High Diabetes Distress Among Ethnic Minorities Is Not Explained by Metabolic, Cardiovascular, or Lifestyle Factors: Findings From the Dutch Diabetes Pearl Cohort.

OBJECTIVE: Diabetes distress among patients from ethnic minorities is still poorly understood. We investigated the association between ethnicity and diabetes distress among ethnic minority groups of people with type 2 diabetes in the Netherlands, focusing on the possible effects of glycemic control, lifestyle factors, cardiovascular risk factors, and diabetes complications. RESEARCH DESIGN AND METHODS: Cross-sectional data from the Dutch Diabetes Pearl cohort included people with type 2 diabetes from primary, secondary, and tertiary diabetes care programs. We used the 20-item Problem Areas in Diabetes Survey (PAID) scale to assess diabetes distress; a score ≥40 is considered to represent high distress. Ethnicity was estimated on the basis of country of birth. Sociodemographic and lifestyle data were self-reported; cardiovascular and metabolic data were retrieved from medical charts. Logistic regression analysis determined the association between ethnicity and diabetes distress, with Caucasians as the reference group. RESULTS: Diabetes distress scores and ethnicity were available for 4,191 people with type 2 diabetes: 3,684 were Caucasian, 83 were Asian, 51 were Moroccan, 92 were African, 134 were Latin American, 46 were Turkish, and 101 were Hindustani-Surinamese. Overall, participants in minority groups had worse health outcomes than those of Caucasian descent, and diabetes distress was more prevalent (ranging from 9.6 to 31.7%, compared with 5.8% among Caucasians), even after adjusting for age, sex, education level, alcohol use, smoking, BMI, lipid profile, HbA1c, medication use, and the presence of diabetes complications. CONCLUSIONS: Among people with type 2 diabetes in the Netherlands, ethnicity is independently associated with high diabetes distress. Further research is warranted to explain the higher prevalence of diabetes distress in minority groups and to develop effective interventions.

Renal function markers and insulin sensitivity after 3 years in a healthy cohort, the EGIR-RISC study.

BACKGROUND: People with chronic renal disease are insulin resistant. We hypothesized that in a healthy population, baseline renal function is associated with insulin sensitivity three years later. METHODS: We studied 405 men and 528 women from the European Group for the study of Insulin Resistance - Relationship between Insulin Sensitivity and Cardiovascular disease cohort. Renal function was characterized by the estimated glomerular filtration rate (eGFR) and by the urinary albumin-creatinine ratio (UACR). At baseline only, insulin sensitivity was quantified using a hyperinsulinaemic-euglycaemic clamp; at baseline and three years, we used surrogate measures: the Matsuda insulin sensitivity index (ISI), the HOmeostasis Model Assessment of Insulin Sensitivity (HOMA-IS). Associations between renal function and insulin sensitivity were studied cross-sectionally and longitudinally. RESULTS: In men at baseline, no associations were seen with eGFR, but there was some evidence of a positive association with UACR. In women, all insulin sensitivity indices showed the same negative trend across eGFR classes, albeit not always statistically significant; for UACR, women with values above the limit of detection, had higher clamp measured insulin sensitivity than other women. After three years, in men only, ISI and HOMA-IS showed a U-shaped relation with baseline eGFR; women with eGFR> 105 ml/min/1.73m2 had a significantly higher insulin sensitivity than the reference group (eGFR: 90-105 ml/min/1.73m2). For both men and women, year-3 insulin sensitivity was higher in those with higher baseline UACR. All associations were attenuated after adjusting on significant covariates. CONCLUSIONS: There was no evidence to support our hypothesis that markers of poorer renal function are associated with declining insulin sensitivity in our healthy population.

External Validation of a Tool Predicting 7-Year Risk of Developing Cardiovascular Disease, Type 2 Diabetes or Chronic Kidney Disease.

