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Type 2 diabetes is associated with impaired endothelium-dependent, flow-mediated dilation, but impaired glucose metabolism is not

The Hoorn Study

      Abstract

      Background: Type 2 diabetes (DM2) and impaired glucose metabolism (IGM) are associated with an increased cardiovascular disease risk. Impaired endothelial synthesis of nitric oxide (NO) is an important feature of atherothrombosis and can be estimated from endothelium-dependent flow-mediated dilation (FMD). It is controversial whether or not FMD is impaired in DM2 and IGM. We investigated this issue in a population-based setting. Methods and results: In the study population (n=650; 246 with normal glucose metabolism (NGM), 135 with IGM and 269 with DM2; mean age: 67.6 years), FMD and endothelium-independent nitroglycerine-mediated dilation (NMD) were ultrasonically estimated from the brachial artery and expressed as the absolute change in diameter in mm. The increase in diameter (mean ± standard deviation) in NGM, IGM and DM2 was 0.19±0.15, 0.19±0.18 and 0.13±0.17 for FMD and 0.45±0.21, 0.43±0.24 and 0.45±0.25 for NMD. After adjustment for age, sex, baseline diameter and percentage increase in peak systolic velocity, DM2, as compared to NGM, remained associated with impaired FMD (regression coefficient β (95%CI)) as compared to NGM, −0.06 mm (−0.09 to −0.03). IGM was not associated with impaired FMD (β, 0.01 mm (−0.02 to 0.04)). Additional adjustment for conventional cardiovascular risk factors did not alter these associations. Hyperglycemia or hyperinsulinemia explained 2% of the association between DM2 and FMD. NMD was not associated with glucose tolerance. Conclusions: This study shows that DM2 is independently associated with impaired FMD. Hyperglycemia and hyperinsulinemia contribute minimally to this association. Impaired FMD may therefore, in part, explain the increased cardiovascular disease risk in DM2, whereas the normal FMD in IGM suggests that other forms of endothelial dysfunction are important in explaining the increased cardiovascular disease risk in IGM.

