Trevor A. Mori

Advanced glycation end-products: a review.

Abstract Advanced glycation end-products are a complex and heterogeneous group of compounds that have been implicated in diabetes related complications. At present it is not known if they are the cause or the consequence of the complications observed. We discuss the chemistry of advanced glycated end-product formation and their patho-biochemistry particularly in relation to the diabetic microvascular complications of retinopathy, neuropathy and nephropathy as well as their role in the accelerated vasculopathy observed in diabetes. The concept of carbonyl stress as a cause for advanced glycated end-product toxicity is mentioned. We discuss alterations in the concentrations of advanced glycated end-products in the body, particularly in relation to changes occuring with age, diabetes and its complications such as nephropathy. Problems relating to current methods of advanced glycated end-product detection and measurement are highlighted including the lack of a universally established method of detection or unit of measurement. Agents used for the treatment of advanced glycated end-product accumulation are reviewed, with an emphasis on the results of the recent phase III trials using aminoguanidine and diabetes related complications. [Diabetologia (2001) 44: 129–146]

Docosahexaenoic Acid but Not Eicosapentaenoic Acid Lowers Ambulatory Blood Pressure and Heart Rate in Humans

Animal studies suggest that the 2 major omega3 fatty acids found in fish, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may have differential effects on blood pressure (BP) and heart rate (HR). The aim of this study was to determine whether there were significant differences in the effects of purified EPA or DHA on ambulatory BP and HR in humans. In a double-blind, placebo-controlled trial of parallel design, 59 overweight, mildly hyperlipidemic men were randomized to 4 g/d of purified EPA, DHA, or olive oil (placebo) capsules and continued their usual diets for 6 weeks. Fifty-six subjects completed the study. Only DHA reduced 24-hour and daytime (awake) ambulatory BP (P<0.05). Relative to the placebo group, 24-hour BP fell 5.8/3.3 (systolic/diastolic) mm Hg and daytime BP fell 3.5/2.0 mm Hg with DHA. DHA also significantly reduced 24-hour, daytime, and nighttime (asleep) ambulatory HRs (P=0. 001). Relative to the placebo group, DHA reduced 24-hour HR by 3. 5+/-0.8 bpm, daytime HR by 3.7+/-1.2 bpm, and nighttime HR by 2. 8+/-1.2. EPA had no significant effect on ambulatory BP or HR. Supplementation with EPA increased plasma phospholipid EPA from 1. 66+/-0.07% to 9.83+/-0.06% (P<0.0001) but did not change DHA levels. Purified DHA capsules increased plasma phospholipid DHA levels from 4.00+/-0.27% to 10.93+/-0.62% (P<0.0001) and led to a small, nonsignificant increase in EPA (1.52+/-0.12% to 2.26+/-0.16%). Purified DHA but not EPA reduced ambulatory BP and HR in mildly hyperlipidemic men. The results of this study suggest that DHA is the principal omega3 fatty acid in fish and fish oils that is responsible for their BP- and HR-lowering effects in humans. These results have important implications for human nutrition and the food industry.

Differential Effects of Eicosapentaenoic Acid and Docosahexaenoic Acid on Vascular Reactivity of the Forearm Microcirculation in Hyperlipidemic, Overweight Men

BackgroundRecent evidence supports differential effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the 2 major &ohgr;3 fatty acids of marine origin, on blood pressure in humans and vascular reactivity in adult spontaneously hypertensive rats. We investigated possible differences in the effects of purified EPA or DHA on forearm vascular reactivity in overweight hyperlipidemic men that might contribute to the blood pressure–lowering effects of fish oils. Methods and ResultsWith a double-blind, placebo-controlled trial of parallel design, 59 overweight, mildly hyperlipidemic men were randomized to receive 4 g/d purified EPA, DHA, or olive oil (placebo) capsules while continuing their usual diets for 6 weeks. Forearm blood flow (FBF) was measured with venous occlusion, strain-gauge plethysmography during the sequential intra-arterial administration of acetylcholine (7.5, 15, and 30 &mgr;g/min), sodium nitroprusside (1.5, 3, and 10 &mgr;g/min), norepinephrine (10, 20, and 40 ng/min), a single-dose infusion of NG-monomethyl-l-arginine (L-NMMA) (1 mg/min), and coinfusion of acetylcholine (7.5, 15, and 30 &mgr;g/min) and L-NMMA. Forty of the 56 subjects who completed the study underwent FBF measurements. Plasma phospholipid EPA levels increased significantly (P <0.0001) after supplementation with EPA, and DHA composition increased with DHA supplementation (P <0.0001). Relative to placebo, DHA, but not EPA, supplementation significantly improved FBF in response to acetylcholine infusion (P =0.040) and coinfusion of acetylcholine with L-NMMA (P =0.040). Infusion of L-NMMA alone showed no group differences. DHA significantly enhanced dilatory responses to sodium nitroprusside (P <0.0001) and attenuated constrictor responses to norepinephrine (P =0.017). ConclusionsRelative to placebo, DHA, but not EPA, enhances vasodilator mechanisms and attenuates constrictor responses in the forearm microcirculation. Improvements in endothelium-independent mechanisms appear to be predominant and may contribute to the selective blood pressure–lowering effect observed with DHA compared with EPA in humans.