BACKGROUND: Chronic cardiometabolic diseases, including cardiovascular disease (CVD), type 2 diabetes (T2D) and chronic kidney disease (CKD), share many modifiable risk factors and can be prevented using combined prevention programs. Valid risk prediction tools are needed to accurately identify individuals at risk. OBJECTIVE: We aimed to validate a previously developed non-invasive risk prediction tool for predicting the combined 7-year-risk for chronic cardiometabolic diseases. DESIGN: The previously developed tool is stratified for sex and contains the predictors age, BMI, waist circumference, use of antihypertensives, smoking, family history of myocardial infarction/stroke, and family history of diabetes. This tool was externally validated, evaluating model performance using area under the receiver operating characteristic curve (AUC)-assessing discrimination-and Hosmer-Lemeshow goodness-of-fit (HL) statistics-assessing calibration. The intercept was recalibrated to improve calibration performance. PARTICIPANTS: The risk prediction tool was validated in 3544 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab). KEY RESULTS: Discrimination was acceptable, with an AUC of 0.78 (95% CI 0.75-0.81) in men and 0.78 (95% CI 0.74-0.81) in women. Calibration was poor (HL statistic: p < 0.001), but improved considerably after intercept recalibration. Examination of individual outcomes showed that in men, AUC was highest for CKD (0.85 [95% CI 0.78-0.91]) and lowest for T2D (0.69 [95% CI 0.65-0.74]). In women, AUC was highest for CVD (0.88 [95% CI 0.83-0.94)]) and lowest for T2D (0.71 [95% CI 0.66-0.75]). CONCLUSIONS: Validation of our previously developed tool showed robust discriminative performance across populations. Model recalibration is recommended to account for different disease rates. Our risk prediction tool can be useful in large-scale prevention programs for identifying those in need of further risk profiling because of their increased risk for chronic cardiometabolic diseases.

The Hoorn Diabetes Care System (DCS) cohort. A prospective cohort of persons with type 2 diabetes treated in primary care in the Netherlands.

PURPOSE: People with type 2 diabetes (T2D) have a doubled morbidity and mortality risk compared with persons with normal glucose tolerance. Despite treatment, clinical targets for cardiovascular risk factors are not achieved. The Hoorn Diabetes Care System cohort (DCS) is a prospective cohort representing a comprehensive dataset on the natural course of T2D, with repeated clinical measures and outcomes. In this paper, we describe the design of the DCS cohort. PARTICIPANTS: The DCS consists of persons with T2D in primary care from the West-Friesland region of the Netherlands. Enrolment in the cohort started in 1998 and this prospective dynamic cohort currently holds 12 673 persons with T2D. FINDINGS TO DATE: Clinical measures are collected annually, with a high internal validity due to the centrally organised standardised examinations. Microvascular complications are assessed by measuring kidney function, and screening feet and eyes. Information on cardiovascular disease is obtained by 1) self-report, 2) electrocardiography and 3) electronic patient records. In subgroups of the cohort, biobanking and additional measurements were performed to obtain information on, for example, lifestyle, depression and genomics. Finally, the DCS cohort is linked to national cancer and all-cause mortality registers. A selection of published findings from the DCS includes identification of subgroups with distinct development of haemoglobin A1c, blood pressure and retinopathy, and their predictors; validation of a prediction model for personalised retinopathy screening; the assessment of the role of genetics in development and treatment of T2D, providing options for personalised medicine. FUTURE PLANS: We will continue with the inclusion of persons with newly diagnosed T2D, follow-up of persons in the cohort and linkage to morbidity and mortality registries. Currently, we are involved in (inter)national projects on, among others, biomarkers and prediction models for T2D and complications and we are interested in collaborations with external researchers. TRIAL REGISTRATION: ISRCTN26257579.

The Association between Social Jetlag, the Metabolic Syndrome, and Type 2 Diabetes Mellitus in the General Population: The New Hoorn Study.

