Search tips
Search criteria 


Logo of jrsocmedLink to Publisher's site
J R Soc Med. 2002; 95(Suppl 42): 54–61.
PMCID: PMC1308946

Insulin resistance and vessel endothelial function.


IRS is a complex disease consisting of a clustering of metabolic disorders, of which hyperglycaemia, hyper-insulinaemia and dyslipidaemia are the most important. Endothelial dysfunction plays an important role in the pathogenesis of atherosclerosis. The effects of hyperinsulinaemia seem to depend on lipidaemia and glycaemia. Hyperglycaemia and hyperlipidaemia have detrimental effects on endothelial function in the fasting as well as the postprandial states. In both situations, the generation of ROS and vasoactive molecules plays a major role in interfering with the atheroprotective endothelium-dependent NO system. Treatment of IRS in regard to endothelial function should be focused initially on lifestyle improvement, such as stopping smoking and eating a balanced diet containing antioxidant vitamins, folic-acid, L-arginine and long-chain omega-3 unsaturated FA. Strict glucose control has shown to improve endothelial function and decrease microvascular complications. However, macrovascular complications, in line with endothelial functional improvement, have so far been reduced only when treatment was focused on other characteristics of the IRS syndrome, in particular dyslipidaemia. Other relevant treatments include ACE inhibitors and thiazolidinediones, and probably tetrahydrobiopterin and folic acid supplementation. Future studies should address the effects of therapeutic neovascularization on endothelial dysfunction.

Full Text

The Full Text of this article is available as a PDF (588K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Braunwald E. Shattuck lecture--cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. N Engl J Med. 1997 Nov 6;337(19):1360–1369. [PubMed]
  • Després JP, Lamarche B, Mauriège P, Cantin B, Dagenais GR, Moorjani S, Lupien PJ. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med. 1996 Apr 11;334(15):952–957. [PubMed]
  • Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Targher G, Alberiche M, Bonadonna RC, Muggeo M. Prevalence of insulin resistance in metabolic disorders: the Bruneck Study. Diabetes. 1998 Oct;47(10):1643–1649. [PubMed]
  • Fontbonne A, Charles MA, Thibult N, Richard JL, Claude JR, Warnet JM, Rosselin GE, Eschwège E. Hyperinsulinaemia as a predictor of coronary heart disease mortality in a healthy population: the Paris Prospective Study, 15-year follow-up. Diabetologia. 1991 May;34(5):356–361. [PubMed]
  • Ferrannini E, Haffner SM, Mitchell BD, Stern MP. Hyperinsulinaemia: the key feature of a cardiovascular and metabolic syndrome. Diabetologia. 1991 Jun;34(6):416–422. [PubMed]
  • Després JP, Moorjani S, Lupien PJ, Tremblay A, Nadeau A, Bouchard C. Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arteriosclerosis. 1990 Jul-Aug;10(4):497–511. [PubMed]
  • Stout RW. Insulin and atheroma. 20-yr perspective. Diabetes Care. 1990 Jun;13(6):631–654. [PubMed]
  • Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR, Holman RR. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23) BMJ. 1998 Mar 14;316(7134):823–828. [PMC free article] [PubMed]
  • Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW., Jr Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med. 1999 Oct 7;341(15):1097–1105. [PubMed]
  • Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988 Dec;37(12):1595–1607. [PubMed]
  • Kannel WB, McGee DL. Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham study. Diabetes Care. 1979 Mar-Apr;2(2):120–126. [PubMed]
  • Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998 Jul 23;339(4):229–234. [PubMed]