EFFECT OF EICOSAPENTAENOIC ACID AND DOCOSAHEXAENOIC ACID ON OXIDATIVE STRESS AND INFLAMMATORY MARKERS IN TREATED- HYPERTENSIVE TYPE 2 DIABETIC SUBJECTS

n-3 fatty acids reduce the risk of cardiovascular disease via a number of possible mechanisms. Despite this, there has been concern that these fatty acids may increase lipid peroxidation. The data in vivo are inconclusive, due in part to limitations in the methodologies. In this regard, the measurement of F2-isoprostanes provides a reliable assessment of in vivo lipid peroxidation and oxidant stress. This study aimed to assess the effects of supplementation with purified eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), the two major n-3 fatty acids, on urinary F2-isoprostanes and markers of inflammation, in type 2 diabetic patients. In a double-blind, placebo controlled trial of parallel design, 59 nonsmoking, treated-hypertensive, type 2 diabetic subjects, were randomized to 4 g daily of purified EPA, DHA, or olive oil for 6 weeks, while maintaining their usual diet. F2-isoprostanes, measured using gas chromatography-mass spectrometry in 24 h urines and C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), were measured before and after intervention. Thirty-nine men and 12 women aged 61.2 +/- 1.2 years, with body mass index (BMI), 29.5 +/- 0.5 kg/m2; 24 h blood pressure, 138/73 mmHg; HbA1c, 7.3 +/- 0.1% and fasting glucose, 7.9 +/- 0.2 mmol/l completed the intervention. Baseline urinary F2-isoprostanes were positively associated with HbA1c (p=.011) and fasting glucose (p=.032). Relative to the olive oil group, postintervention urinary F2-isoprostanes were decreased 19% by EPA (p=.017) and 20% by DHA (p=.014). There were no significant changes in CRP, IL-6, and TNF-alpha following EPA or DHA supplementation. In regression analysis, Delta F2-isoprostanes were positively associated with Delta HbA1c (p=.007) independent of treatment group; and with Delta TNF-alpha (p=.034) independent of age, gender, BMI, and treatment group. There were no associations with Delta CRP or Delta IL-6. This study is the first report demonstrating that either EPA or DHA reduce in vivo oxidant stress without changing markers of inflammation, in treated hypertensive, type 2 diabetic subjects.

Effects of Dietary Fish and Weight Reduction on Ambulatory Blood Pressure in Overweight Hypertensives

Obesity is a major factor contributing to hypertension and increased risk of cardiovascular disease. Regular consumption of dietary fish and omega3 fatty acids of marine origin can lower blood pressure (BP) levels and reduce cardiovascular risk. This study examined the potential effects of combining dietary fish rich in omega3 fatty acids with a weight loss regimen in overweight hypertensive subjects, with ambulatory BP levels as the primary end point. Using a factorial design, 69 overweight medication-treated hypertensives were randomized to a daily fish meal (3.65 g omega3 fatty acids), weight reduction, the 2 regimens combined, or a control regimen for 16 weeks. Sixty-three subjects with a mean+/-SEM body mass index of 31.6+/-0.5 kg/m2 completed the study. Weight fell by 5.6+/-0.8 kg with energy restriction. Dietary fish and weight loss had significant independent and additive effects on 24-hour ambulatory BP. Effects were greatest on awake systolic and diastolic BP (P<0.01); relative to control, awake pressures fell 6.0/3.0 mm Hg with dietary fish alone, 5.5/2.2 mm Hg with weight reduction alone, and 13.0/9.3 mm Hg with fish and weight loss combined. These results also remained significant after further adjustment for changes in urinary sodium, potassium, or the sodium/potassium ratio, as well as dietary macronutrients. Dietary fish also significantly reduced 24-hour (-3.1+/-1.4 bpm, P=0.036) and awake (-4.2+/-1.6 bpm, P=0. 013) ambulatory heart rates. Weight reduction had a significant effect on sleeping heart rate only (-3.2+/-1.7 bpm, P=0.037). Combining a daily fish meal with a weight-reducing regimen led to additive effects on ambulatory BP and decreased heart rate. The effects were large, suggesting that cardiovascular risk and antihypertensive drug requirements are likely to be reduced substantially by combining dietary fish meals rich in omega3 fatty acids with weight-loss regimens in overweight medication-treated hypertensives. The reduction in heart rate seen with dietary fish suggests a cardiac/autonomic component, as well as vascular effects, of increased consumption of omega3 fatty acid from fish.