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      References

        • Pyorala K.
        • Laakso M.
        • Uusitupa M.
        Diabetes and atherosclerosis: an epidemiologic view.
        Diabetes Metab. Rev. 1987; 3: 463-524
        • de Vegt F.
        • Dekker J.M.
        • Ruhe H.G.
        • et al.
        Hyperglycemia is associated with all-cause and cardiovascular mortality in the Hoorn population: The Hoorn Study.
        Diabetologia. 1999; 42: 926-931
        • Kannel W.B.
        • McGee D.L.
        Diabetes and cardiovascular disease. The Framingham study.
        JAMA. 1979; 241: 2035-2038
        • Cosentino F.
        • Luscher T.F.
        Endothelial dysfunction in diabetes mellitus.
        J. Cardiovasc Pharmacol. 1998; 32: S54-S61
        • Pieper G.M.
        Review of alterations in endothelial nitric oxide production in diabetes: protective role of arginine on endothelial dysfunction.
        Hypertension. 1998; 31: 1047-1060
        • Lloyd-Jones D.M.
        • Bloch K.D.
        The vascular biology of nitric oxide and its role in atherogenesis.
        Ann. Rev. Med. 1996; 47: 365-375
        • McNeill K.L.
        • Fontana L.
        • Russell-Jones D.L.
        • et al.
        Inhibitory effects of low-density lipoproteins from men with type II diabetes on endothelium-dependent relaxation.
        J. Am. Coll. Cardiol. 2000; 35: 1622-1627
        • Tan K.C.
        • Chow W.S.
        • Ai V.H.
        Advanced glycation end products and endothelial dysfunction in type 2 diabetes.
        Diabetes Care. 2002; 25: 1055-1059
        • Vehkavaara S.
        • Seppala-Lindroos A.
        • Westerbacka J.
        • et al.
        In vivo endothelial dysfunction characterizes patients with impaired fasting glucose.
        Diabetes Care. 1999; 22: 2055-2060
        • Enderle M.D.
        • Benda N.
        • Schmuelling R.M.
        • et al.
        Preserved endothelial function in IDDM patients, but not in NIDDM patients, compared with healthy subjects.
        Diabetes Care. 1998; 21: 271-277
        • Makimattila S.
        • Liu M.L.
        • Vakkilainen J.
        • et al.
        Impaired endothelium-dependent vasodilation in type 2 diabetes. Relation to LDL size, oxidized LDL, and antioxidants.
        Diabetes Care. 1999; 22: 973-981
        • Watts G.F.
        • O’Brien S.F.
        • Silvester W.
        • et al.
        Impaired endothelium-dependent and independent dilatation of forearm resistance arteries in men with diet-treated non-insulin-dependent diabetes.
        Clin. Sci. 1996; 91: 567-573
        • Hogikyan R.V.
        • Galecki A.T.
        • Pitt B.
        • et al.
        Specific impairment of endothelium-dependent vasodilation in subjects with type 2 diabetes independent of obesity.
        J. Clin. Endocrinol. Metab. 1998; 83: 1946-1952
        • Ihlemann N.
        • Stokholm K.H.
        • Eskildsen P.C.
        Impaired vascular reactivity is present despite normal levels of von Willebrand factor in patients with uncomplicated type 2 diabetes.
        Diabet. Med. 2002; 19: 476-481
        • Wendelhag I.
        • Fagerberg B.
        • Hulthe J.
        • et al.
        Endothelium-dependent flow-mediated vasodilatation, insulin resistance and the metabolic syndrome in 60-year-old men.
        J. Intern. Med. 2002; 252: 305-313
        • Goodfellow J.
        • Ramsey M.W.
        • Luddington L.A.
        • et al.
        Endothelium and inelastic arteries: an early marker of vascular dysfunction in non-insulin dependent diabetes.
        BMJ. 1996; 312: 744-745
        • Jaap A.J.
        • Hammersley M.S.
        • Shore A.C.
        • et al.
        Reduced microvascular hyperaemia in subjects at risk of developing type 2 diabetes.
        Diabetologia. 1994; 37: 214-216
        • Yu H.I.
        • Sheu W.H.
        • Lai C.J.
        • et al.
        Endothelial dysfunction in type 2 diabetes subjects with peripheral artery disease.
        Int. J. Cardiol. 2001; 78: 19-25
        • Avogaro A.
        • Piarulli F.
        • Valerio A.
        • et al.
        Forearm nitric oxide balance, vascular relaxation, and glucose metabolism in NIDDM patients.
        Diabetes. 1997; 46: 1040-1046
        • McVeigh G.E.
        • Brennan G.M.
        • Johnston G.D.
        • et al.
        Impaired endothelium-dependent and independent vasodilation in patients with type 2 diabetes.
        Diabetologia. 1992; 35: 771-776
        • Morris S.J.
        • Shore A.C.
        • Tooke J.E.
        Responses of the skin microcirculation to acetylcholine and sodium nitroprusside in patients with NIDDM.
        Diabetologia. 1995; 38: 1337-1344
        • Heitzer T.
        • Krohn K.
        • Albers S.
        • et al.
        Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with type II diabetes.
        Diabetologia. 2000; 43: 1435-1438
        • Ting H.H.
        • Timimi F.K.
        • Boles K.S.
        • et al.
        Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes.
        J. Clin. Invest. 1996; 97: 22-28
        • Huvers F.C.
        • Schaper N.C.
        • Houben A.J.
        • et al.
        Impaired arterial but not venous responsiveness to nitroglycerin in non-insulin-dependent diabetes mellitus.
        Eur. J. Clin. Invest. 1997; 27: 360-365
        • Irving R.J.
        • Walker B.R.
        • Noon J.P.
        • et al.
        Microvascular correlates of blood pressure, plasma glucose, and insulin resistance in health.
        Cardiovasc Res. 2002; 53: 271-276
        • Steinberg H.O.
        • Paradisi G.
        • Cronin J.
        • et al.
        Type II diabetes abrogates sex differences in endothelial function in premenopausal women.
        Circulation. 2000; 101: 2040-2046
        • Caballero A.E.
        • Arora S.
        • Saouaf R.
        • et al.
        Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes.
        Diabetes. 1999; 48: 1856-1862
        • Nitenberg A.
        • Valensi P.
        • Sachs R.
        • et al.
        Impairment of coronary vascular reserve and ACh-induced coronary vasodilation in diabetic patients with angiographically normal coronary arteries and normal left ventricular systolic function.
        Diabetes. 1993; 42: 1017-1025
        • Mooy J.M.
        • Grootenhuis P.A.
        • de Vries H.
        • et al.
        Prevalence and determinants of glucose intolerance in a Dutch caucasian population. The Hoorn Study.
        Diabetes Care. 1995; 18: 1270-1273
        • Spijkerman A.M.
        • Adriaanse M.C.
        • Dekker J.M.
        • et al.
        Diabetic patients detected by population-based stepwise screening already have a diabetic cardiovascular risk profile.
        Diabetes Care. 2002; 25: 1784-1789
        • Alberti K.G.
        • Zimmet P.Z.
        Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus. Provisional Report of a WHO consultation.
        Diabetic Medicine. 1998; 15: 539-553
        • Corretti M.C.
        • Anderson T.J.
        • Benjamin E.J.
        • 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.
        J. Am. Coll. Cardiol. 2002; 39: 257-265
        • Brands P.J.
        • Hoeks A.P.
        • Willigers J.
        • et al.
        An integrated system for the non-invasive assessment of vessel wall and hemodynamic properties of large arteries by means of ultrasound.
        Eur. J. Ultrasound. 1999; 9: 257-266
        • Hoeks A.P.
        • Brands P.J.
        • Willigers J.M.
        • et al.
        Non-invasive measurement of mechanical properties of arteries in health and disease.
        Proc. Inst. Mech. Eng. [H]. 1999; 213: 195-202
        • Henry R.M.A.
        • Kostense P.J.
        • Spijkerman A.M.W.
        • et al.
        Arterial stiffness increases with deteriorating glucose tolerance status. The Hoorn Study.
        Circulation. 2003; 107: 2089-2095
        • Lambert J.
        • Aarsen M.
        • Donker A.J.
        • Stehouwer C.D.A.
        Endothelium-dependent and -independent vasodilation of large arteries in normoalbuminuric insulin-dependent diabetes mellitus.
        Arterioscler Thromb Vasc. Biol. 1996; 16: 705-711
        • Jager A.
        • Kostense P.J.
        • Nijpels G.
        • et al.
        Microalbuminuria is strongly associated with NIDDM and hypertension, but not with the insulin resistance syndrome: The Hoorn Study.
        Diabetologia. 1998; 41: 694-700
      1. Prineas RJ. In: M. Wright (Ed.), The Minnesota Code Manual of electrocardiographic findings: standards and procedures for measurement and classification. Boston: Littlejohn, 1982.