Only a few studies have investigated the metabolic consequences of social jetlag. Therefore, we examined the association of social jetlag with the metabolic syndrome and type 2 diabetes mellitus in a population-based cohort. We used cross-sectional data from the New Hoorn Study cohort ( n = 1585, 47% men, age 60.8 ± 6 years). Social jetlag was calculated as the difference in midpoint sleep (in hours) between weekdays and weekend days. Poisson and linear regression models were used to study the associations, and age was regarded as a possible effect modifier. We adjusted for sex, employment status, education, smoking, physical activity, sleep duration, and body mass index. In the total population, we only observed an association between social jetlag and the metabolic syndrome, with prevalence ratios adjusted for sex, employment status, and educational levels of 1.64 (95% CI 1.1-2.4), for participants with >2 h social jetlag, compared with participants with <1 h social jetlag. However, we observed an interaction effect of median age (<61 years). In older participants (≥61 years), no significant associations were observed between social jetlag status, the metabolic syndrome, and diabetes or prediabetes. In the younger group (<61 years), the adjusted prevalence ratios were 1.29 (95% CI 0.9-1.9) and 2.13 (95% CI 1.3-3.4) for the metabolic syndrome and 1.39 (95% CI 1.1-1.9) and 1.75 (95% CI 1.2-2.5) for diabetes/prediabetes, for participants with 1-2 h and >2 h social jetlag, compared with participants with <1 h social jetlag. In conclusion, in our population-based cohort, social jetlag was associated with a 2-fold increased risk of the metabolic syndrome and diabetes/prediabetes, especially in younger (<61 years) participants.

Clustering of cardiovascular risk factors and carotid intima-media thickness: The USE-IMT study.

BACKGROUND: The relation of a single risk factor with atherosclerosis is established. Clinically we know of risk factor clustering within individuals. Yet, studies into the magnitude of the relation of risk factor clusters with atherosclerosis are limited. Here, we assessed that relation. METHODS: Individual participant data from 14 cohorts, involving 59,025 individuals were used in this cross-sectional analysis. We made 15 clusters of four risk factors (current smoking, overweight, elevated blood pressure, elevated total cholesterol). Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) between clusters using those without any of the four risk factors as reference group. RESULTS: Compared to the reference, those with 1, 2, 3 or 4 risk factors had a significantly higher common CIMT: mean difference of 0.026 mm, 0.052 mm, 0.074 mm and 0.114 mm, respectively. These findings were the same in men and in women, and across ethnic groups. Within each risk factor cluster (1, 2, 3 risk factors), groups with elevated blood pressure had the largest CIMT and those with elevated cholesterol the lowest CIMT, a pattern similar for men and women. CONCLUSION: Clusters of risk factors relate to increased common CIMT in a graded manner, similar in men, women and across race-ethnic groups. Some clusters seemed more atherogenic than others. Our findings support the notion that cardiovascular prevention should focus on sets of risk factors rather than individual levels alone, but may prioritize within clusters.

Predicting glycated hemoglobin levels in the non-diabetic general population: Development and validation of the DIRECT-DETECT prediction model - a DIRECT study.

AIMS/HYPOTHESIS: To develop a prediction model that can predict HbA1c levels after six years in the non-diabetic general population, including previously used readily available predictors. METHODS: Data from 5,762 initially non-diabetic subjects from three population-based cohorts (Hoorn Study, Inter99, KORA S4/F4) were combined to predict HbA1c levels at six year follow-up. Using backward selection, age, BMI, waist circumference, use of anti-hypertensive medication, current smoking and parental history of diabetes remained in sex-specific linear regression models. To minimize overfitting of coefficients, we performed internal validation using bootstrapping techniques. Explained variance, discrimination and calibration were assessed using R2, classification tables (comparing highest/lowest 50% HbA1c levels) and calibration graphs. The model was externally validated in 2,765 non-diabetic subjects of the population-based cohort METSIM. RESULTS: At baseline, mean HbA1c level was 5.6% (38 mmol/mol). After a mean follow-up of six years, mean HbA1c level was 5.7% (39 mmol/mol). Calibration graphs showed that predicted HbA1c levels were somewhat underestimated in the Inter99 cohort and overestimated in the Hoorn and KORA cohorts, indicating that the model's intercept should be adjusted for each cohort to improve predictions. Sensitivity and specificity (95% CI) were 55.7% (53.9, 57.5) and 56.9% (55.1, 58.7) respectively, for women, and 54.6% (52.7, 56.5) and 54.3% (52.4, 56.2) for men. External validation showed similar performance in the METSIM cohort. CONCLUSIONS/INTERPRETATION: In the non-diabetic population, our DIRECT-DETECT prediction model, including readily available predictors, has a relatively low explained variance and moderate discriminative performance, but can help to distinguish between future highest and lowest HbA1c levels. Absolute HbA1c values are cohort-dependent.

Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium.

BACKGROUND: Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality. METHODS: In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488. FINDINGS: We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH)D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and <30 nmol/L were 1.15 (1.00-1.29), 1.33 (1.16-1.51), and 1.67 (1.44-1.89), respectively. We observed similar results for cardiovascular mortality, but there was no significant linear association between 25(OH)D and cancer mortality. There was also no significantly increased mortality risk at high 25(OH)D levels up to 125 nmol/L. INTERPRETATION: In the first IPD meta-analysis using standardized measurements of 25(OH)D we observed an association between low 25(OH)D and increased risk of all-cause mortality. It is of public health interest to evaluate whether treatment of vitamin D deficiency prevents premature deaths.

BclI Glucocorticoid Receptor Polymorphism in Relation to Arterial Stiffening and Cardiac Structure and Function: The Hoorn and CODAM Studies.

BACKGROUND: Chronic glucocorticoid excess is associated with arterial stiffening and cardiac dysfunction. The BclI glucocorticoid receptor (GR) polymorphism increases GR sensitivity and is associated with a higher body mass index (BMI) and some proxies for cardiovascular disease (CVD). Whether BclI influences arterial stiffening and cardiac dysfunction is currently unknown. Therefore, the aim of the present study was to investigate the association of the BclI polymorphism with arterial stiffening and cardiac structure and function. METHODS: We conducted an observational cohort study, combining 2 cohort studies designed to investigate genetic and metabolic determinants of CVD. We genotyped 1,124 individuals (age: 64.7 ± 8.5 years) from the Hoorn study and Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study for BclI. Several arterial stiffening indices of the carotid (Hoorn and CODAM study), brachial and femoral artery and the carotid-femoral pulse wave velocity (Hoorn study only) were determined. In addition, in the Hoorn study, we determined several variables of cardiac structure and function. RESULTS: We identified 155 homozygous carriers (GG), 498 heterozygous carriers (CG), and 471 noncarriers (CC) of the BclI polymorphism. BclI genotypes did not display significant differences in variables of arterial stiffening (e.g., carotid distensibility coefficient (DC): 12.41 ± 5.37 vs. 12.87 ± 5.55 10-3/kPa [mean ± SD]; P = 0.38; homozygous vs. noncarriers). In addition, no clear differences in estimates of cardiac structure and function were found. CONCLUSIONS: Even though BclI is associated with a higher BMI and some proxies of CVD, our results do not support the concept that BclI carrier status is associated with greater arterial stiffening or cardiac dysfunction.

Sustained influence of metformin therapy on circulating glucagon-like peptide-1 levels in individuals with and without type 2 diabetes.

AIMS: To investigate, in the Carotid Atherosclerosis: Metformin for Insulin Resistance (CAMERA) trial (NCT00723307), whether the influence of metformin on the glucagon-like peptide (GLP)-1 axis in individuals with and without type 2 diabetes (T2DM) is sustained and related to changes in glycaemia or weight, and to investigate basal and post-meal GLP-1 levels in patients with T2DM in the cross-sectional Diabetes Research on Patient Stratification (DIRECT) study. MATERIALS AND METHODS: CAMERA was a double-blind randomized placebo-controlled trial of metformin in 173 participants without diabetes. Using 6-monthly fasted total GLP-1 levels over 18 months, we evaluated metformin's effect on total GLP-1 with repeated-measures analysis and analysis of covariance. In the DIRECT study, we examined active and total fasting and 60-minute post-meal GLP-1 levels in 775 people recently diagnosed with T2DM treated with metformin or diet, using Student's t-tests and linear regression. RESULTS: In CAMERA, metformin increased total GLP-1 at 6 (+20.7%, 95% confidence interval [CI] 4.7-39.0), 12 (+26.7%, 95% CI 10.3-45.6) and 18 months (+18.7%, 95% CI 3.8-35.7), an overall increase of 23.4% (95% CI 11.2-36.9; P < .0001) vs placebo. Adjustment for changes in glycaemia and adiposity, individually or combined, did not attenuate this effect. In the DIRECT study, metformin was associated with higher fasting active (39.1%, 95% CI 21.3-56.4) and total GLP-1 (14.1%, 95% CI 1.2-25.9) but not post-meal incremental GLP-1. These changes were independent of potential confounders including age, sex, adiposity and glycated haemoglobin. CONCLUSIONS: In people without diabetes, metformin increases total GLP-1 in a sustained manner and independently of changes in weight or glycaemia. Metformin-treated patients with T2DM also have higher fasted GLP-1 levels, independently of weight and glycaemia.