  • Pyorälä K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S) Diabetes Care. 1997 Apr;20(4):614–620. [PubMed]
  • Goldberg RB, Mellies MJ, Sacks FM, Moyé LA, Howard BV, Howard WJ, Davis BR, Cole TG, Pfeffer MA, Braunwald E. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators. Circulation. 1998 Dec 8;98(23):2513–2519. [PubMed]
  • Fontbonne A, Eschwège E, Cambien F, Richard JL, Ducimetière P, Thibult N, Warnet JM, Claude JR, Rosselin GE. Hypertriglyceridaemia as a risk factor of coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes. Results from the 11-year follow-up of the Paris Prospective Study. Diabetologia. 1989 May;32(5):300–304. [PubMed]
  • Laakso M, Lehto S, Penttilä I, Pyörälä K. Lipids and lipoproteins predicting coronary heart disease mortality and morbidity in patients with non-insulin-dependent diabetes. Circulation. 1993 Oct;88(4 Pt 1):1421–1430. [PubMed]
  • Kawamura M, Heinecke JW, Chait A. Pathophysiological concentrations of glucose promote oxidative modification of low density lipoprotein by a superoxide-dependent pathway. J Clin Invest. 1994 Aug;94(2):771–778. [PMC free article] [PubMed]
  • Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation. 1979 Sep;60(3):473–485. [PubMed]
  • Coppack SW. Postprandial lipoproteins in non-insulin-dependent diabetes mellitus. Diabet Med. 1997 Aug;14 (Suppl 3):S67–S74. [PubMed]
  • Syvänne M, Hilden H, Taskinen MR. Abnormal metabolism of postprandial lipoproteins in patients with non-insulin-dependent diabetes mellitus is not related to coronary artery disease. J Lipid Res. 1994 Jan;35(1):15–26. [PubMed]
  • Lewis GF, Steiner G. Hypertriglyceridemia and its metabolic consequences as a risk factor for atherosclerotic cardiovascular disease in non-insulin-dependent diabetes mellitus. Diabetes Metab Rev. 1996 Apr;12(1):37–56. [PubMed]
  • Lewis GF, O'Meara NM, Soltys PA, Blackman JD, Iverius PH, Pugh WL, Getz GS, Polonsky KS. Fasting hypertriglyceridemia in noninsulin-dependent diabetes mellitus is an important predictor of postprandial lipid and lipoprotein abnormalities. J Clin Endocrinol Metab. 1991 Apr;72(4):934–944. [PubMed]
  • Temelkova-Kurktschiev TS, Koehler C, Henkel E, Leonhardt W, Fuecker K, Hanefeld M. Postchallenge plasma glucose and glycemic spikes are more strongly associated with atherosclerosis than fasting glucose or HbA1c level. Diabetes Care. 2000 Dec;23(12):1830–1834. [PubMed]
  • Lefèbvre PJ, Scheen AJ. The postprandial state and risk of cardiovascular disease. Diabet Med. 1998;15 (Suppl 4):S63–S68. [PubMed]
  • Lefer AM. Nitric oxide: nature's naturally occurring leukocyte inhibitor. Circulation. 1997 Feb 4;95(3):553–554. [PubMed]
  • Langford EJ, Wainwright RJ, Martin JF. Platelet activation in acute myocardial infarction and unstable angina is inhibited by nitric oxide donors. Arterioscler Thromb Vasc Biol. 1996 Jan;16(1):51–55. [PubMed]
  • Sarkar R, Meinberg EG, Stanley JC, Gordon D, Webb RC. Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells. Circ Res. 1996 Feb;78(2):225–230. [PubMed]
  • Draijer R, Atsma DE, van der Laarse A, van Hinsbergh VW. cGMP and nitric oxide modulate thrombin-induced endothelial permeability. Regulation via different pathways in human aortic and umbilical vein endothelial cells. Circ Res. 1995 Feb;76(2):199–208. [PubMed]
  • Sattar N, Petrie JR, Jaap AJ. The atherogenic lipoprotein phenotype and vascular endothelial dysfunction. Atherosclerosis. 1998 Jun;138(2):229–235. [PubMed]
  • Williams SB, Goldfine AB, Timimi FK, Ting HH, Roddy MA, Simonson DC, Creager MA. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation. 1998 May 5;97(17):1695–1701. [PubMed]
