Glucose lowering and diabetes prevention: are they the same?
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Blood Glucose↗
Biomedical subjects
Nicholas Wareham
Publications and source records attributed to Nicholas Wareham.
Work and leisure time physical activity assessed using a simple, pragmatic, validated questionnaire and incident cardiovascular disease and all-cause mortality in men and women: The European Prospective Investigation into Cancer in Norfolk prospective population study.
BACKGROUND: The health benefits of physical activity are well established, but the overall amount of physical activity associated with cardiovascular and other health outcomes, and whether the relationships are similar in men and women and at different ages is still debated. This may be partly related to different methods for assessing physical activity. Most studies have focused on leisure time physical activity. METHODS: We examined the prospective relationship between usual physical activity, taking into account both leisure and work activity, using a simple, pragmatic, four-point rating scale validated against heart rate monitoring, and cardiovascular disease incidence and total mortality after an average 8 years follow-up in 22,191 community living men and women aged 45-79 years with no known cardiovascular disease or cancer at baseline. RESULTS: The relative risks (95% confidence interval) for all-cause mortality (1,553 deaths) for men and women who were moderately inactive, moderately active, and active compared with those who were inactive were 0.83 (0.73-0.95), 0.68 (0.58-0.80), and 0.68 (0.57-0.81), respectively, after adjusting for age, sex, systolic blood pressure, blood cholesterol, cigarette smoking, alcohol intake, diabetes, body mass index, and social class. The relationships were also consistent for cardiovascular disease incidence (3,079 events), in subgroups stratified by age, sex, body mass index, smoking status and social class, and after excluding deaths in the first 2 years. The combined scale was more consistently associated with mortality than the individual work and leisure time components separately. CONCLUSIONS: When both work and leisure time physical activity patterns are taken into account, using a simple, pragmatic, validated questionnaire feasible for use in clinical and public health practice, even very moderate levels of usual physical activity are associated with significantly reduced risk of mortality and cardiovascular disease in men and women in the general population and potential population attributable impact of 14% for inactive compared with active levels. These findings may encourage efforts to increase physical activity levels not only in leisure time but also in usual daily working life.
Aged↗
Serum lipid concentration in relation to anthropometric indices of central and peripheral fat distribution in 20,021 British men and women: results from the EPIC-Norfolk population-based cohort study.
AIMS: Central adiposity has been linked with adverse metabolic profile including dyslipidaemia but recent studies suggested that peripheral fat distribution play a role in regulating daily fluxes in circulating non-esterified fatty acids. We examine whether lipid levels vary between central and peripheral fat distribution in the general population. METHODS AND RESULTS: We examined the cross-sectional relation between fat distribution indices and lipid concentration in 20,021 apparently healthy men and women of the Norfolk cohort of the European Investigation into Cancer and Nutrition (EPIC-Norfolk). Waist-hip ratio was positively related to total and low density lipoprotein (LDL) cholesterol and negatively related to high density lipoprotein (HDL) cholesterol in both men and women, independently of body mass index (BMI). Although similar results were noted for waist circumference, individuals with bigger hip circumference had lower total and LDL-cholesterol and higher HDL-cholesterol when adjusting for BMI and/or waist circumference in both men and women. CONCLUSION: Regional fat distribution was related to lipid profile independently of BMI. The independent contribution of waist and hip circumference in opposite directions was intriguing. These findings may help explain the associations observed between different fat distribution phenotypes and coronary heart disease.
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Non-DNA binding, dominant-negative, human PPARgamma mutations cause lipodystrophic insulin resistance.
PPARgamma is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPARgamma in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPARgamma coactivators and inhibit coexpressed wild-type receptor. Expression of PPARgamma target genes is markedly attenuated in mutation-containing versus receptor haploinsufficent primary cells, indicating that such dominant-negative inhibition operates in vivo. Our observations suggest that these mutants restrict wild-type PPARgamma action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting coactivators.
DNA↗
Glycated hemoglobin as a marker of cardiovascular risk.
