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Biomedical subjects

N J Wareham

Publications and source records attributed to N J Wareham.

At least 91 records · Page 5Linked to original sources
PubMed1999

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↗
PubMed1998

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↗
PubMed1998

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↗
PubMed1998

The validation of physical activity instruments for measuring energy expenditure: problems and pitfalls.

OBJECTIVE: To review and categorize the problems associated with undertaking physical activity validation studies and to construct a checklist against which any study could be compared. RESULTS: The studies reviewed demonstrated problems in defining the dimension of physical activity that is of interest and in the selection of an appropriate comparison technique. Ideally this should be closely related to the true exposure of interest and assess that exposure objectively and without correlated error from the study instrument in question. In many studies inappropriate comparison methods have been chosen which do not measure the true underlying exposure and which are likely to have correlated error. The choice of study populations, the frame of reference of the exposure measurement and the use of appropriate statistical methods are also problematic areas. CONCLUSIONS: There is no ideal measurement instrument or validation study design that is suitable for all situations. However, the checklist in this paper provides a means whereby the appropriateness of studies already undertaken or at the planning stage can be assessed.

Adolescent↗
PubMed1998

Accessibility and health service utilization for asthma in Norfolk, England.

BACKGROUND: Good access to health services may be important for effective asthma management amongst patients. Previously, we found elevated asthma mortality in parts of England with poor access to acute hospitals. A possible explanation is that barriers of access to care may lead to residents of more remote areas having a lower propensity to utilize health services, with the result that their asthma is poorly controlled. Here, we examine the relationship between utilization and the geographical accessibility of health services amongst self-reported asthmatics in a rural county of England. METHODS: The study involved analysis by logistic regression of questionnaire responses from a 10 per cent population sample of 9764 adults aged between 20 and 44 years, and resident within the catchment area of Norwich Health Authority. RESULTS: Utilization behaviour was associated with the smoking status of respondents, and levels of car ownership in their ward of residence. After controlling for these factors, respondents reporting asthma were less likely to have ever visited a general practitioner if they lived outside a settlement containing a surgery (odds ratio (OR) 3.07, 95 per cent confidence interval (CI) 1.11-8.48, p = 0.03), and the likelihood of consultation declined with distance from a surgery (OR for a 1 minute increase in travel time 0.79, 95 per cent CI 0.66-0.94, p < 0.01). Those living further from an acute hospital unit were also less likely to have consulted a hospital doctor in the previous 12 months (OR for a 1 minute increase in travel time 0.95, 95 per cent CI 0.9-0.99, p = 0.01). CONCLUSIONS: Our finding of lower levels of health service utilization amongst some self-reported asthmatics living further from health facilities suggests that the condition of some individuals might be poorly treated, which could increase the risk of fatality.

Adult↗
PubMed1998

The assessment of physical activity in individuals and populations: why try to be more precise about how physical activity is assessed?

Simple epidemiological measures of physical activity have proved sufficient to demonstrate associations with many chronic disease outcomes, but they have infrequently separated physical activity into its different dimensions, nor have they allowed estimation of dose-response effects. Generating greater clarity about the nature of the exposure-disease relationship, is an important step in the development of an appropriate public health intervention. This clarity can only be achieved with reliable and valid measurement instruments, which objectively and quantitatively assess the dimension of physical activity that is of interest for a particular health outcome. Objective techniques, such as heart rate monitoring, which have been directly compared to gold standard assessment methods, may be of use in medium-sized epidemiological studies and as a validation tool for questionnaires to be used in larger studies. The combination of methods with uncorrelated error, would result in an improved estimation of the true exposure and is an important area for research. Improved assessment would be of use in aetiological studies, in tracking trends in physical activity within populations, making objective comparisons between populations and in monitoring the effect of interventions.

Adult↗
PubMed1997

Congenital leptin deficiency is associated with severe early-onset obesity in humans.

The extreme obesity of the obese (ob/ob) mouse is attributable to mutations in the gene encoding leptin, an adipocyte-specific secreted protein which has profound effects on appetite and energy expenditure. We know of no equivalent evidence regarding leptin's role in the control of fat mass in humans. We have examined two severely obese children who are members of the same highly consanguineous pedigree. Their serum leptin levels were very low despite their markedly elevated fat mass and, in both, a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found. The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans.

Adult↗
PubMed1997

Homozygosity for a common polymorphism in the islet-specific promoter of the glucokinase gene is associated with a reduced early insulin response to oral glucose in pregnant women.