  • Aljada A, Saadeh R, Assian E, Ghanim H, Dandona P. Insulin inhibits the expression of intercellular adhesion molecule-1 by human aortic endothelial cells through stimulation of nitric oxide. J Clin Endocrinol Metab. 2000 Jul;85(7):2572–2575. [PubMed]
  • Aljada A, Dandona P. Effect of insulin on human aortic endothelial nitric oxide synthase. Metabolism. 2000 Feb;49(2):147–150. [PubMed]
  • Marfella R, Quagliaro L, Nappo F, Ceriello A, Giugliano D. Acute hyperglycemia induces an oxidative stress in healthy subjects. J Clin Invest. 2001 Aug;108(4):635–636. [PMC free article] [PubMed]
  • Leyva F, Rauchhaus M, Anker SD, Proudler AJ, Godsland IF, Stiefel P, Coats AJ, Poole-Wilson PA, Stevenson JC. Non-invasive assessment of vascular function; paradoxical vascular response to intravenous glucose in coronary heart disease. Eur Heart J. 2000 Jan;21(1):39–44. [PubMed]
  • Roberts K, Dunn K, Jean SK, Lardinois CK. Syndrome X: medical nutrition therapy. Nutr Rev. 2000 May;58(5):154–160. [PubMed]
  • Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000 Apr;6(4):389–395. [PubMed]
  • Bussolati B, Dunk C, Grohman M, Kontos CD, Mason J, Ahmed A. Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide. Am J Pathol. 2001 Sep;159(3):993–1008. [PubMed]
  • Ziche M, Morbidelli L. Nitric oxide and angiogenesis. J Neurooncol. 2000 Oct-Nov;50(1-2):139–148. [PubMed]
  • Albertini JP, Valensi P, Lormeau B, Vaysse J, Attali JR, Gattegno L. Soluble L-selectin level is a marker for coronary artery disease in type 2 diabetic patients. Diabetes Care. 1999 Dec;22(12):2044–2048. [PubMed]
  • Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res. 2001 Oct 26;89(9):763–771. [PubMed]
  • Hak AE, Pols HA, Stehouwer CD, Meijer J, Kiliaan AJ, Hofman A, Breteler MM, Witteman JC. Markers of inflammation and cellular adhesion molecules in relation to insulin resistance in nondiabetic elderly: the Rotterdam study. J Clin Endocrinol Metab. 2001 Sep;86(9):4398–4405. [PubMed]
  • Jang Y, Lincoff AM, Plow EF, Topol EJ. Cell adhesion molecules in coronary artery disease. J Am Coll Cardiol. 1994 Dec;24(7):1591–1601. [PubMed]
  • Morise T, Takeuchi Y, Kawano M, Koni I, Takeda R. Increased plasma levels of immunoreactive endothelin and von Willebrand factor in NIDDM patients. Diabetes Care. 1995 Jan;18(1):87–89. [PubMed]
  • Blann AD, Dobrotova M, Kubisz P, McCollum CN. von Willebrand factor, soluble P-selectin, tissue plasminogen activator and plasminogen activator inhibitor in atherosclerosis. Thromb Haemost. 1995 Aug;74(2):626–630. [PubMed]
  • Kinlay S, Libby P, Ganz P. Endothelial function and coronary artery disease. Curr Opin Lipidol. 2001 Aug;12(4):383–389. [PubMed]
  • Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, Lieberman EH, Ganz P, Creager MA, Yeung AC, et al. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995 Nov 1;26(5):1235–1241. [PubMed]
  • Nitenberg A, Valensi P, Sachs R, Dali M, Aptecar E, Attali JR. 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 Jul;42(7):1017–1025. [PubMed]
  • Treasure CB, Klein JL, Weintraub WS, Talley JD, Stillabower ME, Kosinski AS, Zhang J, Boccuzzi SJ, Cedarholm JC, Alexander RW. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med. 1995 Feb 23;332(8):481–487. [PubMed]
  • Schächinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000 Apr 25;101(16):1899–1906. [PubMed]
  • Britten MB, Zeiher AM, Schächinger V. Clinical importance of coronary endothelial vasodilator dysfunction and therapeutic options. J Intern Med. 1999 Apr;245(4):315–327. [PubMed]
  • Sarabi M, Vessby B, Millgård J, Lind L. Endothelium-dependent vasodilation is related to the fatty acid composition of serum lipids in healthy subjects. Atherosclerosis. 2001 Jun;156(2):349–355. [PubMed]
