Advertisement

Insulin resistant young subjects at risk of accelerated atherosclerosis exhibit a marked reduction in peripheral endothelial function early in life but not differences in intima-media thickness

      Abstract

      Reduced bio-availability of nitric oxide leading to disturbed flow mediated (endothelial dependent) vasodilation (FMD) has been shown to be an early functional abnormality of the vascular system in insulin resistant individuals and other subjects at high risk for accelerated atherosclerosis. In addition, an increase of the intima-media thickness (IMT) is regarded as an early marker of morphological alterations of the vessel wall. Whether endothelial dysfunction (ED) is evident already at an early stage when morphological changes of the vessel wall are not apparent is still an open question.
      We, therefore, examined IMT and peripheral endothelial function in a group of young insulin resistant subjects in a cross-sectional study and compared these results with a metabolically healthy (insulin sensitive) control group.
      We measured IMT (distal common carotid arteries), endothelium-dependent and endothelium-independent vasodilation (flow mediated and glyceroltrinitrate induced vasodilation of the brachial artery) non-invasively with high resolution ultrasound (13 MHz) in 91 young normoglycemic subjects (40/51 M/F, median: 31 years, range 18–50 years). Insulin sensitivity was measured with a euglycemic, hyperinsulinemic glucose clamp.
      Despite a marked reduction in flow-mediated vasodilation in insulin resistant (IR) subjects (FMD: median 3.4%, range −4.0 to 12.5 in IR versus 6.6%, range −1.2 to 20.1% in insulin sensitive subjects; P=0.017), there was no difference in endothelial independent vasodilation (16.3%, range 5.7–41.0% versus 16.1%, range 0.5–39.2%) and in IMT (0.50 mm, range 0.39–0.66 and 0.51, 0.40–0.70 mm, respectively).
      These data suggest that ED can be detected very early in the life of insulin resistant subjects whereas no significant structural changes, indicated by a thickening of the intima-media layer, could be found. We therefore conclude that for identification of subjects with a high risk for accelerated atherosclerosis at an early stage, measurement of flow mediated vasodilation of the brachial artery may be more helpful than measuring thickness of the vascular wall.

      Abbreviations:

      IMT (intima-media thickness), ED (endothelial dysfunction), FDR (first degree relatives), OGTT (oral glucose tolerance test), MCR (metabolic clearence rate), ECG (electrocardiography), GTN (glyceryl trinitrate), FMD (flow mediated dilation), IR (insulin resistant), IS (insulin sensitive), BL (borderline)

