Advertisement

Combined effect of coenzyme Q10 and fenofibrate on forearm microcirculatory function in type 2 diabetes

      Abstract

      Arteriopathy is the principal complication of type 2 diabetes mellitus. It develops from endothelial dysfunction, which we have hypothesised occurs in diabetes primarily as a consequence of dyslipidaemia and oxidative stress. Fenofibrate and CoQ may improve endothelial function by regulating dyslipidaemia and oxidative stress, respectively. We therefore aimed to assess the independent and combined effects of fenofibrate and coenzyme Q10 (CoQ) on endothelium-dependent and endothelium-independent vasodilator function of the forearm microcirculation in type 2 diabetes. Eighty dyslipidaemic type 2 diabetics were randomized to receive fenofibrate (200 mg/daily), CoQ (200 mg/daily), fenofibrate plus CoQ (200+200 mg daily), or placebo for 12 weeks. Forearm microcirculatory function was assessed with venous occlusion plethysmography during the infusion of acetylcholine (ACh), bradykinin (BK), sodium nitroprusside (SNP) and NG-monomethyl-l-arginine (l-NMMA) into the brachial artery. Blood flow responses were calculated as area under the curve (AUC). Fenofibrate significantly lowered plasma cholesterol, triglyceride and fibrinogen (P<0.001), and elevated HDL-cholesterol and homocysteine (P<0.001). CoQ did not change plasma isoprostanes, but significantly lowered systolic blood pressure and HbA1c (P<0.05). Fenofibrate plus CoQ significantly improved (P<0.05) the AUC for ACh, BK and SNP without significantly altering basal responses to l-NMMA. Fenofibrate or CoQ alone did not significantly alter blood flow responses. Improvements in blood flow were independent of changes in plasma lipids, blood pressure, homocysteine and isoprostanes, but were correlated (P=0.013) with HbA1c. In conclusion, in this factorial trial we found that only the combination of fenofibrate and CoQ markedly improved endothelial and non-endothelial forearm vasodilator function in dyslipidemic type 2 diabetic patients. The favourable vascular effect of this therapeutic combination could be due to increase in the bioactivity of and/or responses to endothelium-derived relaxing factors, including nitric oxide, and this may entail synergistic stimulation of peroxisome proliferator-activated receptors.

      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

        • Cohen R.A
        Dysfunction of vascular endothelium in diabetes mellitus.
        Circulation. 1993; 87: V67-V76
        • Watts G.F
        • Playford D.A
        Dyslipoproteinaemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non-insulin dependent diabetes mellitus: an hypothesis.
        Atherosclerosis. 1998; 141: 7-30
        • Giugliano D
        • Ceriello A
        • Paolisso G
        Oxidative stress and diabetic vascular complications.
        Diabetes Care. 1996; 19: 257-267
        • Heitzer T
        • Schlinzig T
        • Krohn K
        • Meinertz T
        • Munzel T
        Endothelial dysfunction, oxidative stress and risk of cardiovascular events in patients with coronary heart disease.
        Circulation. 2001; 27: 2673-2678
        • Watts G.F
        • O'Brien S.F
        • Silvester W
        • Millar J.A
        Impaired endothelium-dependent and independent dilatation of forearm resistance arteries in men with diet-treated non-insulin-dependent diabetes: role of dyslipidaemia.
        Clin. Sci. 1996; 91: 567-573
        • O'Brien S.F
        • Watts G.F
        • Playford D.A
        • Burke V
        • O'Neal D.A
        • Best J.D
        Low-density lipoprotein size, high-density lipoprotein concentration, and endothelial dysfunction in non-insulin-dependent diabetes.
        Diabet. Med. 1997; 14: 974-978
        • Anderson R.A
        • Evans M.L
        • Ellis G.R
        • et al.
        The relationship between post-prandial lipaemia, endothelial function and oxidative stress in healthy individuals and patients with type 2 diabetes.
        Atherosclerosis. 2002; 154: 475-483
        • Watts G.F
        • Dimmitt S.B
        Fibrates, dyslipoproteinaemia and cardiovascular disease.
        Curr. Opin. Lipidol. 1999; 10: 561-574
        • Rubins H.B
        • Robins S.J
        • Collins D
        • et al.
        Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.
        N. Engl. J. Med. 1999; 341: 410-418
        • Elkeles R.S
        • Diamond J.R
        • Poulter C
        • et al.
        Cardiovascular outcomes in type 2 diabetes. A double-blind placebo-controlled study of bezafibrate: the St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study.
        Diabetes Care. 1998; 21: 641-648
      1. Steiner G, Hamston A, Hosking J et al. for the Diabetes Atherosclerosis Intervention Study Investigators: effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 2001;357: 905–910.