PURPOSE OF REVIEW: Diabetes mellitus is an established risk factor for cardiovascular disease. This review examines glycated hemoglobin, an indicator of long-term average blood glucose concentrations, in risk prediction for cardiovascular disease. RECENT FINDINGS: Glycated hemoglobin concentrations predict cardiovascular disease risk in people with diabetes, and trial data suggest that good blood glucose control is associated with reduction in cardiovascular disease. Elevated glycated hemoglobin levels below the thresholds accepted for diabetes are also associated with increasing cardiovascular disease risk independent of classical risk factors in a continuous relationship across the whole normal distribution. A 1% increase in absolute concentrations of glycated hemoglobin is associated with about 10-20% increase in cardiovascular disease risk. The continuous relationship is most evident for coronary heart disease in men; the shape of the risk curve is less clear for women and for other cardiovascular endpoints such as stroke or peripheral vascular disease. SUMMARY: Glycated hemoglobin concentration predicts cardiovascular risk both in people with diabetes and in the general population, and may help identify individuals at higher risk of cardiovascular disease for targeted interventions, including blood pressure or cholesterol reduction. Understanding the nature of this relationship may inform new preventive and therapeutic interventions.
Biomarkers↗
Cigarette smoking and fat distribution in 21,828 British men and women: a population-based study.
OBJECTIVE: To examine the relationship between cigarette smoking habits and fat distribution in a population-based cohort of men and women. RESEARCH METHODS AND PROCEDURES: We analyzed cross-sectional data from 21,828 men and women who were 45 to 79 years of age, residents in Norfolk, United Kingdom, and were recruited between 1993 and 1997. Cigarette smoking habits and other lifestyle factors were assessed using self-reported questionnaires. Anthropometric measures were obtained during a health examination. RESULTS: Waist-hip ratio was highest among current smokers and least among never smokers after adjusting for age, BMI, alcohol intake, total energy intake, physical activity, and education. Higher waist-hip ratio was directly associated with higher smoking pack-years in current and former smokers and inversely with duration since quitting smoking in former smokers. Adjusting for age, BMI, and other covariates, current smokers had higher waist circumference but lower hip circumference compared with former or never smokers. DISCUSSION: Cigarette smoking habits seem to influence fat distribution patterns. Although smokers have lower mean BMI compared with nonsmokers, they have a more metabolically adverse fat distribution profile, with higher central adiposity. The explanation for this association may help elucidate the mechanisms underlying the adverse health consequences of cigarette smoking and abdominal obesity.
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Plasma ascorbic acid concentrations and fat distribution in 19,068 British men and women in the European Prospective Investigation into Cancer and Nutrition Norfolk cohort study.
BACKGROUND: Antioxidants, such as ascorbic acid, play a role in scavenging free radicals to protect against oxidative endothelial damage. Excess fat may promote fatty acid oxidation and increase free radical concentrations, which could result in increased antioxidant use. Whether plasma ascorbic acid concentrations are associated with fat distribution remains unclear. OBJECTIVE: Our aim was to examine the association between abdominal obesity, as measured by the waist-to-hip ratio, and plasma ascorbic acid concentrations in the general population. DESIGN: We examined the cross-sectional relation between anthropometric measurements of fat distribution and plasma ascorbic acid concentrations in 19 068 men and women aged 45-79 y without known chronic illness. Dietary ascorbic acid intake was estimated for a subgroup of 8178 men and women who kept 7-d food diaries coded for nutrient intake. RESULTS: The waist-to-hip ratio was inversely related to plasma ascorbic acid concentrations in both men and women. This association was independent of body mass index, age, vitamin supplement use, cigarette smoking, and socioeconomic group. Waist and hip circumferences showed separate and opposite associations with plasma ascorbic acid concentrations, independent of body mass index and other covariates. Dietary ascorbic acid intake only partly explained the observed associations. CONCLUSIONS: Plasma ascorbic acid was associated with fat distribution independent of body mass index. Differences in dietary intake and lifestyle habits, underlying systemic oxidative stress, or both may explain the inverse relation between fat distribution and plasma ascorbic acid concentrations. Additional studies are needed to determine the underlying explanation of these observations.
Abdominal Fat↗
The ProActive trial protocol - a randomised controlled trial of the efficacy of a family-based, domiciliary intervention programme to increase physical activity among individuals at high risk of diabetes [ISRCTN61323766].
