. 2002;  105 213-217

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