Diabetes care needs evidence based interventions to reduce risk of vascular disease.
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Adult↗
Biomedical subjects
C D Byrne
Publications and source records attributed to C D Byrne.
A common apolipoprotein B signal peptide polymorphism modifies the relation between plasma non-esterified fatty acids and triglyceride concentration in men.
Insulin and non-esterified fatty acids (NEFA) are important regulators of triglyceride metabolism. The relations between these compounds and the effect of a common 3 amino acid deletion in the apolipoprotein B (ApoB) signal peptide (SP) following an oral glucose challenge have been investigated. The frequency of the shorter SP-24 allele was 32% (95% C.I. 29.5-36.5) in 725 subjects undergoing an oral glucose tolerance test (OGTT). Fasting plasma triglyceride concentration was positively correlated with fasting plasma insulin concentration and negatively with the degree of plasma NEFA suppression following the glucose challenge. Linear regression analysis showed the relation between triglyceride concentration and NEFA suppression, but not the relation between triglyceride concentration and fasting insulin, to be altered by the SP polymorphism in men but not in women. The strength of the association was dependent on the number of SP-24 alleles, with SP-24 homozygotes showing the greatest dependence (men P=0.031, women P=0. 914). It was proposed that the complex regulation of very low density lipoprotein (VLDL) output by NEFA and by insulin may explain, at least in part, the conflicting reports concerning the presence of the ApoB SP polymorphism, fasting serum lipids and ischaemic heart disease (IHD).
Adult↗
Hypertension and its treatment influence changes in fasting nonesterified fatty acid concentrations: a link between the sympathetic nervous system and the metabolic syndrome?
In previous studies, a cross-sectional association has been described between blood pressure (BP) and nonesterified fatty acid (NEFA) concentrations. The direction of causality, and thus, the mechanism explaining this relationship, remains uncertain. Therefore, we analyzed a prospective population-based cohort of 937 subjects who underwent an oral glucose tolerance test (OGTT) on two occasions separated by 4.5 years. In cross-sectional analysis, NEFA measures were correlated with systolic and diastolic BP, both at baseline and at follow-up study. In longitudinal analysis, baseline systolic and diastolic BP predicted changes in fasting NEFA levels (both P < .01). However, baseline NEFA levels did not predict change in BR In multivariate analysis, the relationship between baseline BP and change in fasting NEFA was independent of age and sex. Obesity and its interaction with BP did not explain this association. Absolute changes in NEFA concentrations were greater among subjects who were hypertensive at baseline compared with the normotensive individuals. This change was greater in subjects treated with diuretics compared with those treated with beta-adrenergic antagonists (P < .01), an observation that provides support for a role of sympathetic nervous system (SNS) activity in explaining the relationship between BP and NEFA concentration.
Adrenergic beta-Antagonists↗
Fetal origins of adult disease: epidemiology and mechanisms.
The past 10 years have provided unequivocal evidence that there are associations between birth size measures and future development of adult diseases, such as type 2 diabetes and coronary artery disease. Despite initial concern that bias or residual confounding in the analyses had produced these rather bizarre associations, the findings have now been reproduced in different cohorts by independent investigators from many parts of the world. The challenge for the next decade must be to discover the cellular and molecular mechanisms giving rise to these associations. If this aim is accomplished, it might be possible to devise strategies to reduce the impact of these disabling, chronic, and expensive diseases. The purpose of this review is to describe some of the relevant, important, and more recent epidemiological studies, and also to discuss potential mechanisms underpinning the associations.
Adult↗
Differential hepatic lobar gene expression in offspring exposed to altered maternal dietary protein intake.