BACKGROUND: Increasing prevalence of obesity and disorders associated with sedentary living constitute a major global public health problem. While previous evaluations of interventions to increase physical activity have involved communities or individuals with established disease, less attention has been given to interventions for individuals at risk of disease. METHODS/DESIGN: ProActive aims to evaluate the efficacy of a theoretical, evidence- and family-based intervention programme to increase physical activity in a sedentary population, defined as being at-risk through having a parental family history of diabetes. Primary care diabetes or family history registers were used to recruit 365 individuals aged 30-50 years, screened for activity level. Participants were assigned by central randomisation to three intervention programmes: brief written advice (comparison group), or a psychologically based behavioural change programme, delivered either by telephone (distance group) or face-to-face in the family home over one year. The protocol-driven intervention programme is delivered by trained facilitators, and aims to support increases in physical activity through the introduction and facilitation of a range of self-regulatory skills (e.g. goal setting). The primary outcome is daytime energy expenditure and its ratio to resting energy expenditure, measured at baseline and one year using individually calibrated heart rate monitoring. Secondary measures include self-report of individual and family activity, psychological mediators of behaviour change, physiological and biochemical correlates, acceptability, and costs, measured at baseline, six months and one year. The primary intention to treat analysis will compare groups at one-year post randomisation. Estimation of the impact on diabetes incidence will be modelled using data from a parallel ten-year cohort study using similar measures. DISCUSSION: ProActive is the first efficacy trial of an intervention programme to promote physical activity in a defined high-risk group accessible through primary care. The intervention programme is based on psychological theory and evidence; it introduces and facilitates the use of self-regulatory skills to support behaviour change and maintenance. The trial addresses a range of methodological weaknesses in the field by careful specification and quality assurance of the intervention programme, precise characterisation of participants, year-long follow-up and objective measurement of physical activity. Due to report in 2005, ProActive will provide estimates of the extent to which this approach could assist at-risk groups who could benefit from changes in behaviours affecting health, and inform future pragmatic trials.
Adult↗
Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk.
BACKGROUND: Increasing evidence suggests a continuous relationship between blood glucose concentrations and cardiovascular risk, even below diagnostic threshold levels for diabetes. OBJECTIVE: To examine the relationship between hemoglobin A1c, cardiovascular disease, and total mortality. DESIGN: Prospective population study. SETTING: Norfolk, United Kingdom. PARTICIPANTS: 4662 men and 5570 women who were 45 to 79 years of age and were residents of Norfolk. MEASUREMENTS: Hemoglobin A1c and cardiovascular disease risk factors were assessed from 1995 to 1997, and cardiovascular disease events and mortality were assessed during the follow-up period to 2003. RESULTS: In men and women, the relationship between hemoglobin A1c and cardiovascular disease (806 events) and between hemoglobin A1c and all-cause mortality (521 deaths) was continuous and significant throughout the whole distribution. The relationship was apparent in persons without known diabetes. Persons with hemoglobin A1c concentrations less than 5% had the lowest rates of cardiovascular disease and mortality. An increase in hemoglobin A1c of 1 percentage point was associated with a relative risk for death from any cause of 1.24 (95% CI, 1.14 to 1.34; P < 0.001) in men and with a relative risk of 1.28 (CI, 1.06 to 1.32; P < 0.001) in women. These relative risks were independent of age, body mass index, waist-to-hip ratio, systolic blood pressure, serum cholesterol concentration, cigarette smoking, and history of cardiovascular disease. When persons with known diabetes, hemoglobin A(1c) concentrations of 7% or greater, or a history of cardiovascular disease were excluded, the result was similar (adjusted relative risk, 1.26 [CI, 1.04 to 1.52]; P = 0.02). Fifteen percent (68 of 521) of the deaths in the sample occurred in persons with diabetes (4% of the sample), but 72% (375 of 521) occurred in persons with HbA1c concentrations between 5% and 6.9%. LIMITATIONS: Whether HbA1c concentrations and cardiovascular disease are causally related cannot be concluded from an observational study; intervention studies are needed to determine whether decreasing HbA1c concentrations would reduce cardiovascular disease. CONCLUSIONS: The risk for cardiovascular disease and total mortality associated with hemoglobin A1c concentrations increased continuously through the sample distribution. Most of the events in the sample occurred in persons with moderately elevated HbA1c concentrations. These findings support the need for randomized trials of interventions to reduce hemoglobin A1c concentrations in persons without diabetes.
Aged↗
Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus: EPIC-Norfolk prospective population study.
BACKGROUND: A quarter of fractures needing admission happen in men, but few data are available that show the value of bone measures for prediction of fracture risk in men. We aimed to assess quantitative ultrasound of the calcaneum and fracture incidence in a prospective observational population study. METHODS: Calcaneum broadband ultrasound attenuation (BUA) was measured in men and women in the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk) between 1997 and 2000. Incident fractures were ascertained by hospital record linkage. FINDINGS: In 14824 men and women aged 42-82 years, during mean follow-up of 1.9 years (SD 0.7), there were 121 incident fractures that needed admission, including 31 hip fractures. Men and women in the lowest 10% of the calcaneum BUA distribution had a relative risk of fracture of 4.44 (95% CI 2.24-8.89, p<0.0001) compared with those in the upper 30% of the distribution. A fall of about 1 SD in BUA (20 db/MHz) was associated with a relative risk of fracture of 1.95 (95% CI 1.50-2.52, p<0.0001), independent of age, sex, weight, height, cigarette smoking habit, and past history of fracture. BUA predicted fractures with consistent magnitude in subgroups stratified by sex, age 65 years or older and younger than 65 years, smoking habit, past history of fracture, and hip and non-hip fractures separately. The sex difference in fracture risk was largely accounted for by differences in BUA. INTERPRETATION: Quantitative calcaneum ultrasound predicts total and hip fracture risk in men and women in a continuous relation. The challenge now is to identify interventions to improve bone health in the whole population.