Interactions Between Dietary Fat, Fish, and Fish Oils and Their Effects on Platelet Function in Men at Risk of Cardiovascular Disease

Recent studies have suggested that omega 3-fats of marine origin may have a protective role in heart disease. This study aimed to compare the effects of fish or fish oil, in the setting of a high- or low-fat diet, on platelet aggregation and platelet thromboxane in men with increased risk of cardiovascular disease. One hundred twenty men who were nonsmokers, 30 to 60 years old, with mildly elevated blood pressure and cholesterol were randomly allocated to one of five high-fat (40% of daily energy) or two low-fat (30%) groups for 12 weeks. The five high-fat groups took either 6 or 12 fish oil capsules daily; fish; a combination of fish and fish oil; or placebo capsules. The two low-fat groups took either fish or placebo capsules. Fish meals provided 1.3 g of eicosapentaenoic acid daily, equivalent to 6 fish oil capsules, and contained an average of 3.65 g/d of omega 3-fatty acids. Multiple regression analysis of the combined groups showed that all groups taking omega 3-fatty acids reduced platelet aggregation to both collagen (P < .0001) and platelet-activating factor (PAF) (P < .05) and platelet thromboxane B2 responses (P < .05) to collagen-induced aggregation. The low-fat diet alone had no effect on PAF-induced platelet aggregation and only a small effect on platelet responses to collagen (P < .05). Platelet aggregation responses to PAF were reduced more by fish oil than fish in a high-fat diet, whereas fish had a greater effect when part of a low-fat rather than a high-fat diet. There was no significant difference in collagen-induced platelet aggregation or platelet thromboxane between fish and fish oils on a high or low fat intake. In conjunction with our previous findings of improvements in lipoproteins, blood pressure, and heart rate in this population, these results on platelet function suggest that dietary omega 3-fatty acids incorporated into a low- rather than a high-fat diet have a wider spectrum of more favorable effects on cardiovascular risk factors.

THE INDEPENDENT EFFECTS OF EICOSAPENTAENOIC ACID AND DOCOSAHEXAENOIC ACID ON CARDIOVASCULAR RISK FACTORS IN HUMANS

Purpose of reviewThis review details the independent effects of purified eicosapentaenoic acid and docosahexaenoic acid on cardiovascular risk factors in humans. We report data from the recent literature and our own controlled clinical trials which compared the independent effects of these fatty acids in individuals at increased risk of cardiovascular disease, namely overweight hyperlipidaemic men and treated-hypertensive, type 2 diabetic men and women. We discuss the biological effects of these fatty acids and the potential mechanisms through which they may affect cardiovascular disease risk factors. Recent findingsA cardioprotective effect for ω3 fatty acids is supported by prospective studies demonstrating an inverse association between fish intake and coronary heart disease mortality. Data from secondary prevention trials support a reduction in ventricular fibrillation as a primary mechanism for the decreased incidence of myocardial infarction. Clinical trials and experimental studies have shown that ω3 fatty acids have many other potentially important antiatherogenic and antithrombotic effects. Omega-3 fatty acids lower blood pressure and heart rate, improve dyslipidaemia, reduce inflammation, and improve vascular and platelet function. These favourable effects have until recently been primarily attributed to the ω3 fatty acid eicosapentaenoic acid, which is present in large amounts in fish oil. Controlled studies in humans now demonstrate that docosahexaenoic acid, although often present in lower quantities, has equally important anti-arrhythmic, anti-thrombotic and anti-atherogenic effects. SummaryAvailable evidence strongly suggests that eicosapentaenoic acid and docosahexaenoic acid have differing haemodynamic and anti-atherogenic properties. The effects of the two fatty acids may also differ depending on the target population.

