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D J Betteridge

Publications and source records attributed to D J Betteridge.

At least 19 recordsLinked to original sources
PubMed2000

What is oxidative stress?

Oxidative stress, defined as a disturbance in the balance between the production of reactive oxygen species (free radicals) and antioxidant defenses, is discussed in relation to its possible role in the production of tissue damage in diabetes mellitus. Important free radicals are described and biological sources of origin discussed, together with the major antioxidant defense mechanisms. Examples of the possible consequences of free radical damage are provided with special emphasis on lipid peroxidation. Finally, the question of whether oxidative stress is increased in diabetes mellitus is discussed.

Diabetes Mellitus↗
PubMed1999

Platelet aggregation may not be a prerequisite for collagen-stimulated platelet generation of nitric oxide.

By determining the sum of the supernatant concentrations of nitrite and nitrate the stimulated generation of nitric oxide (NO) by human washed platelets induced by a range of fibrillar collagen concentrations (0.0156-25 microg ml(-1)) was investigated. Platelet serotonin (5-hydroxytryptamine, 5-HT) efflux and platelet aggregation were also measured. Under resting conditions (0 microg ml(-1) collagen) platelet NO release was equivalent to 1.06+/-0.17 nmol per 10(8) platelets. Maximal NO release, equivalent to 2.1+/-0. 37 nmol per 10(8) platelets, was observed with only 0.0625 microg ml(-1) collagen (P<0.02, stimulated vs. resting release), higher collagen concentrations producing no further increases in platelet NO output. By contrast, maximal platelet aggregation and 5-HT efflux did not occur until collagen concentrations of 2.5 microg ml(-1) and 10-25 microg ml-1), respectively, had been achieved. L-NAME (1 mmol l(-1)) and L-NMMA (1 mmol l(-1)) inhibited stimulated platelet NO generation by 78+/-6% and 72%, respectively. Contrasting with fibrillar collagen, fibrillar beta-amyloid protein had no effect on platelet NO generation, or on 5-HT efflux or aggregation. These data perhaps indicate that NO generation by human platelets is stimulated by concentrations of fibrillar collagen insufficient to elicit an aggregatory response. Such a mechanism could operate in vivo to inhibit platelet aggregation which might otherwise be induced by low concentrations of circulating agonists.

Blood Platelets↗
PubMed1999

Diabetic dyslipidaemia.

Type 2 diabetic patients have an increased risk of cardiovascular disease and, although many factors contribute to this risk, it is likely that diabetic dyslipidaemia plays an important role. Dyslipidaemia in Type 2 diabetic patients is characterized by low levels of HDL cholesterol and high triglyceride levels. In Type 2 diabetes, the total amount of LDL cholesterol is the same as in healthy people, but there are qualitative changes, e.g. a shift to smaller, denser LDL particles and an increased susceptibility to oxidation. Oxidized LDL may promote the development of atherosclerosis. It is possible to modify the major abnormalities of diabetic dyslipidaemia by combining lifestyle modifications (e.g. increased physical activity, cessation of smoking and weight reduction) with improved glycaemic control and hypolipidaemic drugs to reduce the burden of CVD within this high-risk population.

Cardiovascular Diseases↗
PubMed1999

International multicentre comparison of cerivastatin with placebo and simvastatin for the treatment of patients with primary hypercholesterolaemia. International Cerivastatin Study Group.

