Clinical profiles of post-load glucose subgroups and their association with glycaemic traits over time: An IMI-DIRECT study.

AIM: To examine the hypothesis that, based on their glucose curves during a seven-point oral glucose tolerance test, people at elevated type 2 diabetes risk can be divided into subgroups with different clinical profiles at baseline and different degrees of subsequent glycaemic deterioration. METHODS: We included 2126 participants at elevated type 2 diabetes risk from the Diabetes Research on Patient Stratification (IMI-DIRECT) study. Latent class trajectory analysis was used to identify subgroups from a seven-point oral glucose tolerance test at baseline and follow-up. Linear models quantified the associations between the subgroups with glycaemic traits at baseline and 18 months. RESULTS: At baseline, we identified four glucose curve subgroups, labelled in order of increasing peak levels as 1-4. Participants in Subgroups 2-4, were more likely to have higher insulin resistance (homeostatic model assessment) and a lower Matsuda index, than those in Subgroup 1. Overall, participants in Subgroups 3 and 4, had higher glycaemic trait values, with the exception of the Matsuda and insulinogenic indices. At 18 months, change in homeostatic model assessment of insulin resistance was higher in Subgroup 4 (ß = 0.36, 95% CI 0.13-0.58), Subgroup 3 (ß = 0.30; 95% CI 0.10-0.50) and Subgroup 2 (ß = 0.18; 95% CI 0.04-0.32), compared to Subgroup 1. The same was observed for C-peptide and insulin. Five subgroups were identified at follow-up, and the majority of participants remained in the same subgroup or progressed to higher peak subgroups after 18 months. CONCLUSIONS: Using data from a frequently sampled oral glucose tolerance test, glucose curve patterns associated with different clinical characteristics and different rates of subsequent glycaemic deterioration can be identified.

Alcohol and red wine consumption, but not fruit, vegetables, fish or dairy products, are associated with less endothelial dysfunction and less low-grade inflammation: the Hoorn Study.

PURPOSE: Endothelial dysfunction and low-grade inflammation are key phenomena in the pathobiology of cardiovascular disease (CVD). Their dietary modification might explain the observed reduction in CVD that has been associated with a healthy diet rich in fruit, vegetables and fish, low in dairy products and with moderate alcohol and red wine consumption. We investigated the associations between the above food groups and endothelial dysfunction and low-grade inflammation in a population-based cohort of Dutch elderly individuals. METHODS: Diet was measured by food frequency questionnaire (n = 801; women = 399; age 68.5 ± 7.2 years). Endothelial dysfunction was determined (1) by combining von Willebrand factor, and soluble intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1, endothelial selectin and thrombomodulin, using Z-scores, into a biomarker score and (2) by flow-mediated vasodilation (FMD), and low-grade inflammation by combining C-reactive protein, serum amyloid A, interleukin 6, interleukin 8, tumour necrosis factor α and sICAM-1 into a biomarker score, with smaller FMD and higher scores representing more dysfunction and inflammation, respectively. We used linear regression analyses to adjust associations for sex, age, energy, glucose metabolism, body mass index, smoking, prior CVD, educational level, physical activity and each of the other food groups. RESULTS: Moderate [ß (95% CI) -0.13 (-0.33; 0.07)] and high [-0.22 (-0.45; -0.003)] alcohol consumption, and red wine [-0.16 (-0.30; -0.01)] consumption, but none of the other food groups, were associated with a lower endothelial dysfunction biomarker score and a greater FMD. The associations for FMD were, however, not statistically significant. Only red wine consumption was associated with a lower low-grade inflammation biomarker score [-0.18 (-0.33; -0.04)]. CONCLUSIONS: Alcohol and red wine consumption may favourably influence processes involved in atherothrombosis.

Low vitamin D levels are not a contributing factor to higher prevalence of depressive symptoms in people with Type 2 diabetes mellitus: the Hoorn study.

AIM: To test whether a low serum 25-hydroxyvitamin D level explains the greater prevalence of depression among people with Type 2 diabetes. METHODS: We performed a cross-sectional analysis of 527 people, aged 60-87 years, who participated in a population-based cohort study. Type 2 diabetes, impaired glucose tolerance, impaired fasting glucose and normal glucose tolerance were defined according to the 2006 WHO criteria. The Centre for Epidemiologic Studies Depression questionnaire was administered, using a cut-off score of ≥ 16 to determine clinically relevant depressive symptoms. RESULTS: Logistic regression analysis confirmed that women with impaired glucose tolerance/impaired fasting glucose and people with Type 2 diabetes did have a higher risk of depressive symptoms [unadjusted odds ratios 3.66 (95% CI 1.59 to 8.43) and 3.04 (95% CI 1.57 to 5.88), respectively], compared with people with normal glucose tolerance. Serum 25-hydroxyvitamin D level was not a mediating factor in the association between impaired glucose tolerance/impaired fasting glucose or Type 2 diabetes and depressive symptoms [unstandardized indirect effect 0.001 (95% CI -0.063 to 0.079) and 0.004 (95% CI -0.025 to 0.094), respectively]. CONCLUSIONS: The study found no evidence that low vitamin D levels are a contributing factor to higher depression scores in people with Type 2 diabetes.