Increased plasma fibrinogen concentrations are a recognized risk factor for coronary heart disease, and increased fibrinogen levels in adults are associated with parameters of reduced early growth. We studied fibrinogen gene expression in adult offspring of dams fed either a 20% (control) or an 8% protein diet [maternal low-protein (MLP) rats] during pregnancy and lactation and determined whether any effects were consistent between left and right liver lobes, since the fetal liver has a unique blood supply that produces differential stimuli to the left and right lobes. In MLP offspring, there was a reduction in all three fibrinogen mRNA copy numbers in the left liver lobe [left vs. right lobes for alpha-, beta-, and gamma-fibrinogen (x10(6) copies/ng total RNA): 8.04 vs. 23.16, P<0.001; 4.74 vs. 13.07, P<0.001; and 4.61 vs. 16.38, P = 0.007, respectively], with a parallel reduction in fibrinogen concentration in the left liver lobe (8.53+/-0.33 vs. 10.41 +/-0.65 arbitrary units, P = 0.014, left and right lobes, respectively). No such effect was observed in offspring of control dams. To investigate the underlying mechanism, glucocorticoid receptor function and mRNA levels were studied, since expression of fibrinogen genes is regulated by glucocorticoid hormones. The binding affinity of the high-affinity glucocorticoid receptor was reduced only in the left liver lobe of the MLP offspring (P = 0.02, left. vs. right), with a parallel reduction in this lobe in glucocorticoid receptor mRNA level (P = 0.006, left vs. right). In conclusion, maternal dietary protein restriction reduces fibrinogen gene expression, fibrinogen protein, and mRNA level and binding affinity of glucocorticoid receptors only in the left liver lobe of the adult offspring.
Animals↗
Does tumour necrosis factor alpha influence insulin sensitivity in skeletal muscle?
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Animals↗
Activated protein C resistance: effect of platelet activation, platelet-derived microparticles, and atherogenic lipoproteins.
Plasma and platelet factor Va represent different substrates for activated protein C (APC). In this study, we have measured platelet-dependent APC resistance and the effect of aspirin and a platelet glycoprotein IIbIIIa antagonist (GR144053F) on this phenomenon. In platelet rich plasma (PRP), progressive APC resistance was observed with increasing platelet activation. APC sensitivity ratios of 1.8, 1.7, and 1.4 were observed after platelet activation with thrombin receptor activating peptide (TRAP), collagen, and A23187, respectively. Ultracentrifugation at 77,000g for 1 hour abolished APC resistance indicating that the phenotype is associated exclusively with the platelet membrane. APC resistance was not observed in the presence of phosphatidylcholine-phosphatidylserine (PCPS) vesicles or purified human plasma lipoproteins. APC resistance was observed in the presence of platelet-derived microparticles, but to a lesser degree than that in the presence of activated platelets. The platelet-dependent APC resistance phenotype was also observed when endogenous APC was generated by Protac (American Diagnostica, Inc, Greenwich, CT). In vitro inhibition of platelet activation with aspirin had no effect, but the fibrinogen receptor antagonist, GR144053F, inhibited platelet-dependent APC resistance. These results indicate that platelet activation results in an APC-resistant phenotype comparable to that observed in the plasma of patients with factor V gene mutations affecting critical APC cleavage sites. This suggests that platelet activation at the site of endothelial damage downregulates a critical natural anticoagulant mechanism. The antithrombotic effect of aspirin may be due to an indirect effect on platelet-dependent APC resistance with reduced platelet retention within a developing thrombus. The more potent antithrombotic effect of glycoprotein IIbIIIa antagonists may in addition be the result of reduced platelet factor Va expression and modulation of the platelet-dependent APC resistance phenotype.
Activated Protein C Resistance↗
Differential priming of RNA templates during cDNA synthesis markedly affects both accuracy and reproducibility of quantitative competitive reverse-transcriptase PCR.