A commonly occurring sequence variant in the islet-specific promoter of the glucokinase gene (-30 G to A) has been variably reported to be associated with reduced insulin secretory responses to oral glucose. The effect of this promoter variant may be subtle and only become apparent under conditions of beta-cell 'stress'. As late pregnancy is a time of increased insulin secretory demand, we have examined whether this common genetic variant was associated with impairment of insulin secretory responses to oral glucose in 92 women in the third trimester of pregnancy. The three women who were homozygous for the variant sequence had a markedly diminished 30' insulin incremental response to oral glucose (10.4, 11.4, and 17.2 pmol insulin mmol-1 glucose, respectively) compared to either heterozygous (49.3 (37.6-64.6 pmol insulin mmol-1 glucose)) (p < 0.002) or homozygous wild-type (51.4 (40.9-64.7 pmol insulin mmol-1 glucose)) (p < 0.002) Mann-Whitney U test) women. In a subset of 35 British Caucasian women with gestational diabetes, no mutations resulting in a change of amino acid sequence were detected by molecular scanning of all exons of the glucokinase gene. In summary, in a cohort of 35 British Caucasian women with gestational diabetes neither missense nor nonsense glucokinase mutations were found. However, in women in the third trimester of pregnancy, homozygosity for a common polymorphic variant in the islet-specific promoter of the glucokinase gene was associated with a highly significant reduction of early insulin secretory responsiveness to oral glucose. Under the conditions of increased secretory demand represented by late pregnancy, a promoter variant in the glucokinase gene may influence the early insulin secretory response to oral glucose.

Base Sequence↗
PubMed1997

Is an exaggerated postprandial triglyceride response associated with the component features of the insulin resistance syndrome?

To investigate whether individual component features of the insulin resistance syndrome were associated with the postprandial triglyceride response, 57 healthy Caucasian men between 57 and 70 years of age underwent a fat tolerance test lasting 8 h. Fasting triglyceride concentrations were associated with the total unfractionated postprandial triglyceride response (r(s) = 0.54, p < 0.001) and the triglyceride-rich lipoprotein (TGRLP) fraction (d < 1.006) at 8 h was associated with the maximum non-esterified fatty acid concentration (NEFA) (r(s) = 0.33, p = 0.01). Measures of obesity (BMI and WHR) were not associated with the postprandial triglyceride response but were inversely related to NEFA suppression (NEFA nadir and BMI, r(s) = 0.31, p = 0.02; and NEFA nadir and WHR, r(s) = 0.36, p = 0.006). Other component features of the IRS, including glucose tolerance and two proxy measures of insulin resistance (fasting insulin concentration and HOMA measurement) were not associated with the postprandial triglyceride response despite being strongly associated with fasting triglyceride concentration. Current smoking habit, chronic alcohol consumption and birth weight were also not associated with an altered postprandial triglyceride response. In conclusion these results show that although component features of the IRS were associated with increased fasting triglyceride concentrations many of these features, including two proxy measures of insulin sensitivity were not associated with an exaggerated postprandial triglyceride response.

Aged↗
PubMed1997

Glucose intolerance is associated with altered calcium homeostasis: a possible link between increased serum calcium concentration and cardiovascular disease mortality.

Serum calcium concentration has recently been shown to predict cardiovascular mortality in a large health-screening program. Since impaired glucose tolerance (IGT) is an independent cardiovascular risk factor, we examined the association between glucose intolerance and serum calcium in a population-based cohort study. To characterize this association, we measured total serum calcium, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), and 1,25-dihydroxyvitamin D (1,25-(OH)2D) levels in a cohort of 1,071 randomly selected white individuals aged 40 to 65 years in whom an oral glucose tolerance test had been completed. In multivariate analyses, the 2-hour plasma glucose was positively associated with increasing total serum calcium and PTH in men and women after adjustment for age, obesity, season, and 25OHD. The adjusted odds ratio (OR) between increasing quintiles of total serum calcium and IGT was 1.63 (95% confidence interval [CI], 1.42 to 1.88). The OR comparing the top with the bottom quintile was 8.5 (95% CI, 4.5 to 16.0). The association with quintile of serum PTH was 1.30 (95% CI, 1.14 to 1.49). These data suggest that IGT is associated with an increase in both total serum calcium and PTH that cannot be explained by confounding by aging, obesity, or 25OHD. This relationship may explain the previously observed association between serum calcium and cardiovascular mortality. Whether this association is a manifestation of a shared cellular defect or represents a common relationship with an unknown etiologic factor are important questions for further research.