Individual and partner's level of occupation and the association with HbA1c levels in people with Type 2 diabetes mellitus: the Dutch Diabetes Pearl cohort.

AIMS: Individual indicators of socio-economic status have been associated with glycaemic control in people with Type 2 diabetes, but little is known about the association between partner's socio-economic status and HbA1c levels. We therefore examined the cross-sectional association between individual and partner's level of occupation on HbA1c levels in people with Type 2 diabetes in the Netherlands. METHODS: We included people with Type 2 diabetes with a partner who were treated in primary, secondary and tertiary care in the Diabetes Pearl cohort. Occupational level was classified according to International Standard Classification of Occupations (ISCO)-08 skill levels. Linear regression analyses were performed stratified for sex, and corrected for age, recruitment centre and diabetes medication. RESULTS: In total, 3257 participants (59.8% men, mean 62.2±9.4 years) were included. For men, having a partner with an intermediate level of occupation was associated with lower HbA1c levels [e.g. ISCO level 3: -2 mmol/mol (95% CI -4;-1) or -0.2% (95% CI -0.4;-0.1)], compared with having a partner of the highest occupational level (ISCO level 4). In women, having an unemployed partner was associated with higher HbA1c levels [14 mmol/mol (95% CI 6; 22) or 1.3% (95% CI 0.6; 2.0)], compared with having a partner of the highest occupational level. CONCLUSIONS: Partner's occupational status provided additional information on the association between socio-economic status and HbA1c levels in people with Type 2 diabetes. Women seemed to benefit from a partner with a higher occupational status, while men seemed to benefit from a partner with a lower status. Because of the cross-sectional nature of the present study, more research is necessary to explore this association.

Effects of self-monitoring of glucose on distress and self-efficacy in people with non-insulin-treated Type 2 diabetes: a randomized controlled trial.

AIMS: To investigate the effects of self-monitoring of glucose in blood or urine, on diabetes-specific distress and self-efficacy, compared with usual care in people with non-insulin-treated Type 2 diabetes mellitus. METHODS: One hundred and eighty-one participants with non-insulin-treated Type 2 diabetes mellitus [diabetes duration ≥ 1 year, age 45-75 years, HbA1c ≥ 53.0 mmol/mol (7.0%), self-monitoring frequency < 3 times in the previous year] were randomly assigned to blood self-monitoring (n = 60), urine self-monitoring (n = 59) or usual care (n = 62). Primary outcomes were between-group differences in diabetes-specific distress [Problem Areas in Diabetes scale (PAID)] and self-efficacy [Confidence in Diabetes Self-Care questionnaire (CIDS-2)] after 12 months. Secondary outcomes included changes in HbA1c , treatment satisfaction and depressive symptoms. RESULTS: There were no statistically significant between-group differences in changes in PAID and CIDS-2 after 12 months. Mean difference in PAID between blood monitoring and control was -2.2 [95% confidence interval (CI) -7.1 to 2.7], between urine monitoring and control was -0.9 (95% CI -4.4 to 2.5) and between blood monitoring and urine monitoring was -2.0 (95% CI -4.1 to 0.1). Mean difference in CIDS-2 between blood monitoring and control was 0.6 [95% CI (-2.0 to 2.1), between urine monitoring and control was 2.8 (95% CI -2.3 to 7.9)] and between blood monitoring and urine monitoring was -3.3 (95% CI -7.9 to 1.3). No statistically significant between-group differences in change in any of the secondary outcome measures were found. CONCLUSIONS: This study did not find statistical or clinical evidence for a long-term effect of self-monitoring of glucose in blood or urine on diabetes-specific distress and self-efficacy in people with moderately controlled non-insulin-treated Type 2 diabetes mellitus. (Current Controlled Trials ISRCTN84568563).

Effectiveness of insulin therapy in people with Type 2 diabetes in the Hoorn Diabetes Care System.

