The aim of this study was to investigate the effects of acute, methionine-induced hyperhomocysteinaemia on endothelial function of skin microcirculation in diabetic compared with non-diabetic persons. Endothelial- and non-endothelial-dependent vasodilatation of the skin microcirculation were evaluated in 20 persons with type 2 diabetes (59.95±2.36 years old) and 24 age- and gender-matched controls using laser Doppler flowmetry, during fasting and four hours after 0.1 g/kg methionine-induced acute hyperhomocysteinaemia. Methionine loading caused a comparable increase of homocysteine in the two groups. Four hours after induction of acute hyperhomocysteinaemia, endothelial-dependent vasodilatation (acetylcholine effect) was lower in the diabetic patients compared with the controls ([mean±SEM] 8.09±1.18-fold increase in diabetic patients vs. 11.11±1.33-fold increase in controls, p=0.027). The same was observed for the endothelial-independent vasodilatation (sodium-nitroprusside effect, 7.55±0.80-fold increase in the diabetic patients vs. 12.19±1.26-fold increase in controls, p=0.008). Acute hyperhomocysteinaemia causes a decreased response of both endothelial-dependent and endothelial-independent vasodilatation of the skin microcirculation in diabetic compared with non-diabetic persons. These alterations might contribute to the vascular complications of hyperhomocysteinaemia in diabetes, and especially the microvascular ones.
Ueland PM, Refsum H. ( 1989) Plasma homocysteine, a risk factor for vascular disease: Plasma levels in health, disease and drug therapy. J Lab Clin Med114:473-501.
2.
Humphrey LL, Fu R., Rogers K., Freeman M., Helfand M. ( 2008) Homocysteine level and coronary heart disease incidence: A systematic review and meta-analysis. Mayo Clin Proc83:1203-12.
3.
Den Heijer M. , Koster T., Blom HJ, et al. (1996) Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med334:759-62.
4.
Ebbing M., Bleie O., Ueland PM, et al. (2008) Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA300:795-804.
5.
Kannel WB, MacGee DL ( 1979) Diabetes and glucose tolerance as risk factors for cardiovascular disease: The Framingham study. Diabetes Care2:120-6.
6.
UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet352(9131):837-53.
7.
Hoogeveen EK , Kostense PJ, Jakobs C., et al. (2000) Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes: 5-year follow-up of the Hoorn Study. Circulation101:1506-11.
8.
Stabler SP, Estacio R., Jeffers BW, Cohen JA, Allen RH, Schrier RW ( 1999) Total homocysteine is associated with nephropathy in non-insulin-dependent diabetes mellitus. Metabolism48:1096-101.
9.
Heitzer T., Schlinzig T., Krohn K., Meinertz T., Munzel T. ( 2001) Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation104:2673-8.
10.
Austin RC, Lentz SR, Werstuck GH ( 2004) Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ11(Suppl 1): S56-S64.
11.
Celermajer DS, Sorensen K., Ryalls M., et al. (1993) Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not their heterozygous parents. J Am Coll Cardiol22:854-8.
12.
Tawakol A., Omland T., Gerhard M., Wu JT, Creager MA ( 1997) Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation95:1119-21.
13.
Woo KS, Chook P., Lolin YI, et al. (1997) Hyperhomocyst(e) inemia is a risk factor for arterial endothelial dysfunction in humans. Circulation96:2542-4.
14.
Bellamy MF, McDowell IFW, Ramsey MW, et al. (1998) Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. Circulation98:1848-52.
15.
Roman MJ, Naqvi TZ, Gardin JM, Gerhard-Herman M., Jaff M., Mohler E. ( 2006) Clinical application of noninvasive vascular ultrasound in cardiovascular risk stratification: a report from the American Society of Echocardiography and the Society of Vascular Medicine and Biology. J Am Soc Echocardiogr19:943-54.
16.
Holowatz LA , Thompson-Torgerson CS, Kenney WL (2008) The human cutaneous circulation as a model of generalized microvascular function . J Appl Physiol105:370-2.
17.
Kasha PC, Banga AK ( 2008) A review of patent literature for iontophoretic delivery and devices. Recent Pat Drug Deliv Formul2:41-50.
18.
Davis KR, Pearson H., Moat S., Bonham JR, Donelly R. ( 2001) Acute hyperhomocysteinaemia affects pulse pressure but not microvascular vasodilator function. Br J Pharmacol52:327-32.
19.
Abahji TN, Nill L., Ide N., Keller C., Hoffmann U., Weiss N. ( 2007) Acute hyperhomocysteinaemia induces microvascular and macrovascular endothelial dysfunction. Arch Med Res38:411-6.
20.