Quantitative competitive reverse-transcriptase PCR is the most sensitive method for studying gene expression. To investigate whether the accuracy of the calculated target mRNA copy number is affected by the cDNA priming process, we utilized primers of different lengths, concentrations and primer sequences to prime cDNA synthesis reactions. Our results show a approximately 19-fold increase in the calculated mRNA copy number from cDNA synthesis reactions primed with random hexamers (P<0.001, n=4), and a approximately 4-fold increase in copy number with a specific hexamer (P<0.001, n=4) compared with that obtained with a 22-mer-sequence-specific primer. The increase in calculated mRNA copy number obtained by priming cDNA synthesis with the shorter specific and non-specific primers could be explained largely by the synthesis of truncated standard cDNA molecules lacking a requisite binding site for amplification with PCR primers. Since these truncated standard cDNA molecules could not be amplified and standard RNA is used to quantify target mRNA copy number, this phenomenon resulted in overestimation of target mRNA copy number. In conclusion, accurate determination of target mRNA copy number is most likely if a long specific antisense primer is used to prime cDNA synthesis.
Base Sequence↗
Triglyceride-rich lipoproteins: are links with atherosclerosis mediated by a procoagulant and proinflammatory phenotype?
Specific treatment that primarily reduces low density lipoprotein cholesterol (LDLc) levels improves survival of patients with pre-existing vascular disease by 20-30%. Failure to produce a more marked improvement in outcome is most likely explained by: (1) the observation from angiographic studies that established atherosclerotic vascular disease (AVD) is largely irreversible with current therapy and (2) other important factors cause AVD besides LDLc. One such risk factor predicting development of AVD is the atherogenic lipoprotein phenotype (ALP), comprising abnormalities of triglyceride enriched lipoproteins, high density lipoprotein cholesterol (HDLc) and small dense LDL particles. Despite strong links between the ALP and AVD, the mechanism(s) linking these relatively subtle lipoprotein abnormalities to vascular disease is poorly understood. Recent evidence suggests that a procoagulant and proinflammatory state develops within the vasculature, perhaps mediating a link between the ALP and AVD. The purpose of this review is to discuss mechanisms by which the ALP, and specifically, certain triglyceride-rich lipoproteins, may cause AVD by adverse affects on platelet function, coagulation and vascular inflammation. All rights reserved.
Animals↗
Frequent salad vegetable consumption is associated with a reduction in the risk of diabetes mellitus.
This cross-sectional study was undertaken to investigate the association between the reported frequency of consumption of vegetables and fruits, the choice of staple carbohydrate, and glucose intolerance. One thousand one hundred twenty-two subjects aged 40-64 years in a population-based study underwent an oral glucose tolerance test, and their food consumption was assessed using a food-frequency questionnaire. The crude prevalence of undiagnosed non-insulin-dependent diabetes mellitus (NIDDM) was 4.5%, and that of impaired glucose tolerance (IGT) 16.8%. The age-standardized prevalence rates were 2.3 and 11.2%, respectively. Frequent consumption of vegetables throughout the year was inversely associated with the risk of having NIDDM (odds ratio [OR] = 0.16; 95% confidence interval [CI] = 0.04-0.69). This association was maintained after adjustment for age, gender, and family history. Vegetable consumption during the summer months had a much weaker inverse association with the risk of having NIDDM that failed to reach statistical significance. A nonsignificant inverse association between frequent consumption of fruits and NIDDM was observed. Frequent self-reported pasta and rice consumption was associated with a reduction in the risk of having IGT and NIDDM. (OR = 0.62, 95% CI = 0.44-0.87, and OR = 0.51, 95% CI = 0.27-0.99, respectively) but this relationship was not independent of age. Whether these associations reflect specific effects of particular nutrients or are a reflection of the patterning of lifestyle factors remains to be determined.
Adult↗
Prospective cohort study of the relationship of markers of insulin resistance and secretion with weight gain and changes in regional adiposity.