Coenzyme Q10 improves endothelial dysfunction of the brachial artery in Type II diabetes mellitus

Abstract.Aim/hypothesis: We assessed whether dietary supplementation with coenzyme Q10 improves endothelial function of the brachial artery in patients with Type II (non-insulin-dependent) diabetes mellitus and dyslipidaemia. Methods: A total of 40 patients with Type II diabetes and dyslipidaemia were randomized to receive 200 mg of coenzyme Q10 or placebo orally for 12 weeks. Endothelium-dependent and independent function of the brachial artery was measured as flow-mediated dilatation and glyceryl-trinitrate-mediated dilatation, respectively. A computerized system was used to quantitate vessel diameter changes before and after intervention. Arterial function was compared with 18 non-diabetic subjects. Oxidative stress was assessed by measuring plasma F2-isoprostane concentrations, and plasma antioxidant status by oxygen radical absorbance capacity. Results: The diabetic patients had impaired flow-mediated dilation [3.8 % (SEM 0.5) vs 6.4 % (SEM 1.0), p = 0.016], but preserved glyceryl-trinitrate-mediated dilation, of the brachial artery compared with non-diabetic subjects. Flow-mediated dilation of the brachial artery increased by 1.6 % (SEM 0.3) with coenzyme Q10 and decreased by –0.4 % (SEM 0.5) with placebo (p = 0.005); there were no group differences in the changes in pre-stimulatory arterial diameter, post-ischaemic hyperaemia or glyceryl-trinitrate-mediated dilation response. Coenzyme Q10 treatment resulted in a threefold increase in plasma coenzyme Q10 (p < 0.001) but did not alter plasma F2-isoprostanes, oxygen radical absorbance capacity, lipid concentrations, glycaemic control or blood pressure. Conclusion/interpretation: Coenzyme Q10 supplementation improves endothelial function of conduit arteries of the peripheral circulation in dyslipidaemic patients with Type II diabetes. The mechanism could involve increased endothelial release and/or activity of nitric oxide due to improvement in vascular oxidative stress, an effect that might not be reflected by changes in plasma F2-isoprostane concentrations. [Diabetologia (2002) 45: 420–426]

Effects of purified eicosapentaenoic acid and docosahexaenoic acid on platelet, fibrinolytic and vascular function in hypertensive type 2 diabetic patients

BACKGROUND Type 2 diabetes and hypertension are both associated with an increased risk of atherothrombosis. We assessed whether purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil have differential effects on platelet, fibrinolytic and vascular function in patients with both conditions. METHODS In a double-blind placebo-controlled trial of parallel design, 59 treated-hypertensive Type 2 diabetic men and postmenopausal women, were randomised to 4 g/day of EPA, DHA or olive oil (placebo) for 6 weeks. Collagen and PAF-stimulated platelet aggregation, collagen-stimulated thromboxane release (TXB2), plasma tPA and PAI-1 antigens, von Willebrand factor, p-selectin, and flow-mediated and glyceryl-trinitrate-mediated dilatation of the brachial artery, were examined before and at the end of intervention. RESULTS Thirty-nine men and 12 women aged 61.2+/-1.2 year completed the study. Relative to placebo, DHA but not EPA supplementation significantly reduced collagen aggregation (16.9%, P=0.05) and TXB2 (18.8%, P=0.03). There were no significant changes in either PAF-stimulated platelet aggregation, fibrinolytic function or vascular function in either the EPA or DHA group relative to placebo. CONCLUSION Highly purified DHA may be a more effective anti-thrombotic agent than EPA. However, longer-term studies assessing morbidity and mortality are needed in order to establish if DHA contributes to reducing CHD amongst Type 2 diabetic patients with treated hypertension.

Long-chain omega 3 fatty acids, blood lipids and cardiovascular risk reduction.

Increasing evidence suggests that omega 3 fatty acids derived from fish and fish oils may play a protective role in coronary heart disease and its many complications, through a variety of actions, including effects on lipids, blood pressure, cardiac and vascular function, prostanoids, coagulation and immunological responses. Interesting differences between the effects of highly purified eicosapentaenoic acid and docosahexaenoic acid are emerging, which may be relevant in the choice of omega 3 fatty acid for incorporation into food products. On the basis of our current knowledge, we believe it is justified to recommend, particularly to high-risk populations, an increased dietary intake of omega 3 fatty acids through the consumption of fish.