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Uusitupa M.
        • Siitonen O.
        • Aro A.
        • Pyorala K.
        Prevalence of coronary heart disease, left ventricular failure and hypertension in middle-aged, newly diagnosed type 2 (non-insulin-dependent) diabetic subjects.
        Diabetologia. 1985; 28: 22-27
        • Uusitupa M.
        • Niskanen L.
        • Siitonen O.
        • Pyorala K.
        Hyperinsulinemia and hypertension in patients with newly diagnosed non-insulin-dependent diabetes.
        Diabetes Metab. 1987; 13: 369-374
        • Volk A.
        • Renn W.
        • Overkamp D.
        • Mehnert B.
        • Maerker E.
        • Jacob S.
        • et al.
        Insulin action and secretion in healthy, glucose tolerant first degree relatives of patients with type 2 diabetes mellitus. Influence of body weight.
        Exp. Clin. Endocrinol. Diabetes. 1999; 107: 140-147
        • Ross R.
        Atherosclerosis—an inflammatory disease.
        N. Engl. J. Med. 1999; 340: 115-126
        • Belcaro G.
        • Laurora G.
        • Cesarone M.R.
        • De Sanctis M.T.
        • Renton S.
        • Chong L.C.
        Evaluation of arteriosclerosis progression with ultrasonic biopsy and intima-media thickness measurements.
        Vasa. 1993; 22: 15-21
        • Celermajer D.S.
        • Sorensen K.E.
        • Gooch V.M.
        • Spiegelhalter D.J.
        • Miller O.I.
        • Sullivan I.D.
        • et al.
        Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis.
        Lancet. 1992; 340: 1111-1115
        • Pignoli P.
        • Tremoli E.
        • Poli A.
        • Oreste P.
        • Paoletti R.
        Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging.
        Circulation. 1986; 74: 1399-1406
        • Balletshofer B.M.
        • Rittig K.
        • Enderle M.D.
        • Volk A.
        • Maerker E.
        • Jacob S.
        • et al.
        Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance.
        Circulation. 2000; 101: 1780-1784
        • Hashimoto M.
        • Akishita M.
        • Eto M.
        • Ishikawa M.
        • Kozaki K.
        • Toba K.
        • et al.
        Modulation of endothelium-dependent flow-mediated dilatation of the brachial artery by sex and menstrual cycle.
        Circulation. 1995; 92: 3431-3435
        • Enderle M.D.
        • Sayer R.
        • Balletshofer B.
        • Meisner C.
        • Muck A.O.
        • Haasis R.
        • et al.
        Acute improvement of peripheral endothelial function in postmenopausal women with coronary artery disease after single oral intake of 17beta-estradiol valerate.
        Exp. Clin. Endocrinol. Diabetes. 2000; 108: 382-385
        • DeFronzo R.A.
        • Tobin J.D.
        • Andres R.
        Glucose clamp technique: a method for quantifying insulin secretion and resistance.
        Am. J. Physiol. 1979; 237: E214-E223
        • Ferrannini E.
        • Vichi S.
        • Beck-Nielsen H.
        • Laakso M.
        • Paolisso G.
        • Smith U.
        Insulin action and age. European Group for the Study of Insulin Resistance (EGIR).
        Diabetes. 1996; 45: 947-953
        • Joannides R.
        • Haefeli W.E.
        • Linder L.
        • Richard V.
        • Bakkali E.H.
        • Thuillez C.
        • et al.
        Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo.
        Circulation. 1995; 91: 1314-1319
        • Sorensen K.E.
        • Celermajer D.S.
        • Spiegelhalter D.J.
        • Georgakopoulos D.
        • Robinson J.
        • Thomas O.
        • et al.
        Non-invasive measurement of human endothelium dependent arterial responses: accuracy and reproducibility.
        Br. Heart J. 1995; 74: 247-253
        • Balletshofer B.M.
        • Goebbel S.
        • Rittig K.
        • Lehn-Stefan A.
        • Renn W.
        • Enderle M.D.
        Influence of experience on intra- and interindividual variability in assessing peripheral endothelial dysfunction by measurement of flow associated vasodilation with high resolution ultrasound.
        Ultraschall Med. 2001; 22: 1-5
        • Enderle M.D.
        • Balletshofer B.M.
        • Schmulling R.M.
        • Haring H.U.
        • Pfohl M.
        Early detection of atherosclerosis with high resolution ultrasound exemplified by type II diabetic patients.
        Ultraschall Med. 1998; 19: 16-21
        • Wendelhag I.
        • Gustavsson T.
        • Suurkula M.
        • Berglund G.
        • Wikstrand J.
        Ultrasound measurement of wall thickness in the carotid artery: fundamental principles and description of a computerized analysing system.
        Clin. Physiol. 1991; 11: 565-577
        • Kanters S.D.
        • Algra A.
        • van Leeuwen M.S.
        • Banga J.D.
        Reproducibility of in vivo carotid intima-media thickness measurements: a review.
        Stroke. 1997; 28: 665-671
        • Caballero A.E.
        • Arora S.
        • Saouaf R.
        • Lim S.C.
        • Smakowski P.
        • Park J.Y.
        Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes.
        Diabetes. 1999; 48: 1856-1862
        • Thalhammer C.
        • Balzuweit B.
        • Busjahn A.
        • Walter C.
        • Luft F.C.
        • Haller H.
        Endothelial cell dysfunction and arterial wall hypertrophy are associated with disturbed carbohydrate metabolism in patients at risk for cardiovascular disease.
        Arterioscler Thromb. Vasc. Biol. 1999; 19: 1173-1179
        • Temelkova-Kurktschiev T.
        • Koehler C.
        • Schaper F.
        • Henkel E.
        • Hahnefeld A.
        • Fuecker K.
        • et al.
        Relationship between fasting plasma glucose atherosclerosis risk factors and carotid intima-media thickness in non-diabetic individuals.
        Diabetologia. 1998; 41: 706-712
        • O’Leary D.H.
        • Polak J.F.
        • Kronmal R.A.
        • Manolio T.A.
        • Burke G.L.
        • Wolfson Jr., S.K.
        Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group.
        N. Engl. J. Med. 1999; 340: 14-22
        • Agewall S.
        • Fagerberg B.
        • Attvall S.
        • Wendelhag I.
        • Urbanavicius V.
        • Wikstrand J.
        Carotid artery wall intima-media thickness is associated with insulin-mediated glucose disposal in men at high and low coronary risk.
        Stroke. 1995; 26: 956-960
        • Bokemark L.
        • Wikstrand J.
        • Attvall S.
        • Hulthe J.
        • Wedel H.
        • Fagerberg B.
        Insulin resistance and intima-media thickness in the carotid and femoral arteries of clinically healthy 58-year-old men. The Atherosclerosis and Insulin Resistance Study (AIR).
        J. Intern. Med. 2001; 249: 59-67
        • Olsen M.H.
        • Fossum E.
        • Hjerkinn E.
        • Wachtell K.
        • Hoieggen A.
        • Nesbitt S.D.
        • et al.
        Relative influence of insulin resistance versus blood pressure on vascular changes in longstanding hypertension. ICARUS: a LIFE sub study. Insulin Carotids US Scandinavia.
        J. Hypertens. 2000; 18: 75-81
        • Barenbrock M.
        • Hausberg M.
        • Kosch M.
        • Golubev S.A.
        • Kisters K.
        • Rahn K.H.
        Flow-mediated vasodilation and distensibility in relation to intima-media thickness of large arteries in mild essential hypertension.
        Am. J. Hypertens. 1999; 12: 973-979
        • Ferrannini E.
        • Buzzigoli G.
        • Bonadonna R.
        • Giorico M.A.
        • Oleggini M.
        • Graziadei L.
        • et al.
        Insulin resistance in essential hypertension.
        N. Engl. J. Med. 1987; 317: 350-357
        • Heitzer T.
        • Schlinzig T.
        • Krohn K.
        • Meinertz T.
        • Munzel T.
        Endothelial dysfunction, oxidative stress and risk of cardiovascular events in patients with coronary artery disease.
        Circulation. 2001; 104: 2673-2678
        • Neunteufl T.
        • Heher S.
        • Katzenschlager R.
        • Wolfl G.
        • Kostner K.
        • Maurer G.
        • 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