OBJECTIVE: To examine whether fasting insulin concentrations and markers of first-phase insulin secretion are associated with weight gain and changes in distribution of adiposity over 4.4y. DESIGN: Longitudinal prospective population-based cohort study of middle-aged Caucasians. SUBJECTS: 767 subjects (40-65y at baseline) were followed up for a mean of 4.4y. MEASUREMENTS: 75 g oral glucose tolerance test performed at baseline and follow-up. Insulin was measured at fasting, and 30 and 120 min post-glucose load using a highly specific assay. RESULTS: Fasting insulin levels were correlated with baseline weight (r = 0.32, P<0.001), as was the 30 min insulin incremental response (r = 0.17, P<0.001). Mean weight gain over the 4.4y of follow-up was 2.17 kg (range: -6.17-10.5 kg) for men and 2.49 kg (range: -7.41-12.39 kg) for women. In women, the 30 min insulin incremental response was negatively associated with percentage weight gain (P<0.001), but there was no relationship between fasting insulin levels and weight gain. The baseline fasting insulin was positively correlated with percentage increase in waist- hip ratio (r = 0.12, P = 0.01). In stratified analysis, this relationship was confined to women over the age of 50 y. However, in men, none of these relationships were demonstrable. CONCLUSION: In middle-aged women reduced first-phase insulin secretion was associated with an increased risk of future weight gain, whereas fasting hyperinsulinaemia was associated with an increase in waist-hip ratio over time.
Adult↗
Cross-sectional but not longitudinal associations between non-esterified fatty acid levels and glucose intolerance and other features of the metabolic syndrome.
AIMS: Cross-sectional studies have demonstrated an association between high non-esterified fatty acid (NEFA) concentrations and glucose intolerance. However, the direction of causality in these studies is uncertain. The aim of this study was to examine whether NEFA levels predicted the development of glucose intolerance in a prospective population-based cohort study. METHOD: Four hundred and eighty-one women and 345 men participated in a prospective cohort study in which NEFA concentrations and glucose tolerance were measured at baseline and then repeated at follow-up 4.5 years later. RESULTS: The data do not show longitudinal relationships between baseline NEFA levels and either glucose intolerance or other features of the metabolic syndrome at follow-up. In contrast, strong cross-sectional associations were observed between NEFA measures and glucose intolerance (and other features of the metabolic syndrome) in both baseline and follow-up studies. At follow-up, fasting NEFA levels and two measures of NEFA suppression were markedly different in subjects with features of the metabolic syndrome, compared to subjects with normal glucose tolerance (NGT) (NGT vs. metabolic syndrome for each NEFA value, P< 0.001). CONCLUSIONS: These results support the hypothesis that plasma NEFA levels change as a consequence of the metabolic syndrome and do not support the notion that increased NEFA levels cause either the metabolic syndrome or diabetes.
Adult↗
Fasting proinsulin concentrations predict the development of type 2 diabetes.
OBJECTIVE: The development of specific assays allows the different molecules in the proinsulin processing pathway to be measured separately. 32,33 Split proinsulin is the predominant form of proinsulin and accounts for the disproportionate hyperproinsulinemia seen in individuals with prevalent type 2 diabetes. This study was established to examine whether the concentration of this molecule predicts diabetes. RESEARCH DESIGN AND METHODS: A population-based longitudinal cohort study was conducted in Ely, Cambridgeshire. At baseline, 1,122 individuals completed a 75-g oral glucose tolerance test (OGTT). At the 4.5-year follow-up study, repeat OGTTs were performed on 937 of the cohort of 1,071 individuals who had been nondiabetic at baseline. RESULTS: A total of 26 people progressed to diabetes as determined by the OGTTs. The risk of progression was strongly related to the fasting glucose concentration (relative risk [RR] comparing top with bottom quartile 17.6 [95% CI 2.4-130.4]) and fasting 32,33 split proinsulin (RR 16.4 [2.2-121.9]), but less strongly to the fasting insulin (RR 4.41 [1.5-12.9]) or intact proinsulin (RR 5.2 [1.5-17.3]). In multivariate analyses, these associations were independent of age, sex, BMI, and baseline glucose tolerance category. Subjects in the top quartile for fasting glucose and total proinsulin with a family history of diabetes were a high-risk subgroup (incidence 65.8 per 1,000 person-years of follow-up [pyfu]); 30% of them progressed to diabetes at follow-up. CONCLUSIONS: Fasting 32,33 split proinsulin independently predicts the development of diabetes. This prediction was better than that observed for either the insulin or intact proinsulin concentrations. The combination of family history, fasting glucose, and total proinsulin identified a subgroup of individuals at high risk of progression who might benefit from targeted interventions.