Adult↗
Blood pressure and urinary sodium in men and women: the Norfolk Cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk).
BACKGROUND: Abundant evidence indicates that a high sodium intake is causally related to high blood pressure, but debate over recommendations to reduce dietary sodium in the general population continues. A key issue is whether differences in usual sodium intake within the range feasible in free-living populations have clinical or public health relevance. OBJECTIVE: We examined the relation between blood pressure and urinary sodium as a marker of dietary intake. DESIGN: This was a study of 23104 community-living adults aged 45-79 y. RESULTS: Mean systolic and diastolic blood pressure increased as the ratio of urinary sodium to creatinine increased (as estimated from a casual urine sample), with differences of 7.2 mm Hg for systolic blood pressure and 3.0 mm Hg for diastolic blood pressure (P < 0.0001) between the top and bottom quintiles. This trend was independent of age, body mass index, urinary potassium:creatinine, and smoking and was consistent by sex and history of hypertension. The prevalence of those with systolic blood pressure >/= 160 mm Hg halved from 12% in the top quintile to 6% in the bottom quintile; the odds ratio for having systolic blood pressure >/= 160 mm Hg was 2.48 (95% CI: 1.90, 3.22) for men and 2.67 (95% CI: 2.08, 3.43) for women in the top compared with the bottom quintile of urinary sodium. Estimated mean sodium intakes in the lowest and highest quintiles were approximately 80 and 220 mmol/d, respectively. CONCLUSIONS: Within the usual range found in a free-living population, differences in urinary sodium, an indicator of dietary sodium intake, are associated with blood pressure differences of clinical and public health relevance. Our findings reinforce recommendations to lower average sodium intakes in the general population.
Aged↗
Fat distribution, body mass index and blood pressure in 22,090 men and women in the Norfolk cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) study.
OBJECTIVE: To determine the relation between fat distribution and blood pressure, independent of body mass index. DESIGN: Cross-sectional, population-based study. PARTICIPANTS AND METHODS: Participants, 9936 men and 12,154 women aged 45-79 years, were recruited from general practices in Norfolk, United Kingdom for the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) study. Participants filled in a health and lifestyle questionnaire and their blood pressure and anthropometry were measured at a clinic. We mainly used waist-hip ratio (WHR) to assess body fat distribution. RESULTS: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) increased linearly across the whole range of waist-hip ratio in both men and women. The relation was independent of age, body mass index (BMI) and other covariates. Separately, waist and hip circumferences were positively related to SBP and DBP. When adjusted for BMI, waist circumference was positively related to SBP (in women) and DBP (in both men and women), whereas hip circumference was inversely related to SBP (but not DBP) in both men and women. Stratifying by tertiles of waist and hip circumference, age- and BMI-adjusted SBP and DBP were highest among those with high waist and small hip circumference measures. CONCLUSION: Waist-hip ratio was independently related to blood pressure. Waist-hip ratio could reflect the separate and opposite relations of waist and hip circumferences on blood pressure. Characterizing patterns of fat distribution may have implications in the assessment and control of obesity-related blood pressure elevation.
Abdomen↗
Residential area deprivation predicts fruit and vegetable consumption independently of individual educational level and occupational social class: a cross sectional population study in the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk).
STUDY OBJECTIVE: To investigate the independent association between individual and area based socioeconomic measures and fruit and vegetable consumption. DESIGN: Cross sectional population based study. SETTING AND PARTICIPANTS: 22,562 men and women aged 39-79 years living in the general community in Norfolk, United Kingdom, recruited using general practice age-sex registers. OUTCOME MEASURES: Fruit and vegetable intake assessed using a food frequency questionnaire. MAIN RESULTS: Being in a manual occupational social class, having no educational qualifications, and living in a deprived area all independently predicted significantly lower consumption of fruit and vegetables. The effect of residential area deprivation was predominantly in those in manual occupational social class and no educational qualifications. CONCLUSIONS: Understanding some of the community level barriers to changing health related behaviours may lead to more effective interventions to improving health in the whole community, particularly those who are most vulnerable.