An international multicentre double-blind randomised trial compared the efficacy and safety of cerivastatin (0.025, 0.05, 0.1 and 0.2 mg once daily) with placebo and simvastatin (20 mg) over a period of 12 weeks, with study extensions to 52 and 100 weeks. The primary efficacy parameter was the percentage change in low density lipoprotein cholesterol (LDL-C). This was reduced from the baseline by 12.5% (0.025 mg) to 30.6% (0.2 mg) compared with falls of 2.0% on placebo and 40.3% on simvastatin. All four cerivastatin doses and simvastatin (20 mg) produced significantly greater falls than placebo (p < 0.0001) and the decrease in LDL-C was dose-dependent for cerivastatin. Simvastatin produced significantly greater falls than any cerivastatin dose or placebo (p < 0.0001). The effect was maintained at 1 year but somewhat attenuated at 100 weeks. Significant falls were also seen in serum total cholesterol and triglycerides. High density lipoprotein cholesterol (HDL-C) levels were significantly increased by cerivastatin (0.1 and 0.2 mg) and simvastatin (20 mg) at 12 weeks and increased further by 100 weeks. Mean fasting apolipoprotein A1 and lipoprotein A1 were increased and apolipoprotein B decreased by cerivastatin and simvastatin therapy. All doses of cerivastatin produced significant falls in the total cholesterol/HDL-C ratio at 12 weeks (0.5-1.6) compared with a fall of 2.1 for simvastatin (20 mg). Cerivastatin was well tolerated. Elevations in creatine phosphokinase, aspartate aminotransferase and alanine aminotransferase were mostly minor and transitory. Vital signs, electrocardiogram determinations, urinalysis and ophthalmic assessment showed similar results for both drugs. Cerivastatin, at doses of 0.1 mg and 0.2 mg daily, is considered to be of therapeutic value in the treatment of patients with primary hypercholesterolaemia, with 0.2 mg cerivastatin achieving reductions of LDL-C and total cholesterol similar to those achieved in the WOSCOP and CARE studies.

Anticholesteremic Agents↗
PubMed1997

Relationships between plasma measures of oxidative stress and metabolic control in NIDDM.

Diabetes mellitus may be associated with increased lipid peroxidation which may contribute to long-term tissue damage. To test this hypothesis, we measured hydroperoxides (ROOHs) as well as alpha-tocopherol in plasma from healthy subjects and individuals with non-insulin-dependent diabetes mellitus (NIDDM) (n = 41 and 87, respectively). ROOHs were analysed using the ferrous oxidation with xylenol orange version II (FOX2) assay in conjunction with a specific ROOH reductant, triphenylphosphine, alpha-Tocopherol was analysed by HPLC with fluorimetric detection. NIDDM patients had lower cholesterol standardised alpha-tocopherol levels as compared to control subjects (3.3 +/- 1.0 vs 5.1 +/- 2.3 (mumol/l)/(mmol/l); p < 0.0005, Mann-Whitney test): range (1.5-6.5 vs 1.9-13.0, respectively). Plasma ROOHs were substantially higher in the diabetic subjects compared to those of the control subjects (9.4 +/- 3.3 vs 4.1 +/- 2.2 mumol/l; p < 0.0005 Mann-Whitney test: range 2.7-16.8 vs 0.4-10.3, respectively). ROOH/cholesterol standardised alpha-tocopherol ratio was significantly higher in the diabetic patients compared to control subjects (3.2 +/- 1.6 vs 0.9 +/- 0.6; p < 0.0005, Mann-Whitney test: range 0.7-8.3 and 0.1-2.7, respectively). Plasma levels of ROOHs and alpha-tocopherol were similar in diabetic patients with or without complications as well as in smokers and non-smokers. The present study confirms previous findings from this laboratory that NIDDM is associated with increased oxidative stress as assessed by plasma ROOHs. Increased oxidative stress in diabetic patients appears to be related to the underlying metabolic abnormalities in diabetes, rather than to the complications of this disease. We therefore suggest that oxidative stress is an early stage in the disease pathology, which may contribute to the development of complications.

Adolescent↗
PubMed1997

Reduced platelet serotonin content and release in familial hypercholesterolaemia.