Adult↗
PubMed1997

The role of insulin and proinsulin in the regulation of triglyceride metabolism.

The mechanisms underlying the associations between abnormal glucose tolerance and myocardial infarction are poorly understood. It has often been suggested that an increased plasma insulin concentration is causally linked to many of the metabolic abnormalities that are associated with abnormal glucose tolerance, although this suggestion remains controversial. Recently it has been proposed that proinsulin and proinsulin-like molecules may also be involved in the atherogenic process. Both hyperinsulinaemia and insulin resistance are associated with fasting hypertriglyceridaemia and both increased VLDL production and increased plasma triglyceride concentrations commonly occur in association with abnormal glucose tolerance and atheromatous vascular disease. In order to study the effects of insulin, proinsulin and proinsulin-like molecules on hepatic triglyceride secretion we have undertaken experiments in vitro using the liver cell line HepG2. In conjunction with these in vitro experiments we have also studied, in vivo, the associations between insulin, proinsulin, proinsulin-like molecules and plasma triglyceride concentrations in subjects with both normal and abnormal glucose tolerance. Our results in vitro show that proinsulin and proinsulin-like molecules have similar and not different effects to insulin but are less biologically active. In vivo, our results show that concentrations of insulin, proinsulin and proinsulin-like molecules per se are not an important determinant of plasma triglyceride concentrations. Both abnormal NEFA suppression during an oral glucose tolerance test and increased central adiposity are closely linked to poor glucose tolerance and are the most important determinants of plasma triglyceride concentrations. Taken together these results suggest that it is not insulin nor proinsulin concentrations per se that are causally linked to hypertriglyceridaemia. We suggest that abnormal NEFA suppression plays an important part in the increase in risk of vascular disease associated with insulin resistance.

Adult↗
PubMed1997

Feasibility of heart-rate monitoring to estimate total level and pattern of energy expenditure in a population-based epidemiological study: the Ely Young Cohort Feasibility Study 1994-5.

Increasing the precision of measurements of total energy expenditure in population-based epidemiological studies is important for accurately quantifying the relationship between this exposure and disease. Current questionnaire-based methods cannot accurately quantify total energy expenditure, although they may provide an estimate of the frequency of vigorous activities. Heart rate monitoring with individual calibration has been advocated as a method for assessing energy expenditure in field studies and has been compared with the 'gold standard' techniques of doubly-labelled water and indirect calorimetry. However the method has previously only been used on small and selected populations. This study was, therefore, established to test the feasibility of using heart rate monitoring in a population-based study of adults. A total of 167 individuals aged 30-40 years were randomly selected and underwent 4 d heart-rate monitoring. Only three individuals could not complete the protocol. The mean physical activity level (PAL) measured over 4 d was 1.89 (SD 0.40) in men and 1.76 (sd 0.31) in women. There was no difference between mean PAL on weekend days compared with weekdays (mean paired difference 0.0008, 95% CI -0.06 +0.06). The estimate of mean PAL was not correlated with BMI, percentage body fat or the waist:hip ratio. It was, however, correlated with cardio-respiratory fitness as measured by VO2(max) per kg (Spearman rank correlation coefficient 0.50 in men and 0.42 in women). The pattern of energy expenditure was assessed by calculating the percentage of daytime hours in which PAL was greater than five times basal energy expenditure. This measure was strongly correlated with the mean PAL in both men (Spearman correlation coefficient 0.77) and women (0.71). We conclude that heart-rate monitoring is a feasible method for assessing the pattern and total level of energy expenditure in medium-sized epidemiological studies. It may also prove useful as the reference technique for calibrating questionnaires to estimate energy expenditure in larger scale studies.

Adult↗
PubMed1996

The association between free fatty acid concentrations and triglyceride-rich lipoproteins in the post-prandial state is altered by a common deletion polymorphism of the apo B signal peptide.