      2. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1999;57:2413–46.

        • Celermajer D.S.
        • Sorensen K.E.
        • Spiegelhalter D.J.
        • et al.
        Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women.
        J. Am. Coll. Cardiol. 1994; 24: 471-476
        • Herrington D.M.
        • Fan L.
        • Drum M.
        • et al.
        Brachial flow-mediated vasodilator responses in population-based research: methods, reproducibility and effects of age, gender and baseline diameter.
        J. Cardiovasc Risk. 2001; 8: 319-328
        • Leurs P.B.
        • Stolk R.P.
        • Hamulyak K.
        • et al.
        Tissue factor pathway inhibitor and other endothelium-dependent hemostatic factors in elderly individuals with normal or impaired glucose tolerance and type 2 diabetes.
        Diabetes Care. 2002; 25: 1340-1345
        • Calles-Escandon J.
        • Cipolla M.
        Diabetes and endothelial dysfunction: a clinical perspective.
        Endocr. Rev. 2001; 22: 36-52
        • Title L.M.
        • Cummings P.M.
        • Giddens K.
        • et al.
        Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E.
        J. Am. Coll. Cardiol. 2000; 36: 2185-2191
      3. Lee IK, Kim HS, Bae JH. Endothelial dysfunction: its relationship with acute hyperglycemia and hyperlipidemia. Int J Clin Pract Suppl 2002;129:64.