Plasma and platelet serotonin (5-HT) concentrations, and resting and collagen-induced 5-HT release in platelet-rich plasma were studied in normal and familial hypercholesterolaemic (FH) subjects. Platelet 5-HT concentrations were significantly reduced (-37%, P < 0.01) in FH patients whilst mean plasma concentrations, although increased, were not significantly different from those in normal subjects. Platelet 5-HT correlated negatively with plasma cholesterol when the data for normal subjects and FH, patients were combined (r = -0.48, P = 0.005). It also correlated negatively with low-density lipoprotein (LDL) (FH data, r = -0.59, P = 0.03; normal and FH data, r = -0.49, P = 0.004) but positively with high-density lipoprotein (HDL) (FH r = 0.79, P = 0.001; normal and FH, r = 0.37, P = 0.03). Collagen (5-160 micrograms/ml) stimulated platelet 5-HT release occurred in a concentration-dependent manner. In FH patients stimulated 5-HT release was reduced (10 micrograms/ml collagen, -40%, P < 0.05) and accompanied by increased collagen EC50 values (P < 0.02). Resting 5-HT release was increased substantially in FH patients but not significantly. Our data provide evidence for a relationship between circulating cholesterol and platelet serotonergic mechanisms. It is proposed that abnormalities relating to platelet-plasma 5-HT dynamics, perhaps due to enhanced platelet activity or decreased platelet uptake, may contribute to the cardiovascular complications in FH.

Adult↗
PubMed1997

In vitro adrenaline and collagen-induced mobilization of platelet calcium and its inhibition by naftopidil, doxazosin and nifedipine.

AIMS: The aim of the study was to obtain further information regarding the modes of action of doxazosin, naftopidil and nifedipine on platelet function. METHODS: We conducted an in vitro study of drug influences on adrenaline and collagen-induced mobilization of platelet calcium. RESULTS: In the presence of fibrinogen (300 micrograms ml-1) both collagen (5 micrograms ml-1) and adrenaline (16 microM) stimulated the aggregation of washed platelets. Collagen induced a transient rise (+4.97 +/- 0.63 microM) in platelet Ca2+ concentration, [Ca2+]i, as measured using the photoprotein aequorin, which coincided with the onset of aggregation. Adrenaline induced a smaller rise (+3.6 +/- 0.96 microM) which, however, occurred after the onset of aggregation. Naftopidil, an alpha 1-adrenoreceptor antagonist produced a concentration-dependent inhibition of collagen-induced Ca2+ mobilization, maximum inhibition (22.9 +/- 4%, P < 0.05) occurring with 40 microM naftopidil. The inhibition of Ca2+ mobilization was not reflected by a concentration-dependent inhibition of platelet aggregation, although 40 microM naftopidil produced statistically significant inhibition (23.3 +/- 11.7%, P < 0.05). The adrenaline-induced rise in [Ca2+]i was inhibited dose dependently by naftopidil (e.g. 40 microM naftopidil, 100 +/- 0%, P < 0.05), as was aggregation (40 microM naftopidil, 100 +/- 0%, P < 0.05). Doxazosin, another alpha 1-adrenoreceptor blocker, inhibited Ca2+ mobilization induced by collagen to similar extents as for naftopidil (30 microM doxazosin, 17.4 +/- 2.5%, P < 0.05), but did not inhibit platelet aggregation. It also inhibited the adrenaline-induced rise in [Ca2+]i in a concentration-dependent manner (30 microM doxazosin, 37.6 +/- 13.7%, P < 0.05), significant inhibitions of platelet aggregation also being produced (30 microM, 49.6 +/- 17.2%, P < 0.05). As expected, the calcium channel blocker nifedipine produced concentration-dependent inhibitions of both collagen-induced Ca2+ mobilization (e.g. 28 microM nifedipine, 47.8 +/- 2.7%, P < 0.05) and aggregation (28 microM, 55.1 +/- 9.2%, P < 0.05). CONCLUSIONS: These data indicate that the alpha 1-adrenoreceptor blockers, naftopidil and doxazosin, inhibit Ca2+ mobilization, this mechanism being possibly the means whereby these drugs inhibit platelet aggregation.

Adrenergic alpha-Antagonists↗
PubMed1996

Postprandial lipid metabolism and beta-cell function in non-insulin-dependent (type 2) diabetes mellitus after a mixed meal with a high fat content.

