Abstract
Aim: The increased incidence of atherosclerotic macrovascular disease in type 2 diabetic patients is associated both with diabetes specific factors and coexisting classic cardiovascular risk factors as components of the metabolic syndrome. The aim of this study was to investigate the association between the duration of diabetes and early functional and morphological markers of atherosclerosis compared to the impact of coexisting cardiovascular risk factors such as hypertension, dyslipoproteinemia and cigarette smoking.
Methods: 63 type 2 diabetic patients and 25 non-diabetic control subjects were investigated. Lumen diameter of the brachial artery was measured by high-resolution ultrasound at rest and after 5-min suprasystolic arterial compression. Endothelium-independent dilatation of the brachial artery was measured 4 min after sublingual administration of 400 μg of glycerol trinitrate (GTN). Percentage change of arterial lumen diameter during reactive hyperemia (FMD%) and after GTN administration (GTN%) relative to the baseline measurements were calculated. The intima-media thickness (IMT) of the common carotid artery was measured bilaterally and averages were calculated.
Results: FMD% (3.8±0.8% vs. 6.9±0.9%; p<0.01) and GTN% (5.6±0.7% vs. 14.9±1.7%; p<0.01) were reduced in the diabetic patients compared to their control subjects. IMT was increased in diabetic patients compared to their controls (0.82±0.02mm vs. 0.62±0.02mm; p<0.01). The age-adjusted diabetes duration was inversely related to FMD% (r=-0.27; p=0.016). On multiple regression analysis including packyears, hypertension, hypercholesterolemia, and hypertriglyceridemia, only diabetes duration remained a significant independent determinant of FMD. GTN% and IMT were not associated with diabetes duration, packyears, hypertension, hypercholesterolemia, and hypertriglyceridemia when all variables were taken into account.
Conclusion: The present data lend support to the suggestion that diabetic specific factors compared to coexisting cardiovascular risk factors such as hypertension, hyperlipoproteinemia, and smoking are of major importance for the pathogenesis of endothelial dysfunction in type 2 diabetes, because only the diabetes duration was shown to be related to endothelium-dependent vasodilation when all variables were taken into account.
Key words
diabetes duration - endothelial dysfunction - endothelium-dependent vasodilation - endothelium-independent vasodilation - flow-mediated dilation - intima-media thickness - type 2 diabetes
References
1
Anber V, Griffin BA, MacConnel M, Packard CJ, Shepherd J.
Influence of plasma lipid and LDL-subfraction profile on the interaction between low density lipoprotein with human arterial wall proteoglycans.
Arteriosclerosis.
1996;
124
261-271
2
Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, Lieberman EH, Ganz P, Creager MA, Yeung AC.
Close relation of endothelial function in the human coronary and peripheral circulations.
J Am Coll Cardiol.
1995;
26
1235-1241
3
Bucala R, Tracey KJ, Cerami A.
Advanced glycosilation end products quench nitric oxide and mediate defective endothelium-dependent vasodilation in experimental diabetes.
J Clin Invest.
1991;
87
432-438
4
Campuzano R, Moya JL, Garcia-Lledó A, Salido L, Guzmán G, Tomas JP, Catalán P, Muriel A, Asin E.
Endothelial dysfunction and intima-media thickness in relation to cardiovascular risk factors in patients without clinical manifestations of atherosclerosis.
Rev Esp Cardiol.
2003;
56
546-554
5
Cardillo C, Nambi SS, Kilcoyne CM, Choucair WK, Katz A, Quon MJ, Panza JA.
Insulin stimulates both endothelin and nitric oxide activity in the human forearm.
Circulation.
1999;
100
820-825
6
Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robbins J, Deanfield JE.
Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults.
Circulation.
1993;
88
2149-2155
7
Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE.
Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis.
Lancet.
1992;
340
1111-1115
8
Ceriello A, Marchi E, Barbanti M, Milani MR, Giugliano D, Quatraro A, Lefebvre P.
Non-enzymatic glycation reduces heparin cofactor II anti-thrombin activity.
Diabetologia.
1990;
33
205-207
9
Chait A, Brazg RL, Tribble DL, Krauss RM.
Susceptibility of small, dense, low-densitity lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B.
Am J Med.
1993;
94
350-356
10
Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R.
International brachial artery reactivity task force. 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.
J Am Coll Cardiol.
2002;
39
257-265
11
Cosentino F, Eto M, Paolis P De, Loo B van der, Bachschmid M, Ullrich V, Kouroedov A, Delli Gatti C, Joch H, Volpe M, Lüscher TF.