Race/Ethnic Differences in the Associations of the Framingham Risk Factors with Carotid IMT and Cardiovascular Events.

BACKGROUND: Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events. METHODS: We used data from an ongoing individual participant meta-analysis involving 17 population-based cohorts worldwide. We selected 60,211 participants without cardiovascular disease at baseline with available data on ethnicity (White, Black, Asian or Hispanic). We generated a multivariable linear regression model containing risk factors and ethnicity predicting mean common carotid intima-media thickness (CIMT) and a multivariable Cox regression model predicting myocardial infarction or stroke. For each risk factor we assessed how the association with the preclinical and clinical measures of cardiovascular atherosclerotic disease was affected by ethnicity. RESULTS: Ethnicity appeared to significantly modify the associations between risk factors and CIMT and cardiovascular events. The association between age and CIMT was weaker in Blacks and Hispanics. Systolic blood pressure associated more strongly with CIMT in Asians. HDL cholesterol and smoking associated less with CIMT in Blacks. Furthermore, the association of age and total cholesterol levels with the occurrence of cardiovascular events differed between Blacks and Whites. CONCLUSION: The magnitude of associations between risk factors and the presence of atherosclerotic disease differs between race/ethnic groups. These subtle, yet significant differences provide insight in the etiology of cardiovascular disease among race/ethnic groups. These insights aid the race/ethnic-specific implementation of primary prevention.

Is social jetlag associated with an adverse endocrine, behavioral, and cardiovascular risk profile?

Social jetlag represents the discrepancy between circadian and social clocks, which is measured as the difference in hours in midpoint of sleep between work days and free days. Previous studies have shown social jetlag to be associated with body mass index (BMI), glycated hemoglobin levels, heart rate, depressive symptoms, smoking, mental distress and alcohol use. The objective of our current study was to investigate, in a group of 145 apparently healthy participants (67 men and 78 women, aged 18-55 years, BMI 18-35 kg/m(2)), the prevalence of social jetlag and its association with adverse endocrine, behavioral and cardiovascular risk profiles as measured in vivo. participants with ≥2 h social jetlag had higher 5-h cortisol levels, slept less during the week, were more often physically inactive and had an increased resting heart rate, compared with participants who had ≤1 h social jetlag. We therefore concluded that social jetlag is associated with an adverse endocrine, behavioral and cardiovascular risk profile in apparently healthy participants. These adverse profiles put healthy participants at risk for development of metabolic diseases and mental disorders, including diabetes and depression, in the near future.

The association between psychosocial stress and mortality is mediated by lifestyle and chronic diseases: the Hoorn Study.

Psychosocial stress is associated with chronic disease. We evaluated whether in the general population the number of stressful life events is associated with risk of mortality and whether this association is mediated by behavioral factors and morbidities. We conducted this study in the Hoorn cohort; a population-based cohort study among older men and women. Our main variable of interest was the number of stressful life events experienced during the previous 5 years, which were assessed by questionnaire. We calculated Cox proportional hazard ratios (HRs) for all-cause and cause-specific mortality during follow-up for those who experienced stressful life events compared to those who did not. We included 2385 participants (46% male; 62 ± 7 years). During 20 years of follow-up 834 (35%) participants died, of whom 239 (28.6%) died of cardiovascular disease. Compared to the group with no stressful life events, the age, sex and socioeconomic status adjusted HRs (with 95% confidence intervals) for all-cause mortality, for the groups who had 1 event, 2 events, 3 events and ≥4 events were 0.89 (0.72-1.09), 1.01 (0.81-1.24), 1.29 (1.00-1.66) and 1.44 (1.08-1.92), respectively. Similar results were observed for cardiovascular mortality. Mediation analysis showed that smoking, prevalent type 2 diabetes and cardiovascular disease were statistically significant mediators of the association between the number of stressful life events and mortality. Having 3 or more stressful life events is associated with a significantly increased risk for mortality in an elderly population-based cohort. This association is mediated by smoking, type 2 diabetes and cardiovascular disease.