Adult↗
Photophysics of ethidium bromide complexed to ct-DNA: a maximum entropy study.
Time-integrated and time-resolved fluorescence spectroscopies have been used to probe the photophysical properties of ethidium bromide (Eb) complexed to calf thymus DNA (ct-DNA). Fluorescence decay profiles are obtained using the technique of time-correlated single photon counting (TCSPC), and subsequently analysed using conventional sum-of-exponential (SOE) routines and also the maximum entropy method (MEM). Through use of these methods and simulated decay data, it is demonstrated that the kinetics of Eb in the presence of ds-DNA are best described by a generic model consisting of three exponential terms. At all DNA:Eb ratios and NaCl concentrations studied, free Eb is detected. Furthermore, Eb is found to interact with ds-DNA through two mechanisms, each distinguishable by its fluorescence decay time. Eb is shown to interact with DNA through classic intercalation, and also through binding at secondary sites. The component decay times are shown to be a function of NaCl concentration but independent of DNA:Eb molar ratio.
Journal Article↗
Atherogenic lipoproteins support assembly of the prothrombinase complex and thrombin generation: modulation by oxidation and vitamin E.
The importance of lipoproteins in the etiology of atherosclerosis is well established. Evidence is now accumulating to implicate thrombin in the pathogenesis of atherosclerosis. We have investigated whether atherogenic lipoproteins can support thrombin generation. In the absence of platelets or endothelial cells, both very low-density lipoprotein (VLDL) and oxidized low-density lipoprotein (LDL) support assembly of the prothrombinase complex and generation of thrombin. Thrombin generation (per microgram of apolipoprotein) supported by VLDL was 19.4-fold greater than that supported by high-density lipoprotein (HDL), P < .00001, and 11.7-fold greater than that supported by LDL, P < .00001. Oxidation of LDL increased lipoprotein-supported thrombin generation 12-fold compared to unmodified LDL, P < .0001. We have shown that the phenomenon of lipoprotein-supported thrombin generation is mediated predominantly by specific phospholipids and is enhanced by oxidation of these phospholipids. The addition of vitamin E (alpha-tocopherol) markedly reduced the increase in thrombin generation observed after oxidation of LDL (822 +/- 57 v 138 +/- 47 nmol/L; P < .0001). These effects suggest that lipoproteins are important in the production of thrombin and that vitamin E may confer protection from the detrimental effects of lipoprotein oxidation by limiting thrombin formation. These results suggest that atherogenic lipoproteins are linked to the development of atherosclerosis in part by their capacity to support thrombin generation.
Adult↗
Increased PAI activity and PAI-1 antigen occurring with an oral fat load: associations with PAI-1 genotype and plasma active TGF-beta levels.