  • Heitzer T, Krohn K, Albers S, Meinertz T. Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with Type II diabetes mellitus. Diabetologia. 2000 Nov;43(11):1435–1438. [PubMed]
  • Steinberg HO, Tarshoby M, Monestel R, Hook G, Cronin J, Johnson A, Bayazeed B, Baron AD. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest. 1997 Sep 1;100(5):1230–1239. [PMC free article] [PubMed]
  • Kanters SD, Elgersma OE, Banga JD, van Leeuwen MS, Algra A. Reproducibility of measurements of intima-media thickness and distensibility in the common carotid artery. Eur J Vasc Endovasc Surg. 1998 Jul;16(1):28–35. [PubMed]
  • Kanters SD, Algra A, van Leeuwen MS, Banga JD. Reproducibility of in vivo carotid intima-media thickness measurements: a review. Stroke. 1997 Mar;28(3):665–671. [PubMed]
  • Hijmering ML, Stroes ES, Pasterkamp G, Sierevogel M, Banga JD, Rabelink TJ. Variability of flow mediated dilation: consequences for clinical application. Atherosclerosis. 2001 Aug;157(2):369–373. [PubMed]
  • Gnasso A, Carallo C, Irace C, De Franceschi MS, Mattioli PL, Motti C, Cortese C. Association between wall shear stress and flow-mediated vasodilation in healthy men. Atherosclerosis. 2001 May;156(1):171–176. [PubMed]
  • Reddy KG, Nair RN, Sheehan HM, Hodgson JM. Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for atherosclerosis. J Am Coll Cardiol. 1994 Mar 15;23(4):833–843. [PubMed]
  • Benzuly KH, Padgett RC, Kaul S, Piegors DJ, Armstrong ML, Heistad DD. Functional improvement precedes structural regression of atherosclerosis. Circulation. 1994 Apr;89(4):1810–1818. [PubMed]
  • Taskinen MR, Lahdenperä S, Syvänne M. New insights into lipid metabolism in non-insulin-dependent diabetes mellitus. Ann Med. 1996 Aug;28(4):335–340. [PubMed]
  • Swislocki AL, Chen YD, Golay A, Chang MO, Reaven GM. Insulin suppression of plasma-free fatty acid concentration in normal individuals and patients with type 2 (non-insulin-dependent) diabetes. Diabetologia. 1987 Aug;30(8):622–626. [PubMed]
  • Lewis GF, Uffelman KD, Szeto LW, Weller B, Steiner G. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. J Clin Invest. 1995 Jan;95(1):158–166. [PMC free article] [PubMed]
  • Taskinen MR. Lipoprotein lipase in diabetes. Diabetes Metab Rev. 1987 Apr;3(2):551–570. [PubMed]
  • Karpe F, Boquist S, Tang R, Bond GM, de Faire U, Hamsten A. Remnant lipoproteins are related to intima-media thickness of the carotid artery independently of LDL cholesterol and plasma triglycerides. J Lipid Res. 2001 Jan;42(1):17–21. [PubMed]
  • Boquist S, Ruotolo G, Tang R, Björkegren J, Bond MG, de Faire U, Karpe F, Hamsten A. Alimentary lipemia, postprandial triglyceride-rich lipoproteins, and common carotid intima-media thickness in healthy, middle-aged men. Circulation. 1999 Aug 17;100(7):723–728. [PubMed]
  • Teno S, Uto Y, Nagashima H, Endoh Y, Iwamoto Y, Omori Y, Takizawa T. Association of postprandial hypertriglyceridemia and carotid intima-media thickness in patients with type 2 diabetes. Diabetes Care. 2000 Sep;23(9):1401–1406. [PubMed]
  • Niskanen L, Rauramaa R, Miettinen H, Haffner SM, Mercuri M, Uusitupa M. Carotid artery intima-media thickness in elderly patients with NIDDM and in nondiabetic subjects. Stroke. 1996 Nov;27(11):1986–1992. [PubMed]
  • Wilmink HW, Twickler MB, Banga JD, Dallinga-Thie GM, Eeltink H, Erkelens DW, Rabelink TJ, Stroes ES. Effect of statin versus fibrate on postprandial endothelial dysfunction: role of remnant-like particles. Cardiovasc Res. 2001 Jun;50(3):577–582. [PubMed]
  • Marchesi S, Lupattelli G, Schillaci G, Pirro M, Siepi D, Roscini AR, Pasqualini L, Mannarino E. Impaired flow-mediated vasoactivity during post-prandial phase in young healthy men. Atherosclerosis. 2000 Dec;153(2):397–402. [PubMed]