        • Kawano H.
        • Motoyama T.
        • Hirashima O.
        • et al.
        Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery.
        J. Am. Coll. Cardiol. 1999; 34: 146-154
        • Houben A.J.
        • Schaper N.C.
        • de Haan C.H.
        • et al.
        Local 24-h hyperglycemia does not affect endothelium-dependent or -independent vasoreactivity in humans.
        Am. J. Physiol. 1996; 270: H2014-H2020
        • Arcaro G.
        • Cretti A.
        • Balzano S.
        • et al.
        Insulin causes endothelial dysfunction in humans.
        Circulation. 2002; 105: 576-582
        • Aydin A.
        • Orhan H.
        • Sayal A.
        • et al.
        Oxidative stress and nitric oxide related parameters in type 2 diabetes mellitus: effects of glycemic control.
        Clin. Biochem. 2001; 34: 65-71
        • Ceriello A.
        • dello Russo P.
        • Amstad P.
        • et al.
        High glucose induces antioxidant enzymes in human endothelial cells in cultures. Evidence linking hyperglycemia and oxidative stress.
        Diabetes. 1996; 45: 471-477
        • Stehouwer C.D.
        • Lambert J.
        • Donker A.J.
        • et al.
        Endothelial dysfunction and pathogenesis of diabetic angiopathy.
        Cardiovasc Res. 1997; 34: 55-68
        • Jager A.
        • van Hinsbergh V.W.
        • Kostense P.J.
        • et al.
        Increased levels of soluble vascular cell adhesion molecule 1 are associated with risk of cardiovascular mortality among non-insulin-dependent diabetes mellitus: The Hoorn Study.
        Diabetes. 2000; 49: 485-491
        • Jager A.
        • van Hinsbergh V.W.
        • Kostense P.J.
        • et al.
        Von Willebrand factor, C-reactive protein and 5-year mortality in diabetic and non-diabetic subjects: The Hoorn Study.
        Arterioscler Thromb Vasc. Biol. 1999; 19: 3071-3078
        • van Dijk R.A.
        • Dekker J.M.
        • Nijpels G.
        • et al.
        Brachial artery pulse pressure and common carotid artery diameter: mutually independent associations with mortality in subjects with a recent history of impaired glucose tolerance.
        Eur. J. Clin. Invest. 2001; 31: 756-763
        • van Dijk R.A.
        • Nijpels G.
        • Twisk J.W.
        • et al.
        Change in common carotid artery diameter, distensibility and compliance in subjects with a recent history of impaired glucose tolerance: a 3-year follow-up study.
        J. Hypertens. 2000; 18: 293-300
        • Bhagat K.
        • Hingorani A.
        • Vallance P.
        Flow associated or flow mediated dilatation? More than just semantics.
        Heart. 1997; 78: 7-8
        • Leeson P.
        • Thorne S.
        • Donald A.
        • et al.
        Non-invasive measurement of endothelial function: effect on brachial artery dilatation of graded endothelial dependent and independent stimuli.
        Heart. 1997; 78: 22-27
        • Neunteufl T.
        • Heher S.
        • Katzenschlager R.
        • et al.
        Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain.
        Am. J. Cardiol. 2000; 86: 207-210
        • Gokce N.
        • Keaney J.F.
        • Hunter L.M.
        • et al.
        Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study.
        Circulation. 2002; 105: 1567-1572
        • Jaap A.J.
        • Shore A.C.
        • Tooke J.E.
        Relationship of insulin resistance to microvascular dysfunction in subjects with fasting hyperglycaemia.
        Diabetologia. 1997; 40: 238-243