To investigate whether there were associations between the free fatty acid (FFA) response during a fat tolerance test and changes in concentrations of triglyceride-rich lipoproteins 57 healthy Caucasian men between 57 and 70 years of age underwent a fat tolerance test lasting 8 h. FFA concentrations initially decreased from 0.75 +/- 0.03 to 0.64 +/- 0.03 mmol/l at 2 h and thereafter increased to 1.2 +/- 0.04 mmol/l at 8 h. Maximum FFA concentration was the only significant determinant of 8 h triglyceride-rich lipoprotein (TGRLP) concentrations (pooled chylomicron and VLDL fractions d < 1.006) (TGRLP-TG r = 0.33, P = 0.012; TGRLP apo B r = 0.37, P = 0.004; TGRLP cholesterol r = 0.38, P = 0.004). The strength of the association between FFA and TGRLP was affected by the apo B signal peptide genotype. Only in individuals who were homozygous for the 27 amino acid (SP27 or I) allele of the apo B signal peptide were there significant associations between maximum FFA concentration quartile and 8 h TGRLP concentration (P value for linear trend = 0.025). In this genotype group there were lower HDL cholesterol concentrations (1.16 mmol/l compared to 1.38 mmol/l in subjects either heterozygous or homozygous for the SP24 [D] allele; P = 0.005) and there was a trend toward increased 8 h TGRLP concentrations. We propose that the association between post-prandial FFA concentrations and post-prandial TGRLP concentrations in individuals who are homozygous for the SP27 allele may be linked to the increased prevalence of ischemic heart disease (IHD) in this genotypic group.

Aged↗
PubMed1996

Is platelet phospholipid-dependent thrombin generation altered by acute myocardial infarction or aspirin?

The ability of unactivated and calcium ionophore activated platelets to support thrombin generation in defibrinated plasma was measured by a chromogenic substrate assay in the absence of clot formation. Platelet phospholipid-dependent thrombin generation (Platelet-TG) could be measured using platelets isolated from blood collected into either sodium citrate or EDTA as anticoagulant. Measurements were stable in samples kept at room temperature for 24 hours after venesection. There was no significant difference in either the unactivated or activated platelet-TG with platelets collected into either anticoagulant (mean difference 10.12 nmol/min unactivated and 10.60 nmol/min activated). There was no correlation between unactivated and activated platelet-TG and patient age. Platelet-TG was 179 (153-237) nmol/min (median and inter quartile range) for unactivated and 489 (462-508) nmol/min for activated platelets from healthy volunteer subjects (median age 31, range 20-40 years). Platelet-TG was the same in subjects from a population-based cohort study (median age 58, range 45-70 years [162 (142-193) nmol/min and 527 (490-551) nmol/min, unactivated and activated platelets respectively] as compared to patients admitted with acute myocardial infarction (median age 68, range 36-85 years [179 (146-200) nmol/min and 473 (440-517) nmol/min unactivated and activated platelets respectively] (p = 0.497 for comparison between unactivated platelet-TGs and p = 0.487 for comparison between activated platelet-TGs in the two groups). Aspirin inhibited platelet aggregation but did not affect platelet-TG using either unactivated or activated platelets exposed to aspirin in vitro; or in vivo, using platelets obtained from individuals after ingestion of aspirin. In conclusion these results show that for measurement of platelet-TG, blood samples can be anticoagulated with EDTA as well as sodium citrate for up to 24 hours after venesection and that this measurement is not affected by subject age, aspirin treatment or the acute stage of myocardial infarction.

Adult↗
PubMed1996

Cigarette smoking is not associated with hyperinsulinemia: evidence against a causal relationship between smoking and insulin resistance.

Previous reports of a relationship between cigarette smoking and hyperinsulinemia and insulin resistance provide an important possible mechanism by which smoking could be associated with the metabolic cardiovascular syndrome and hence with ischemic heart disease. However, few previous studies have been able to adjust for all the possible confounding factors related both to smoking and to insulin resistance. Therefore, we examined this association in a population-based cohort study of 1,122 individuals aged 40 to 65 years who underwent a 75-g oral glucose tolerance test with specific measurement of insulin, 32,33-split proinsulin, and intact proinsulin concentrations. Physical activity was quantified using the Paffenbarger questionnaire, and smoking status and alcohol consumption were determined using the Health and Lifestyle Survey questionnaire; 17.4% of the population were current smokers and 32.4% were ex-smokers. Current smoking was associated with reduced overall obesity as indicated by the body mass index (BMI) but an increase in central adiposity as measured by the waist to hip ratio (WHR). There were also significant associations between cigarette smoking and the pattern of alcohol intake and physical inactivity. In unadjusted analyses, current smoking was associated with lower fasting and 120-minute insulin and also 120-minute glucose compared with levels in nonsmokers. Adjustment for confounding by age and BMI reduced these differences, but they were increased by adjustment for central obesity. We conclude from this study that a causal relationship between cigarette smoking and insulin resistance is unlikely.

Cohort Studies↗