Validation of a model to estimate personalised screening frequency to monitor diabetic retinopathy.

AIMS/HYPOTHESIS: Our study aimed to validate a model to determine a personalised screening frequency for diabetic retinopathy. METHODS: A model calculating a personalised screening interval for monitoring retinopathy based on patients' risk profile was validated using the data of 3,319 type 2 diabetic patients in the Diabetes Care System West-Friesland, the Netherlands. Two-field fundus photographs were graded according to the EURODIAB coding system. Sight-threatening retinopathy (STR) was considered to be grades 3-5. Validity of the model was assessed using calibration and discrimination measures. We compared model-based time of screening with time of STR diagnosis and calculated the differences in the number of fundus photographs using the model compared with those in annual or biennial screening. RESULTS: During a mean of 53 months of follow-up, 76 patients (2.3%) developed STR. Using the model, the mean screening interval was 31 months, leading to a reduced screening frequency of 61% compared with annual screening and 23% compared with biennial screening. STR incidence occurred after a mean of 26 months after the model-based time of screening in 67 patients (88.2%). In nine patients (11.8%), STR had developed before the model-based time of screening. The discriminatory ability of the model was good (C-statistic 0.83; 95% CI 0.74, 0.92). Calibration showed that the model overestimated STR risk. CONCLUSIONS/INTERPRETATION: A large reduction in retinopathy screening was achieved using the model in this population of patients with a very low incidence of retinopathy. Considering the number of potentially missed cases of STR, there is room for improvement in the model. Use of the model for personalised screening may eventually help to reduce healthcare use and costs of diabetes care.

Homoarginine and mortality in an older population: the Hoorn study.

BACKGROUND: Homoarginine is an amino acid that may be involved in nitric oxide and energy metabolism. Previous studies in patient populations showed that low homoarginine levels indicate an increased risk of mortality and cardiovascular disease. We evaluated whether low plasma levels of homoarginine are associated with elevated, overall and cause-specific mortality. MATERIALS AND METHODS: The Hoorn study is a population-based study among older men and women. We calculated Cox proportional hazard ratios (HRs) for overall and cause-specific mortality according to sex-specific homoarginine quartiles. RESULTS: We included 606 study participants (51·3% women; 70·0 ± 6·6 years). Homoarginine concentrations were higher in men (1·63 ± 0·51 µM), compared with women (1·30 ± 0·44 µM; P < 0·001). After a median follow-up time of 7·8 years, 112 study participants died, including 31 deaths due to cardiovascular diseases and 30 due to cancer. Associations between homoarginine levels and mortality showed a threshold effect with a significant risk increase from the second to the first quartile. Compared with the upper three quartiles, the age-, sex- and BMI-adjusted HR (with 95% CI) in the first quartile was 2·26 (1·52-3·32) for overall mortality, 4·20 (2·03-8·69) for cardiovascular mortality and 1·25 (0·55-2·85) for cancer mortality. These associations remained materially unchanged after multivariate adjustments. CONCLUSIONS: Low plasma concentrations of homoarginine are a risk marker for overall mortality and especially for cardiovascular mortality in the older general population. Further studies are warranted to elucidate the underlying pathophysiological mechanisms.

HbA1c, fasting and 2 h plasma glucose in current, ex- and never-smokers: a meta-analysis.