        • Malik J
        • Melenovsky V
        • Wichterle D
        • et al.
        Both fenofibrate and atorvastatin improve vascular reactivity in combined hyperlipidaemia (fenofibrate versus atorvastin trial—FAT).
        Cardiovas. Res. 2001; 52: 290-298
        • Stocker R
        Dietary and pharmacological antioxidants in atherosclerosis.
        Curr. Opin. Lipidol. 1999; 10: 589-597
        • Skyrme-Jones R.A
        • O'Brien R.C
        • Berry K.L
        • Meredith I.T
        Vitamin E supplementation improves endothelial function in type I diabetes mellitus: a randomized, placebo-controlled study.
        J. Am. Coll. Cardiol. 2000; 36: 94-102
        • Gazis A
        • White D.J
        • Page S.R
        • Cockcroft J.R
        Effect of oral vitamin E (alpha-tocopherol) supplementation on vascular endothelial function in Type 2 diabetes mellitus.
        Diabet. Med. 1999; 16: 304-311
        • Chowienczyk P.J
        • Brett S.E
        • Gopaul N.K
        • et al.
        Oral treatment with an antioxidant (raxofelast) reduces oxidative stress and improves endothelial function in men with Type II diabetes.
        Diabetologia. 2000; 43: 974-977
        • Ting H.H
        • Timimi F.K
        • Boles K.S
        • Creager S.J
        • Ganz P
        • Creager M.A
        Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus.
        J. Clin. Invest. 1996; 97: 22-28
        • Perticone F
        • Ceravalo R
        • Candigliota M
        • et al.
        Obesity and body fat distribution induce endothelial dysfunction by oxidative stress: protective effect of vitamin C.
        Diabetes. 2001; 50: 159-165
        • Heitzer T
        • Finckh B
        • Albers S
        • Krohn K
        • Kohlschutter A
        • Meinertz T
        Beneficial effects of alpha-lipoic acid and ascorbic acid on endothelium-dependent, nitric oxide-mediated vasodilation diabetic patients: relation to parameters of oxidative stress.
        Free Radical Biol. Med. 2001; 31: 53-61
        • Beyer R.E
        The participation of coenzyme Q in free radical production and anti-oxidation.
        Free Radical Biol. Med. 1990; 8: 465-545
        • McCarthy M.F
        Coenzyme Q versus hypertension: does CoQ decrease endothelial superoxide generation?.
        Med. Hypotheses. 1999; 53: 300-304
        • Stocker R
        • Bowry V.W
        • Frei B
        Ubiquinol-10 protects human low-density lipoprotein more efficiently against lipid peroxidation than does α-topopherol.
        Proc. Natl. Acad. Sci. USA. 1991; 88: 1646-1650
        • Thomas S.R
        • Neuzil J
        • Stocker R
        Co-supplementation with coenzyme Q prevents the proxidant effect of α-tocopherol and increase in the resistance of LDL to transition metal-dependent oxidation initiation.
        Atherioscler. Thromb. Vasc. Biol. 1996; 16: 687-696
        • Jameson S
        Coenzyme Q10 alpha-tocopherol, and free cholesterol levels in sera from diabetic patients.
        in: Folkers K Littarru G Yamagami T Biomedical and Clinical Aspects of Coenzyme Q. Elsevier Science, Amsterdam1991: 151-158
        • McCarthy M.F
        Can correction of sub-optimal coenzyme Q status improve β-cell function in type II diabetes?.
        Med. Hypotheses. 1999; 52: 368-397
        • Thomas S.R
        • Witting P.K
        • Stocker R
        A role for reduced coenzyme Q in atherosclerosis?.
        Biofactors. 1999; 9: 207-224
        • Lang J.K
        • Gohil K
        • Packer L
        Simultaneous determination of tocopherols, ubiquinols and ubiquinones in blood plasma, tissue homogenates and subcellular fractions.
        Anal. Biochem. 1986; 157: 106-116
        • Mori T.A
        • Croft K.D
        • Puddey I.B
        • Beilin L.J
        An improved method for the measurement of urinary and plasma F2-isoprostanes using Gas Chromatography Mass Spectrometry.
        Anal. Biochem. 1999; 268: 117-125
        • Matthews D.R
        • Hosker J.P
        • Rudenski A.S
        • Naylor B.A
        • Treacher D.F
        • Turner R.C
        Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
        Diabetologia. 1985; 28: 412-419
