Influence of the Duration of Type 2 Diabetes on Early Functional and Morphological Markers of Atherosclerosis Compared to the Impact of Coexisting Classic Cardiovascular Risk Factors

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