AIMS/HYPOTHESIS: The relationships between smoking and glycaemic variables have not been well explored. We compared HbA1c, fasting plasma glucose (FPG) and 2 h plasma glucose (2H-PG) in current, ex- and never-smokers. METHODS: This meta-analysis used individual data from 16,886 men and 18,539 women without known diabetes in 12 DETECT-2 consortium studies and in the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) and Telecom studies. Means of three glycaemic variables in current, ex- and never-smokers were modelled by linear regression, with study as a random factor. The I (2) statistic was used to evaluate heterogeneity among studies. RESULTS: HbA1c was 0.10% (95% CI 0.08, 0.12) (1.1 mmol/mol [0.9, 1.3]) higher in current smokers and 0.03% (0.01, 0.05) (0.3 mmol/mol [0.1, 0.5]) higher in ex-smokers, compared with never-smokers. For FPG, there was no significant difference between current and never-smokers (-0.004 mmol/l [-0.03, 0.02]) but FPG was higher in ex-smokers (0.12 mmol/l [0.09, 0.14]). In comparison with never-smokers, 2H-PG was lower (-0.44 mmol/l [-0.52, -0.37]) in current smokers, with no difference for ex-smokers (0.02 mmol/l [-0.06, 0.09]). There was a large and unexplained heterogeneity among studies, with I (2) always above 50%; I (2) was little changed after stratification by sex and adjustment for age and BMI. In this study population, current smokers had a prevalence of diabetes that was 1.30% higher as screened by HbA1c and 0.52% lower as screened by 2H-PG, in comparison with never-smokers. CONCLUSION/INTERPRETATION: Across this heterogeneous group of studies, current smokers had a higher HbA1c and lower 2H-PG than never-smokers. This will affect the chances of smokers being diagnosed with diabetes.

Metabolic syndrome components are associated with DNA hypomethylation.

BACKGROUND: Disturbances of DNA methylation have been associated with multiple diseases, including cardiovascular disease, cancer and, as some have suggested, glucometabolic disturbances. Our aim was to assess the association of the metabolic syndrome and its individual components with DNA methylation in a population-based study. MATERIALS AND METHODS: In a human population (n = 738) stratified by age, sex and glucose metabolism, we explored associations of the metabolic syndrome according to National Cholesterol Education Program/Adult Treatment Panel-III criteria and its individual components (fasting glucose, high-density lipoprotein cholesterol, triglycerides, blood pressure, waist circumference) with global leukocyte DNA methylation. DNA methylation was measured as the methylcytosine/cytosine ratio in peripheral leukocytes using liquid chromatography-tandem mass spectrometry. RESULTS: Individuals with the metabolic syndrome had relative DNA hypomethylation compared to participants without the syndrome (ß = -0.05; p = 0.01). This association was mainly attributable to linear associations of two metabolic syndrome components with DNA methylation: fasting plasma glucose (ß = -0.02; p = 0.004) and high-density lipoprotein cholesterol (ß = 0.07; p = 0.004). People with type 2 diabetes or impaired glucose metabolism had DNA hypomethylation compared to normoglycemic individuals (ß = -0.05; p = 0.004). CONCLUSIONS: DNA hypomethylation is independently associated with hyperglycemia and low high-density lipoprotein cholesterol, both essential components of the metabolic syndrome. The potential implications and direction of possible causality require further study.

S-adenosylmethionine is associated with fat mass and truncal adiposity in older adults.

S-adenosylmethionine (SAM) is synthesized from methionine, which is abundant in animal-derived protein, in an energy-consuming reaction. SAM and S-adenosylhomocysteine (SAH) correlate with body mass index (BMI). Plasma total concentration of the SAM-associated product cysteine (tCys) correlates with fat mass in humans and cysteine promotes adiposity in animals. In a cross-sectional study of 610 participants, we investigated whether SAM and SAH are associated with BMI via lean mass or fat mass and dietary protein sources as determinants of SAM and tCys concentrations. Plasma SAM was not associated with lean mass, but mean adjusted fat mass increased from 24 kg (95% CI: 22.6, 25.1) to 30 kg (95% CI: 28.7, 31.3) across SAM quartiles (P < 0.001) and trunk fat:total fat ratio increased from 0.48 to 0.52 (P < 0.001). Erythrocyte SAM was also positively associated with fat mass and trunk fat:total fat ratio. The association of SAM with fat mass was not weakened by adjustment for serum tCys, lipids, creatinine, or dietary or lifestyle confounders. Concentrations of the SAM precursor, methionine, and the SAM product, SAH, were not independently associated with adiposity. Intake of animal-derived protein was not related to serum methionine but was positively associated with plasma SAM (partial r = 0.11) and serum tCys (partial r = 0.13; P < 0.05 for both after adjustment for age, gender, and total energy intake). In conclusion, plasma SAM, but not methionine, is independently associated with fat mass and truncal adiposity, suggesting increased conversion of methionine to SAM in obese individuals. Prospective studies are needed to investigate the interactions among dietary energy and animal protein content, SAM concentrations, and change in body weight and cardiometabolic risk.