  • Anderson RA, Evans ML, Ellis GR, Graham J, Morris K, Jackson SK, Lewis MJ, Rees A, Frenneaux MP. The relationships between post-prandial lipaemia, endothelial function and oxidative stress in healthy individuals and patients with type 2 diabetes. Atherosclerosis. 2001 Feb 1;154(2):475–483. [PubMed]
  • Jagla A, Schrezenmeir J. Postprandial triglycerides and endothelial function. Exp Clin Endocrinol Diabetes. 2001;109(4):S533–S547. [PubMed]
  • Brown AA, Hu FB. Dietary modulation of endothelial function: implications for cardiovascular disease. Am J Clin Nutr. 2001 Apr;73(4):673–686. [PubMed]
  • Bae JH, Bassenge E, Kim KB, Kim YN, Kim KS, Lee HJ, Moon KC, Lee MS, Park KY, Schwemmer M. Postprandial hypertriglyceridemia impairs endothelial function by enhanced oxidant stress. Atherosclerosis. 2001 Apr;155(2):517–523. [PubMed]
  • Dart AM, Chin-Dusting JP. Lipids and the endothelium. Cardiovasc Res. 1999 Aug 1;43(2):308–322. [PubMed]
  • Betteridge DJ. What is oxidative stress? Metabolism. 2000 Feb;49(2 Suppl 1):3–8. [PubMed]
  • Moers A, Fenselau S, Schrezenmeir J. Chylomicrons induce E-selectin and VCAM-1 expression in endothelial cells. Exp Clin Endocrinol Diabetes. 1997;105 (Suppl 2):35–37. [PubMed]
  • Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. 1996 Jun 15;97(12):2859–2865. [PMC free article] [PubMed]
  • Foley JE. Rationale and application of fatty acid oxidation inhibitors in treatment of diabetes mellitus. Diabetes Care. 1992 Jun;15(6):773–784. [PubMed]
  • Sako Y, Grill VE. A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B cell oxidation through a process likely coupled to fatty acid oxidation. Endocrinology. 1990 Oct;127(4):1580–1589. [PubMed]
  • Hanefeld M, Koehler C, Henkel E, Fuecker K, Schaper F, Temelkova-Kurktschiev T. Post-challenge hyperglycaemia relates more strongly than fasting hyperglycaemia with carotid intima-media thickness: the RIAD Study. Risk Factors in Impaired Glucose Tolerance for Atherosclerosis and Diabetes. Diabet Med. 2000 Dec;17(12):835–840. [PubMed]
  • Title LM, Cummings PM, Giddens K, Nassar BA. 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 Dec;36(7):2185–2191. [PubMed]
  • Cosentino F, Hishikawa K, Katusic ZS, Lüscher TF. High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation. 1997 Jul 1;96(1):25–28. [PubMed]
  • Gopaul NK, Manraj MD, Hébé A, Lee Kwai Yan S, Johnston A, Carrier MJ, Anggård EE. Oxidative stress could precede endothelial dysfunction and insulin resistance in Indian Mauritians with impaired glucose metabolism. Diabetologia. 2001 Jun;44(6):706–712. [PubMed]
  • Price KD, Price CS, Reynolds RD. Hyperglycemia-induced ascorbic acid deficiency promotes endothelial dysfunction and the development of atherosclerosis. Atherosclerosis. 2001 Sep;158(1):1–12. [PubMed]
  • Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000 Apr 13;404(6779):787–790. [PubMed]
  • Honing ML, Morrison PJ, Banga JD, Stroes ES, Rabelink TJ. Nitric oxide availability in diabetes mellitus. Diabetes Metab Rev. 1998 Sep;14(3):241–249. [PubMed]
  • Du X, Stocklauser-Färber K, Rösen P. Generation of reactive oxygen intermediates, activation of NF-kappaB, and induction of apoptosis in human endothelial cells by glucose: role of nitric oxide synthase? Free Radic Biol Med. 1999 Oct;27(7-8):752–763. [PubMed]
  • Massi-Benedetti M, Federici MO. Cardiovascular risk factors in type 2 diabetes: the role of hyperglycaemia. Exp Clin Endocrinol Diabetes. 1999;107 (Suppl 4):S120–S123. [PubMed]
  • Griffin E, Re A, Hamel N, Fu C, Bush H, McCaffrey T, Asch AS. A link between diabetes and atherosclerosis: Glucose regulates expression of CD36 at the level of translation. Nat Med. 2001 Jul;7(7):840–846. [PubMed]