Postprandial lipid profiles and release of insulin (INS), intact proinsulin (PI), and 32-33 split proinsulin (SPI) in response to a mixed meal with a high fat content were determined over a 12 h period in non-obese control subjects (n = 10) and non-insulin-dependent (Type 2) diabetic (NIDDM) patients with normotriglyceridaemia (NTG; n = 11) and hypertriglyceridaemia (HTG; n = 10), by calculation of the 'areas under the curves' (AUC). The postprandial triglyceride-AUC was significantly greater in HTG-NIDDM patients (p < 0.05) than in NTG-NIDDM or control subjects. Chylomicron clearance was impaired only in HTG-NIDDM patients (p < 0.05). Chylomicron-remnant clearance was impaired in both groups of NIDDM patients (p < 0.05). The postprandial suppression of plasma non-esterified fatty acid (NEFA) content was impaired in HTG-NIDDM patients (p < 0.05). The postprandial INS-, PI- and SPI-AUCS were significantly greater than in the control subjects (p < 0.05). In NIDDM, triglyceride-AUC correlated significantly with PI and SPI release (triglyceride-AUC vs PI, p < 0.05; triglyceride-AUC vs SPI, p < 0.01). Chylomicron AUC was unrelated to the fasting plasma INS, PI or SPI content, unlike chylomicron-remnant-AUC (Chylomicron-remnant-AUC vs INS, p = NS; chylomicron-remnant-AUC vs PI, p < 0.01; chylomicron-remnant-AUC vs SPI, p < 0.01). The NEFA response was associated with fasting plasma SPI content (NEFA-AUC vs SPI, p < 0.05). Postprandial chylomicron AUC was not related to the overall secretion of INS, PI or SPI. However, triglyceride-, chylomicron-remnant- and NEFA-AUCs were all associated positively with the release of PI and SPI (p < 0.05). In multivariate analyses, chylomicron-remnant clearance had the major relationship with the release of insulin precursors, accounting for 23% of the variability (p < 0.01). Inclusion of overall response of free fatty acids improved the model, with both parameters together accounting for 30% of the variability (p < 0.01). The output of the beta-cell over the postprandial period differed between the NIDDM patients and the control subjects in that when glycaemic stimulation was moderate, the proportion of insulin-like molecules as a percentage of the total output was greater than in control subjects but this was not the situation when glycaemia was greatest. We conclude that abnormal postprandial lipaemia in NIDDM is associated with beta-cell output, possibly mediated by the availability of free fatty acids.

Blood Glucose↗
PubMed1996

Lipids and atherogenesis in diabetes mellitus.

Premature cardiovascular disease is a major burden in diabetes. Increasing cholesterol is associated with increasing vascular risk in diabetes and the absolute excess risk attributable to cholesterol is higher in diabetes than in non-diabetics. Total cholesterol and low density lipoprotein (LDL) cholesterol correlated with arterial endothelial dysfunction as assessed by reduced flow-mediated brachial artery dilatation in insulin-dependent diabetic patients. In non-insulin dependent diabetic patients hypertriglyceridaemia is common and is associated with the accumulation of intermediate density lipoproteins, abnormal postprandial lipid metabolism and small dense LDL. No trials of lipid lowering therapy in the primary or secondary prevention of cardiovascular disease have been targeted specifically to the diabetic population; nevertheless, guidelines have been published for the treatment of dyslipidaemia in diabetic patients recognising the evidence of benefit in non-diabetics and the high intrinsic risk of the diabetic.

Coronary Artery Disease↗
PubMed1996

Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels.