High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species.
Circulation.
2003;
107
1017-1023
12
Enderle MD, Benda N, Schmuelling RM, Haering HU, Pfohl M.
Preserved endothelial function in IDDM patients, but not in NIDDM patients compared with healthy subjects.
Diabetes Care.
1998;
21
271-277
13
Frank GD, Eguchi S, Motley ED.
The role of reactive oxygen species in insulin signaling in the vasculature.
Antioxid Redox Signal.
2005;
7
1053-1061
14
Fuller JH, Stevens LK, Wang S-L. the Multinational Study group .
Risk factors for cardiovascular mortality and morbidity: The WHO multinational study of vascular disease in diabetes.
Diabetologia.
2001;
44
((Suppl 2))
S54-S64
15
Furuta M, Tsunoda K, Arita M, Nanjo K, Sanke T.
Endothelium-dependent vasodilation in type II diabetes mellitus.
Rinsho Byori.
2003;
51
1111-1115
16
Ghiadoni L, Huang Y, Magagna A, Buralli S, Taddei S, Salvetti A.
Effect of acute blood pressure reduction on endothelial function in the brachial artery of patients with essential hypertension.
J Hypertens.
2001;
19
547-551
17
Giugliano D, Cerielle A, Paolisso G.
Oxidative Stress and vascular complications.
Diabetes Care.
1996;
19
257-267
18
Guzik TJ, West NE, Black E, MacDonald D, Ratnatunga C, Pillai R, Channon KM.
Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors.
Circ Res.
2000;
86
E85-90
19
Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck U, Schmechel H, Ziegelasch HJ, Lindner J.
Risk factors for myocardial infarction and death in newly detected Type II diabetes: the Diabetes Intervention Study, 11-year follow-up.
Diabetologia.
1996;
39
1577-1583
20
Hashimoto M, Miyamoto Y, Matsuda Y, Akita H.
New methods to evaluate endothelial function: non-invasive method for evaluating endothelial function in humans.
J Pharmacol Sci.
2003;
93
405-408
21
Hawthorne GC, Bartlett K, Hetherington CS, Alberti KG.
The effect of high glucose on polyol pathway activity and myoinositol metabolism in cultured human endothelial cells.
Diabetologia.
1989;
32
163-166
22
Henry RM, Ferreira I, Kostense PJ, Dekker JM, Nijpels G, Heine RJ, Kamp O, Bouter LM, Stehouwer CD.
Type 2 diabetes is associated with impaired endothelium-dependent, flow-mediated dilation, but impaired glucose metabolism is not; The Hoorn Study.
Atherosclerosis.
2004;
174
49-56
23
Joannides R, Haefeli WE, Linder L, Richard V, Bakkali H, Thuillez C, Luscher TF.
Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo.
Circulation.
1995;
91
1314-1319
24
Kawamori R, Yamasaki Y, Matsushima H, Nishizawa H, Nao K, Hougaku H, Maeda H, Handa N, Matsumoto M, Kamada T.
Prevalence of carotid atherosclerosis in diabetic patients: ultrasound high-resolution B-mode imaging on carotid arteries.
Diabetes Care.
1993;
15
1290-1294
25
Kim JA, Montagnani M, Koh KK, Quon MJ.
Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms.
Circulation.
2006;
113
1888-1904
26
Krauss RM.
Atherogenecity of triglyceride-rich lipoproteins.
Am J Cardiol.
1998;
81
13B-17B
27
Laakso M, Lehto S, Penttila I, Pyorala K.
Lipids and lipoproteins predicting coronary heart disease mortality and morbidity in patients with non-insulin-dependent diabetes.
Circulation.
1993;
88
1421-1430
28
Libby P.
Molecular bases of the acute coronary syndromes.
Circulation.
1995;
91
2844-2850
29
Loscalzo J.
Nitric oxide insufficiency, platelet activation, and arterial thrombosis.
Circ Res.
2001;
88
756-762
30
Makita Z, Yunagisawa K, Kawajima S, Bucala R, Vlassara H, Koike T.
The role of advanced glycation end products in the pathogenesis of atherosclerosis.
Nephrol Dial Transplant.
1996;
11
((Suppl 5))
31-33
31
Manson JE, Colditz GA, Stampfer MJ, Willett WC, Krolewski AS, Rosner B, Arky RA, Speizer FE, Hennekens CH.
A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women.
Arch Intern Med.