        • Simons L.A
        • von Konigsmark M
        • Simons J
        • Stocker R
        • Celermajer D.S
        Vitamin E ingestion does not improve arterial endothelial dysfunction in older adults.
        Atherosclerosis. 1999; 143: 193-199
        • Evans M
        • Anderson R.A
        • Graham J
        • et al.
        Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus.
        Circulation. 2000; 101: 1773-1779
        • Avogaro A
        • Miola M
        • Favaro A
        • et al.
        Gemfibrozil improves insulin sensitivity and flow-mediated vasodilation in type 2 diabetic patients.
        Eur. Clin. Invest. 2001; 31: 603-609
        • Cohen R.A
        • Vanhoutte P.M
        Endothelium-dependent hyperpolarization.
        Circulation. 1995; 92: 3337-3349
        • Aydin A
        • Orhan H
        • Sayal A
        • Ozata M
        • Sahin G
        • Isimer A
        Oxidative stress and nitric oxide related parameters in type II diabetes mellitus: effects of glycemic control.
        Clin. Biochem. 2001; 34: 65-70
        • Flavahan N.A
        Atherosclerosis or lipoprotein-induced endothelial dysfunction. Potential mechanisms underlying reduction in EDRF/nitric oxide activity.
        Circulation. 1992; 85: 1927-1938
        • De Vriese A.S
        • Verbeuren T.J
        • Van der Voorde J
        • Lameire N.H
        • Vanhoutte P.M
        Endothelial dysfunction in diabetes.
        Br. J. Pharmacol. 2000; 13: 963-974
        • Watts G.F
        • Playford D.A
        • Croft K.D
        • Ward N.C
        • Mori T.A
        • Burke V
        Coenzyme Q10 improves endothelial dysfunction of the brachial artery in type 2 diabetes mellitus.
        Diabetologia. 2002; 45: 420-426
        • Davi G
        • Ciabattoni G
        • Consoli A
        • et al.
        In vivo formation of 8-iso-prostaglandin F and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation.
        Circulation. 1999; 99: 224-229
        • Williams S.B
        • Goldfine A.B
        • Timimi F.K
        • et al.
        Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo.
        Circulation. 1998; 97: 1695-1701
        • Poderoso J.J
        • Carreras M.C
        • Schopfer F
        • et al.
        The reaction of nitric oxide with ubiquinol: kinetic properties and biological significance.
        Free Radical Biol. Med. 1999; 26: 925-935
        • Hodgson J.M
        • Watts G.F
        • Playford D.A
        • Burke V
        • Croft K.D
        Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes.
        Eur. J. Clin. Nutr. 2002; 56: 1-6
        • Chakravarthy U
        • Hayes R.G
        • Stitt A.W
        • McAuley E
        • Archer D.B
        Constitutive nitric oxide synthase expression in retinal vascular endothelial cells is suppressed by high glucose and advanced glycation end products.
        Diabetes. 1998; 47: 945-952
        • Meagher E.A
        • FitzGerald G.A
        Indices of lipid peroxidation in vivo: strengths and limitations.
        Free Radical Biol. Med. 2000; 28: 1745-1750
        • Kugiyama K
        • Doi H
        • Motoyama T
        • et al.
        Association of remnant lipoprotein levels with impairment of endothelium-dependent vasomotor function in human coronary arteries.
        Circulation. 1998; 97: 2519-2526
        • Fruchart J.C
        • Duriez P
        • Staels B
        Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis.
        Curr. Opin. Lipidol. 1999; 10: 245-257
        • Bissonnette R
        • Treacy E
        • Rozen R
        • Boucher B
        • Cohn J.S
        • Genest Jr., J
        Fenofibrate raises plasma homocysteine levels in the fasted and fed states.
        Atherosclerosis. 2001; 155: 455-462
        • Nitenberg A
        • Valensi P
        • Sachs R
        • Dali M
        • Aptecar E
        • Attali J.R
        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
        • Suwaidi J.A
        • Hamasake S
        • Higano S.T
        • Nishimura R.A
        • Holmes D.R
        • Lerman A
        Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction.
        Circulation. 2000; 101: 948-954