Whether the post-prandial lipemic response is linked to potentially pro-atherogenic and/or prothrombotic changes in plasminogen activator inhibitor (PAI) and transforming growth factor-beta (TGF-beta) is uncertain. The aim of our study was to determine whether PAI-1 antigen and PAI activity were elevated during post-prandial lipemia following a standard fat tolerance test. We also investigated changes in TGF-beta1 antigen and TGF-beta activity, to determine whether changes in TGF-beta activity were associated with changes in PAI measurements. Lastly, the influence of genotype at a common insertion/deletion polymorphism in the PAI-1 promoter on changes in PAI activity and PAI-1 antigen was examined. Fat tolerance tests were undertaken in 57 healthy middle-aged men to investigate associations between plasma concentrations of lipoproteins, PAI (antigen and activity) and TGF-beta. PAI-1 concentration increased by 76% after 8 h (P < 0.0001). PAI activity also increased by 64% (P = 0.0054) and TGF-beta activity decreased by 10% (P < 0.0001). Increases in PAI-I antigen and PAI activity varied markedly between individuals. To investigate these heterogeneous responses we examined whether genotype at the common insertion/deletion polymorphism of the PAI-1 promoter accounted for these differences. Individuals with at least one 4G (deletion) allele showed potentially pro-atherogenic changes in both PAI-1 and TGF-beta, compared to individuals who were homozygous for the 5G (insertion) allele. In conclusion, increased PAI and decreased TGF-beta activity occur during a fat tolerance test and this effect may be modulated by a common insertion/deletion polymorphism in the PAI-1 promoter.
Aged↗
A quantitative analysis of the relationship between habitual energy expenditure, fitness and the metabolic cardiovascular syndrome.
Previous epidemiological studies have suggested an association between low levels of physical activity, fitness and the metabolic cardiovascular syndrome. However, many studies have used subjective non-quantitative questionnaire-based methods for assessing physical activity which do not distinguish between the different dimensions of this complex exposure, and in which measurement error in the exposure has not been estimated. These deficiencies in the measurement of this exposure complicate the interpretation of the results of epidemiological studies, and consequently make it difficult to design appropriate interventions and to estimate the expected benefit which would result from intervention. In particular, it is unclear whether public health advice should be to increase total energy expenditure, or to attempt to raise fitness by recommending periods of vigorous activity. To separate the effects of fitness and total energy expenditure in the aetiology of the metabolic cardiovascular syndrome, we measured the physical activity level (PAL), defined as total energy expenditure: BMR, and fitness (maximum O2 consumption (VO2max per kg), measured in a sub-maximal test) in a cross-sectional population-based study of 162 adults aged 30-40 years. Heart-rate monitoring with individual calibration was used to measure total energy expenditure using the HRFlex method (Ceesay et al. 1989) which has been validated previously against doubly-labelled water and whole-body calorimetry. The relationship between a single measure of PAL, VO2max per kg and the usual or habitual level for each exposure was measured in a sub-study of twenty-two subjects who undertook four repeated measures over the course of 1 year. This study design allows the reliability coefficient to be computed, which is used to adjust the observed associations for measurement error in the exposure. Twelve men (16.4%) and sixteen women (18.0%) were defined as having one or more features of the metabolic cardiovascular syndrome. The univariate odds ratio for each increasing quartile for PAL was 0.64 (95% CI 0.43-0.94) and was 0.49 (95% CI 0.32-0.74) for VO2max per kg, suggesting that the association with the metabolic cardiovascular syndrome was stronger for fitness than for PAL. However, after adjustment for obesity and sex, and correction for exposure measurement error, the odds ratio per quartile for PAL was 0.32 (95% CI 0.13-0.83) and 0.44 (95% CI 0.24-0.78) for VO2max per kg. Thus, although univariate analysis would suggest that fitness has a stronger association with the metabolic cardiovascular syndrome than PAL, this conclusion is reversed once confounding and the differences in measurement error are considered. We conclude from the present study that the metabolic cardiovascular syndrome is strongly associated with reduced habitual energy expenditure. The method employed to assess the exposure in the present study demonstrates the utility of assessing a known dimension of physical activity using a physiologically-based and objective measure with repeated estimation to adjust for measurement error. Such quantitative epidemiological data provide the basis for planning and evaluating the expected benefit of population-level interventions.
Adult↗
Active management of acute hyperlipidaemic pancreatitis in pregnancy.
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Journal Article↗