1991;
151
1141-1147
32
MacVeigh GE, Grennan GM, Johnston GD, MacDermatt BJ, MacGrath LT, Henry WR, Andrews JW, Hayes JR.
Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus.
Diabetologia.
1992;
35
771-776
33
Moncada S, Palmer RJM, Higgs E.
Nitric oxide: physiology, pathophysiology and pharmacology.
Pharmacol Rev.
1991;
43
109-142
34
Naruse K, Rask-Madsen C, Takahara N, Ha S, Suzuma K, Way KJ, Jacobs JRC, Clermont AC, Ueki K, Ohshiro Y, Zhang J, Goldfine AB, King GL.
Activation of vascular protein kinase C-β inhibits Akt-dependent endothelial nitric oxide synthase function in obesity-associated insulin-resistance.
Diabetes.
2006;
55
691-698
35
Oliver FJ, Rubia G de la, Feener EP, Lee ME, Loeken MR, Shiba T, Quertermous T, King GL.
Stimulation of endothelin-1 gene expression by insulin in endothelial cells.
J Biol Chem.
1991;
266
23251-23256
36
Persson J, Formgren J, Israelsson B, Berglund G.
Ultrasound-determined intima-media thickness and atherosclerosis.
Atherioscler Thromb.
1994;
14
261-264
37
Pinkney JH, Stehouwer CDA, Coppack SW, Yudkin JS.
Endothelial dysfunction: Cause of the insulin resistance syndrome.
Diabetes.
1997;
46
((Suppl 2))
S9-S12
38
Rojas A, Morales MA.
Advanced glycation and endothelial functions: a link towards vascular complications in diabetes.
Life Sci.
2004;
76
715-730
39
Scivittaro V, Ganz MB, Weiss MF.
AGE induce oxidative stress and activate protein kinase C-beta (II) in neonatal mesangial cells.
Am J Physiol.
2000;
278
F676-F683
40
Stamler J, Wentworth D, Vaccaro O, Neaton JD.
Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the multiple risk factor intervention trial.
Diabetes Care.
1993;
16
434-444
41
Suarez L, Barrett-Connor E.
Interaction between cigarette smoking and diabetes mellitus in the prediction of death attributed to cardiovascular disease.
Am J Epidemiol.
1984;
120
670-674
42
Tan KC, Chow WS, Ai VH, Metz C, Bucala R, Lam KS.
Advanced glycation end products and endothelial dysfunction in type 2 diabetes.
Diabetes Care.
2002;
25
1055-1059
43
Tanriverdi H, Evrengul H, Kuru O, Tanriverdi S, Seleci D, Enli Y.
Cigarette smoking induced oxidative stress may impair endothelial function and coronary blood flow in angiographically normal coronary arteries.
Circ J.
2006;
70
593-599
44
Tesfamariam B, Brown ML, Cohen RA.
Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C.
J Clin Invest.
1991;
87
1643-1648
45
Tschoepe D, Roesen P.
Heart disease in diabetes mellitus: a challenge for early diagnosis and intervention.
Exp Clin Endocrinol Diabetes.
1998;
106
16-24
46
Turner RC, Millns H, Neil HAW, Stratton IM, Manley SE, Matthews DR. Holman RR for the United Kingdom Prospective Diabetes Study Group .
Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom prospective diabetes study (UKPDS: 23).
BMJ.
1998;
316
823-828
47
Williamson JR, Chang K, Frangos M, Hasan KS, Ido Y, Kawamura T, Nyengaard JR, Enden M van den, Kilo C, Tilton RG.
Perspectives in Diabetes: Hyperglycemic pseudohypoxia and diabetic complications.
Diabetes.
1993;
42
801-813
48
Yamaguchi Y, Haginaka J, Morimoto S, Fujioka Y, Kunitomo M.
Facilitated nitration and oxidation of LDL in cigarette smokers.
Eur J Clin Invest.
2005;
35
186-193
49
Yu HI, Sheu WH, Lai CJ, Lee WJ, Chen YT.
Endothelial dysfunction in type 2 diabetes mellitus subjects with peripheral artery disease.
Int J Cardiol.
2001;
78
19-25
Correspondence
PD Dr. M. F.Meyer
Department of Internal Medicine
University Clinic Bergmannsheil
Bürkle-de-la-Camp-Platz 1
44789 Bochum
Germany
Telefon: +49/234/302 64 00
Fax: +49/234/302 64 15
eMail: martin.meyer-2@rub.de