OBJECTIVES: This study sought to examine whether endothelial function is impaired in the large vessels of asymptomatic young adults with insulin-dependent diabetes and whether endothelial dysfunction is related to duration or control of diabetes, small-vessel disease or other vascular risk factors. BACKGROUND: Endothelial dysfunction is an early event in atherosclerosis, and large-vessel atherosclerotic disease is the major cause of morbidity and mortality in diabetes. METHODS: We compared 80 young adults with insulin-dependent diabetes (15 to 40 years old; mean [+/- SD] diabetes duration 13 +/- 8 years) with 80 matched nondiabetic control subjects. Using high resolution vascular ultrasound, we measured brachial artery responses to reactive hyperemia (with increased flow causing endothelium-dependent dilation) and sublingual glyceryltrinitrate (causing endothelium-independent dilation). RESULTS: Flow-mediated dilation was significantly impaired in diabetic subjects (5.0 +/- 3.7% vs. 9.3 +/- 3.8% in control subjects, p < 0.001). The ratio of flow-mediated dilation to glyceryltrinitrate-induced dilation was significantly lower in the diabetic subjects (p < 0.02), indicating that impaired dilation to increased flow was out of proportion to the impairment of the glyceryltrinitrate response in these subjects (15.6 +/- 5.6% vs. 19.7 +/- 6.6% in control subjects, p < 0.001). On multivariate analysis, flow-mediated dilation was inversely related to both duration of diabetes (r = -0.26, p < 0.05) and low density lipoprotein (LDL) cholesterol levels (r = -0.38, p < 0.005). CONCLUSIONS: Vascular reactivity is impaired in the systemic arteries of asymptomatic young adults with insulin-dependent diabetes and may represent early large-vessel disease. The degree of impairment is related to the duration of diabetes, and these patients appear particularly vulnerable to damage from LDL cholesterol, even at levels considered acceptable in nondiabetic subjects.

Adolescent↗
PubMed1996

Comparative efficacy and safety of ciprofibrate and sustained-release bezafibrate in patients with type II hyperlipidaemia.

The hypolipidaemic efficacy and safety of ciprofibrate were compared with a sustained-release formulation of bezafibrate (Bezalip Mono) in 174 patients with type II hyperlipidaemia. This multicenter, open, parallel-group study was conducted in general practice. A total of 83 patients received 100 mg ciprofibrate once daily and 91 received 400 mg bezafibrate once daily for eight weeks. Concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides were measured at baseline (after stabilisation on a lipid-lowering diet) and after eight weeks. Safety was assessed from reports of adverse events and by measuring haematological and biochemical parameters. After eight weeks, ciprofibrate produced a significantly greater decrease in total cholesterol (-17.8% vs -12.5%), low-density lipoprotein cholesterol (-22.4% vs -17.2%), and triglycerides (-33.9% vs -26.1%). High-density lipoprotein cholesterol concentrations were increased significantly by both drugs (19.6% with ciprofibrate, 24.9% with bezafibrate) but the differences between drugs were non-significant. Both drugs were well tolerated, with headache the most widely reported adverse event.

Adult↗
PubMed1996

Lipid management: past, present, and future.

The therapeutic compounds available to the clinician treating lipid disorders in the 1990s enable the effective management of many patients. The development of the HMG-CoA reductase inhibitors is a major advance, and for the first time benefit in terms of overall mortality has been demonstrated in the impressive 4S study. What is needed now is effective implementation of screening and treatment of high-risk individuals. The UK continues to lag behind in this area. LDL cholesterol is the major target for therapy, but it is likely that over the next few years other lipid and lipoprotein parameters (HDL cholesterol, remnant particles, small dense LDL etc) will become more generally accepted targets for specific therapeutic intervention. Research continues to develop novel compounds targeting new regulatory steps in lipoprotein metabolism. In addition much progress is likely in targeting the arterial wall and atherogenesis other than specifically modulating plasma lipids. In the meantime the task of the clinician is to put into practice what is now known particularly about the secondary prevention of CHD to ensure that patients benefit from recent advances in knowledge.

Adult↗
PubMed1995

Plasma 8-epi-PGF2 alpha levels are elevated in individuals with non-insulin dependent diabetes mellitus.

This study reports plasma levels of a specific nonenzymatic peroxidation product of arachidonic acid, esterified 8-epi-PGF2 alpha, from healthy- and NIDDM individuals as an index of oxidative stress in vivo. Plasma 8-epi-PGF2 alpha was isolated by solid-phase extraction on a C18 followed by an NH2 cartridge and analyzed by GC-MS/NICI as PFB-ester/TMS-ether derivative. We found that the average concentration of esterified 8-epi-PGF2 alpha among NIDDM subjects (0.93 +/- 0.07 nM, n = 39) was higher (P < 0.0001, Mann-Whitney test) than in healthy individuals (0.28 +/- 0.04 nM, n = 15). These data indicate that NIDDM is associated with increased plasma lipid peroxidation.

Adult↗