Weiss N., Ide N., Abahji T., Nill L., Keller C., Hoffmann U. ( 2006) Aged garlic extract improves homocysteine-induced endothelial dysfunction in macro- and microcirculation. J Nutr136(Suppl 3):750S-754S.
21.
Tousoulis D. , Antoniades C., Marinou K., et al. (2008) Methionine-loading rapidly impairs endothelial function, by mechanisms independent of endothelin-1: evidence for an association of fasting total homocysteine with plasma endothelin-1 levels. J Am Coll Nutr27:379-86.
22.
Karabag T., Kaya A., Temizhan A., Koc F., Yavuz S., Cam S. ( 2007) The influence of homocysteine levels on endothelial function and their relation with microvascular complications in T2DM patients without macrovascular disease. Acta Diabetol44:69-75.
23.
Newton DJ, Khan F., Belch JF ( 2001) Assessment of microvascular endothelial function in human skin. Clin Sci101:567-72.
24.
Morris SJ, Shore AC, Tooke JE ( 1995) Responses of the skin microcirculation to acetylcholine and sodium nitroprusside in patients with NIDDM. Diabetologia38:1337-44.
25.
Leahy MJ, de Mul FF, Nilsson GE, Maniewski R. ( 1997) Principles and practice of the laser-Doppler perfusion technique. Technol Health Care7:143-62.
26.
Farkas K., Kolossvary E., Jarai Z., Nemcsik J., Farsang C. ( 2004) Non-invasive assessment of microvascular endothelial function by laser Doppler flowmetry in patients with essential hypertension . Atherosclerosis173:97-102.
27.
Caballero AE , Arora S., Saouaf R., et al. (1999) Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes . Diabetes48:1856-62.
28.
Jorneskog G. , Kalani M., Kuhl J., et al. (2005) Early microvascular dysfunction in healthy normal-weight males with heredity for type 2 diabetes . Diabetes Care28:1495-7.
29.
Friedewald WT, Levy RI, Fredickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem18:499-502.
30.
Cockroft D. , Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron16:31-41.
31.
Matthews DR , Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and b-cell function from fasting plasma glucose and insulin concentration in man. Diabetologia28:412-9.
32.
Myer MF, Lieps D., Schatz H., Pfohl M. ( 2008) Impaired flow mediated vasodilatation in type 2 diabetes: Lack of relation to microvascular dysfunction. Microvasc Res76:61-5.
33.
Hoogeveen EK , Kostense PJ, Beks PJ, et al. (1998) Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus: a population-based study. Arterioscler Thromb Vasc Biol18:133-8.
34.
Soedamah-Muthu SS, Chaturvedi N, Teerlink T, Idzior-Walus B, Fuller JH, Stehouwer CD; Eurodiab Prospective Complications Study Group (2005) Plasma homocysteine and microvascular and macrovascular complications in type 1 diabetes: a cross-sectional nested case-control study. J Intern Med258:450-9.
35.
Eberhardt RT , Forgione MA, Cap A., et al. (2000) Endothelial dysfunction in a murine model of mild hyperhomocyst(e) inemia. J Clin Invest106:483-91.
36.
Cai H., Harrison DG ( 2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res87:840-4.
37.
Di Carli MF , Janisse J., Grunberger G., Ager J. (2003) Role of chronic hyperglycemia in the pathogenesis of coronary microvascular dysfunction in diabetes. J Am Coll Cardiol41:1387-93.
38.
Adams MR, Robinson J., McCredie R., et al. (1998) Smooth muscle dysfunction occurs independently of impaired endothelium-dependent dilation in adults at risk of atherosclerosis . J Am Coll Cardiol32:123-7.
39.
Bucala R., Tracey KJ, Cerami A. ( 1991) Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes . J Clin Invest87:432-8.
40.
Elias AN, Eng S. ( 2005) Homocysteine concentrations in patients with diabetes mellitus - relationship to microvascular and macrovascular disease. Diabetes Obes Metab7:117-21.
41.
Diakoumopoulou E., Tentolouris N., Kirlaki E., et al. (2005) Plasma homocysteine levels in patients with type 2 diabetes in a Mediterranean population: Relation with nutritional and other factors. Nutr Metab Cardiovasc Dis15:109-17.
42.
Emoto M., Kanda H., Shoji T., et al. (2001) Impact of insulin resistance and nephropathy on homocysteine in type 2 diabetes. Diabetes Care24:533-8.
43.
Bulow J., Astrup A., Christensen NJ, Kastrup J. ( 1987) Blood flow in skin, subcutaneous adipose tissue and skeletal muscle in the forearm of normal man during an oral glucose load . Acta Physiol Scand130:657-61.