Preserved GLP-1 and exaggerated GIP secretion in type 2 diabetes and relationships with triglycerides and ALT.

OBJECTIVE: To i) compare incretin responses to oral glucose and mixed meal of diabetic patients with the normoglycaemic population and ii) to investigate whether incretin responses are associated with hypertriglyceridaemia and alanine aminotransferase (ALT) as liver fat marker. DESIGN: A population-based study. METHODS: A total of 163 persons with normal glucose metabolism (NGM), 20 with intermediate hyperglycaemia and 20 with type 2 diabetes aged 40-65 years participated. Participants received a mixed meal and oral glucose load on separate occasions. Glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon profiles were analysed as total area under the curve (tAUC) and incremental area under the curve. RESULTS: In diabetic patients compared with persons with NGM, we found increased GLP-1 secretion (tAUC per hour) following oral glucose (23.2 pmol/l (95% CI 17.7-28.7) vs 18.0 (95% CI 16.9-19.1), P<0.05) but not after the mixed meal. GIP secretion among diabetic patients was increased on both occasions (82.9 pmol/l (55.9-109.8) vs 47.1 (43.8-50.4) for oral glucose and 130.6 (92.5-168.7) vs 83.2 (77.5-88.9) for mixed meal, both P<0.05). After oral glucose, GLP-1 (tAUC per hour) was inversely related to fasting triglycerides. GIP (tAUC per hour) was positively related to fasting and postprandial triglycerides. Higher fasting GIP levels were related to higher fasting and postprandial triglyceride levels and ALT. CONCLUSION: This study confirms that in type 2 diabetes, GLP-1 secretion is generally preserved and that GIP secretion is exaggerated. The mechanism underlying the divergent associations of GLP-1 and GIP metabolism with fat metabolism and liver fat accumulation warrants further study.

L-Homoarginine and L-arginine are antagonistically related to blood pressure in an elderly population: the Hoorn study.

OBJECTIVES: Production of nitric oxide by the vascular endothelium is crucial for the maintenance of vascular tone, an important determinant of blood pressure. L-Arginine and its homolog L-homoarginine are competitive substrates of nitric oxide synthase (NOS), whereas asymmetric dimethylarginine (ADMA) is a NOS inhibitor. We evaluated the relationships between physiological levels of these amino acids and blood pressure. METHODS: The relationship between blood pressure and plasma levels of L-arginine, L-homoarginine, and ADMA was studied in participants of the Hoorn study, a population-based cohort study of elderly participants (n = 746, aged 50-87, 49.5% men). RESULTS: In linear regression models adjusted for age, sex, L-arginine, and ADMA, a positive association was observed between L-homoarginine and SBP [3.90 mmHg per 1-SD increment of L-homoarginine (95% confidence interval, CI 2.28-5.52)] and DBP [1.83 (0.95-2.72)]. In these models, L-arginine was not significantly associated with SBP [-0.68 mmHg per 1-SD increment of L-arginine (95% CI -2.23 to 0.88)], but a significant inverse association with DBP was observed [-1.17 (-2.02 to -0.32)]. These associations were slightly attenuated after further adjustment for glucose or BMI, but not after adjustment for other cardiovascular risk factors (lipids, smoking, inflammation markers, microalbuminuria, prior cardiovascular disease, and antihypertensive medication). ADMA was not significantly associated with either SBP or DBP. CONCLUSION: In elderly participants, plasma levels of L-homoarginine and L-arginine are independently associated with clinically relevant differences in blood pressure in an antagonistic fashion.