  • Summers LK, Samra JS, Frayn KN. Impaired postprandial tissue regulation of blood flow in insulin resistance: a determinant of cardiovascular risk? Atherosclerosis. 1999 Nov 1;147(1):11–15. [PubMed]
  • Steinberg HO, Paradisi G, Hook G, Crowder K, Cronin J, Baron AD. Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production. Diabetes. 2000 Jul;49(7):1231–1238. [PubMed]
  • Schmidt AM, Stern DM. Hyperinsulinemia and vascular dysfunction: the role of nuclear factor-kappaB, yet again. Circ Res. 2000 Oct 27;87(9):722–724. [PubMed]
  • Wollesen F, Berglund L, Berne C. Plasma endothelin-1 and total insulin exposure in diabetes mellitus. Clin Sci (Lond) 1999 Aug;97(2):149–156. [PubMed]
  • Karason K, Wikstrand J, Sjöström L, Wendelhag I. Weight loss and progression of early atherosclerosis in the carotid artery: a four-year controlled study of obese subjects. Int J Obes Relat Metab Disord. 1999 Sep;23(9):948–956. [PubMed]
  • Plotnick GD, Corretti MC, Vogel RA. Effect of antioxidant vitamins on the transient impairment of endothelium-dependent brachial artery vasoactivity following a single high-fat meal. JAMA. 1997 Nov 26;278(20):1682–1686. [PubMed]
  • Solzbach U, Hornig B, Jeserich M, Just H. Vitamin C improves endothelial dysfunction of epicardial coronary arteries in hypertensive patients. Circulation. 1997 Sep 2;96(5):1513–1519. [PubMed]
  • Jensen-Urstad KJ, Reichard PG, Rosfors JS, Lindblad LE, Jensen-Urstad MT. Early atherosclerosis is retarded by improved long-term blood glucose control in patients with IDDM. Diabetes. 1996 Sep;45(9):1253–1258. [PubMed]
  • Bagg W, Whalley GA, Gamble G, Drury PL, Sharpe N, Braatvedt GD. Effects of improved glycaemic control on endothelial function in patients with type 2 diabetes. Intern Med J. 2001 Aug;31(6):322–328. [PubMed]
  • Ryysy L, Yki-Järvinen H. Improvement of glycemic control by 1 year of insulin therapy leads to a sustained decrease in sE-selectin concentrations in type 2 diabetes. Diabetes Care. 2001 Mar;24(3):549–554. [PubMed]
  • Haffner SM. Do interventions to reduce coronary heart disease reduce the incidence of type 2 diabetes? A possible role for inflammatory factors. Circulation. 2001 Jan 23;103(3):346–347. [PubMed]
  • Rongen GA, Tack CJ. Triglycerides and endothelial function in type 2 diabetes. Eur J Clin Invest. 2001 Jul;31(7):560–562. [PubMed]
  • Evans M, Anderson RA, Graham J, Ellis GR, Morris K, Davies S, Jackson SK, Lewis MJ, Frenneaux MP, Rees A. Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus. Circulation. 2000 Apr 18;101(15):1773–1779. [PubMed]
  • Forbat SM, Naoumova RP, Sidhu PS, Neuwirth C, MacMahon M, Thompson GR, Underwood SR. The effect of cholesterol reduction with fluvastatin on aortic compliance, coronary calcification and carotid intimal-medial thickness: a pilot study. J Cardiovasc Risk. 1998 Feb;5(1):1–10. [PubMed]
  • Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J, Bruns C, Cottens S, Takada Y, Hommel U. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med. 2001 Jun;7(6):687–692. [PubMed]
  • Alfon J, Guasch JF, Berrozpe M, Badimon L. Nitric oxide synthase II (NOS II) gene expression correlates with atherosclerotic intimal thickening. Preventive effects of HMG-CoA reductase inhibitors. Atherosclerosis. 1999 Aug;145(2):325–331. [PubMed]
  • Hernández-Perera O, Pérez-Sala D, Navarro-Antolín J, Sánchez-Pascuala R, Hernández G, Díaz C, Lamas S. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest. 1998 Jun 15;101(12):2711–2719. [PMC free article] [PubMed]