Adult↗
Short-term low-dose growth hormone administration in subjects with impaired glucose tolerance and the metabolic syndrome: effects on beta-cell function and post-load glucose tolerance.
OBJECTIVE: Modest elevations in circulating IGF-I levels have been suggested to protect against the development of glucose intolerance in insulin-resistant subjects. To further understand the interactions of GH and IGF-I on beta-cell function and post-load glucose tolerance in glucose-intolerant subjects predisposed to diabetes, we performed a pilot study in 12 subjects with impaired glucose tolerance and the metabolic syndrome using a low GH dose (1.7 microg/kg per day) known to increase endogenous IGF-I production. DESIGN: Fourteen daily GH or placebo injections in a double-blind cross-over study. METHODS: Baseline and post-treatment oral glucose tolerance tests were performed. The homeostasis model assessment and the insulinogenic index was used to estimate fasting insulin sensitivity (S(I)) and beta-cell function respectively, whereas changes in the incremental area under the curve were used to estimate post-load glucose tolerance (DeltaAUC(glu)) and post-load insulin levels (DeltaAUC(ins)). RESULTS: GH increased total IGF-I (P<0.02), free IGF-I (P<0.04) and fasting insulin (P<0.04) levels, but did not modify plasma IGF-binding proteins (IGFBPs)-1 and -3, fasting glucose, non-esterified fatty acid and C-peptide levels, and fasting S(I). After oral glucose intake, glucose tolerance improved (P<0.03), but post-load insulin levels and beta-cell function remained unchanged. CONCLUSION: Short-term low-dose GH administration induced fasting hyperinsulinaemia possibly by reducing insulin clearance but improved post-load glucose tolerance, suggesting that increased bioavailable IGF-I enhanced post-load S(I) without altering beta-cell function. Longer-term studies are required to ascertain whether these positive effects on post-load glucose tolerance and the preservation of beta-cell function can be sustained by this GH dose in these high-risk subjects.
Adult↗
Preliminary communication: glycated hemoglobin, diabetes, and incident colorectal cancer in men and women: a prospective analysis from the European prospective investigation into cancer-Norfolk study.
BACKGROUND: Increasing evidence suggests that abnormal glucose metabolism may be associated with increased risk of colorectal cancer. METHODS: We examined the relationship between known diabetes and glycated hemoglobin (HbA1c) concentrations measured in 1995 to 1997 and subsequent incident colorectal cancer after 6 years follow-up in 9,605 men and women ages 45 to 79 years in the European Prospective Investigation into Cancer-Norfolk Study. RESULTS: Among individuals not known to have cancer at the baseline survey, there were 67 incident colorectal cancers. HbA1c concentration appeared continuously related to incident colorectal cancer risk, with lowest rates observed in those with HbA1c below 5%. Known diabetes was also associated with incident colorectal cancer, with relative risk (RR) 3.18 and 95% confidence interval (CI) 1.36-7.40 (P < 0.01) adjusting for age and sex and RR 2.78 and 95% CI 1.10-7.00 (P = 0.03) adjusting for age, sex, body mass index, and smoking compared with those without known diabetes. The RR (95% CI) of incident colorectal cancer per 1% absolute increase in HbA1c was 1.34 (1.12-1.59; P < 0.001). HbA1c concentrations appeared to explain the increased colorectal cancer risk associated with diabetes in multivariate models. CONCLUSIONS: Known diabetes was associated with approximately 3-fold risk of colorectal cancer in this analysis; this increased risk was largely explained by HbA1c concentrations, which appears continuously related to colorectal cancer risk across the population distribution.
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Are imprecise methods obscuring a relation between fat and breast cancer?
Pooled analyses of cohort studies show no relation between fat intake and breast-cancer risk. However, food-frequency questionnaire (FFQ) methods used in these studies are prone to measurement error. We assessed diet with an FFQ and a detailed 7-day food diary in 13070 women between 1993 and 1997. We compared 168 breast-cancer cases incident by 2000 with four matched controls. Risk of breast cancer was associated with saturated-fat intake measured with the food diary (hazard ratio 1.22 [95% CI 1.06-1.40], p=0.005, per quintile increase in energy-adjusted fat intake), but not with saturated fat measured with the FFQ (1.10 [0.94-1.29], p=0.23). Dietary measurement error might explain the absence of a significant association between dietary fat and breast-cancer risk in cohort studies.
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