  • Yoshida M, Sawada T, Ishii H, Gerszten RE, Rosenzweig A, Gimbrone MA, Jr, Yasukochi Y, Numano F. Hmg-CoA reductase inhibitor modulates monocyte-endothelial cell interaction under physiological flow conditions in vitro: involvement of Rho GTPase-dependent mechanism. Arterioscler Thromb Vasc Biol. 2001 Jul;21(7):1165–1171. [PubMed]
  • Yasunari K, Maeda K, Minami M, Yoshikawa J. HMG-CoA reductase inhibitors prevent migration of human coronary smooth muscle cells through suppression of increase in oxidative stress. Arterioscler Thromb Vasc Biol. 2001 Jun;21(6):937–942. [PubMed]
  • Kaneider NC, Reinisch CM, Dunzendorfer S, Meierhofer C, Djanani A, Wiedermann CJ. Induction of apoptosis and inhibition of migration of inflammatory and vascular wall cells by cerivastatin. Atherosclerosis. 2001 Sep;158(1):23–33. [PubMed]
  • van Ampting Jacobine M A, Hijmering Michel L, Beutler Jaap J, van Etten Ronald E, Koomans Hein A, Rabelink Ton J, Stroes Erik S G. Vascular Effects of ACE Inhibition Independent of the Renin-Angiotensin System in Hypertensive Renovascular Disease : A Randomized, Double-Blind, Crossover Trial. Hypertension. 2001 Jan;37(1):40–45. [PubMed]
  • Wilmink HW, Banga JD, Hijmering M, Erkelens WD, Stroes ES, Rabelink TJ. Effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor antagonism on postprandial endothelial function. J Am Coll Cardiol. 1999 Jul;34(1):140–145. [PubMed]
  • Bae JH, Bassenge E, Lee HJ, Park KR, Park CG, Park KY, Lee MS, Schwemmer M. Impact of postprandial hypertriglyceridemia on vascular responses in patients with coronary artery disease: effects of ACE inhibitors and fibrates. Atherosclerosis. 2001 Sep;158(1):165–171. [PubMed]
  • Watanabe Y, Sunayama S, Shimada K, Sawano M, Hoshi S, Iwama Y, Mokuno H, Daida H, Yamaguchi H. Troglitazone improves endothelial dysfunction in patients with insulin resistance. J Atheroscler Thromb. 2000;7(3):159–163. [PubMed]
  • Fujishima S, Ohya Y, Nakamura Y, Onaka U, Abe I, Fujishima M. Troglitazone, an insulin sensitizer, increases forearm blood flow in humans. Am J Hypertens. 1998 Sep;11(9):1134–1137. [PubMed]
  • Stroes E, Kastelein J, Cosentino F, Erkelens W, Wever R, Koomans H, Lüscher T, Rabelink T. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest. 1997 Jan 1;99(1):41–46. [PMC free article] [PubMed]
  • Verhaar MC, Wever RM, Kastelein JJ, van Loon D, Milstien S, Koomans HA, Rabelink TJ. Effects of oral folic acid supplementation on endothelial function in familial hypercholesterolemia. A randomized placebo-controlled trial. Circulation. 1999 Jul 27;100(4):335–338. [PubMed]
  • Doshi SN, McDowell IF, Moat SJ, Lang D, Newcombe RG, Kredan MB, Lewis MJ, Goodfellow J. Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide? Arterioscler Thromb Vasc Biol. 2001 Jul;21(7):1196–1202. [PubMed]
  • Wilmink HW, Stroes ES, Erkelens WD, Gerritsen WB, Wever R, Banga JD, Rabelink TJ. Influence of folic acid on postprandial endothelial dysfunction. Arterioscler Thromb Vasc Biol. 2000 Jan;20(1):185–188. [PubMed]
  • Carmeliet P. VEGF gene therapy: stimulating angiogenesis or angioma-genesis? Nat Med. 2000 Oct;6(10):1102–1103. [PubMed]
  • Carmeliet P, Luttun A. The emerging role of the bone marrow-derived stem cells in (therapeutic) angiogenesis. Thromb Haemost. 2001 Jul;86(1):289–297. [PubMed]
  • Rivard A, Silver M, Chen D, Kearney M, Magner M, Annex B, Peters K, Isner JM. Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF. Am J Pathol. 1999 Feb;154(2):355–363. [PubMed]
  • Schatteman GC, Hanlon HD, Jiao C, Dodds SG, Christy BA. Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice. J Clin Invest. 2000 Aug;106(4):571–578. [PMC free article] [PubMed]

Articles from Journal of the Royal Society of Medicine are provided here courtesy of Royal Society of Medicine Press