AIMS: To identify HbA1c trajectories after the start of insulin treatment and to identify clinically applicable predictors of the response to insulin therapy. METHODS: The study population comprised 1203 people with Type 2 diabetes included in the Hoorn Diabetes Care System (n = 9849). Inclusion criteria were: age ≥ 40 years; initiation of insulin during follow-up after failure to reach HbA1c levels ≤ 53 mmol/mol (7%) with oral glucose-lowering agents; and a follow up ≥ 2 years after initiating insulin. Latent class growth modelling was used to identify trajectories of HbA1c . Subjects considered to be 'off target' had HbA1c levels ≥ 53 mmol/mol (7.0%) during one-third or more of the follow-up time, and those considered to be 'on target' had HbA1c levels ≥ 53 mmol/mol (7.0%) during less than one-third of the follow-up time. RESULTS: Four HbA1c trajectories were identified. Most people (88.7%) were classified as having a stable HbA1c trajectory of ~57 mmol/mol (7.4%). Only 24.4% of the people were on target in response to insulin; this was associated with lower HbA1c levels and a higher age at the start of insulin treatment. CONCLUSIONS: Using latent class growth modelling, four HbA1c trajectories were identified. A quarter of the people starting insulin were on target. Low HbA1c levels and advanced age at the start of insulin therapy were associated with better response to insulin therapy. Initiating insulin earlier improves the likelihood of achieving and sustaining glycaemic control.

Policy evaluation in diabetes prevention and treatment using a population-based macro simulation model: the MICADO model.

AIMS: To test a simulation model, the MICADO model, for estimating the long-term effects of interventions in people with and without diabetes. METHODS: The MICADO model includes micro- and macrovascular diseases in relation to their risk factors. The strengths of this model are its population scope and the possibility to assess parameter uncertainty using probabilistic sensitivity analyses. Outcomes include incidence and prevalence of complications, quality of life, costs and cost-effectiveness. We externally validated MICADO's estimates of micro- and macrovascular complications in a Dutch cohort with diabetes (n = 498,400) by comparing these estimates with national and international empirical data. RESULTS: For the annual number of people undergoing amputations, MICADO's estimate was 592 (95% interquantile range 291-842), which compared well with the registered number of people with diabetes-related amputations in the Netherlands (728). The incidence of end-stage renal disease estimated using the MICADO model was 247 people (95% interquartile range 120-363), which was also similar to the registered incidence in the Netherlands (277 people). MICADO performed well in the validation of macrovascular outcomes of population-based cohorts, while it had more difficulty in reflecting a highly selected trial population. CONCLUSIONS: Validation by comparison with independent empirical data showed that the MICADO model simulates the natural course of diabetes and its micro- and macrovascular complications well. As a population-based model, MICADO can be applied for projections as well as scenario analyses to evaluate the long-term (cost-)effectiveness of population-level interventions targeting diabetes and its complications in the Netherlands or similar countries.

Endothelial dysfunction is associated with a greater depressive symptom score in a general elderly population: the Hoorn Study.

BACKGROUND: Endothelial dysfunction (ED), low-grade inflammation (LGI) and oxidative stress (OxS) may be involved in the pathobiology of depression. Previous studies on the association of these processes in depression have yielded contradictory results. We therefore investigated comprehensively, in a population-based cohort study, the association between ED, LGI and OxS on the one hand and depressive symptoms on the other. METHOD: We used data from the Hoorn Study and determined biomarkers of ED [flow-mediated dilatation (FMD), von Willebrand factor, soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1, soluble thrombomodulin and soluble endothelial selectin], LGI [C-reactive protein, tumour necrosis factor-α, interleukin 6, interleukin 8, serum amyloid A, myeloperoxidase (MPO) and sICAM-1] and OxS (oxidized low density lipoprotein and MPO). Depressive symptoms were quantified by the Center for Epidemiologic Studies Depression Scale (CES-D) questionnaire (n = 493; age 68 years; 49.9% female). Regression analyses were performed with the use of biomarker Z scores. Adjustments were made for age, sex and glucose metabolism status (cohort stratification variables) and prior cardiovascular disease, hypertension, waist-to-hip ratio, cholesterol levels, education level, physical activity, dietary habits, and the use of antihypertensive and/or lipid-lowering medication and/or metformin (potential confounders). RESULTS: After adjustment for age, sex and glucose metabolism status, one standard deviation increase in the ED Z score was associated with a 1.9 [95% confidence interval (CI) 0.7-3.1] higher CES-D score. Additional adjustments did not materially change this result. LGI and OxS were not associated with the CES-D score. CONCLUSIONS: ED, as quantified by an array of circulating biomarkers and FMD, was independently associated with depressive symptoms. This study supports the hypothesis that ED plays an important role in the pathobiology of depression.

Symptom burden and its association with change in glucose metabolism status over a 7-year period: the Hoorn Study.

AIMS: To study symptom burden among older people and its associations with change in glucose metabolism status over a 7-year period. METHODS: We conducted a prospective population-based cohort study among 397 older people. We used the revised Diabetes Symptom Checklist to assess symptom burden. Glucose metabolism status was determined using an oral glucose tolerance test. Analyses were adjusted for multiple confounders, including cardiovascular risk and risk of depression (Center for Epidemiological Studies Depression Scale score ≥ 16). RESULTS: Revised Diabetes Symptom Checklist total scores (range 0-100) increased slightly over time among people with normal glucose metabolism (mean difference ß1.04; P = 0.04) and those with impaired glucose metabolism (ß1.96; P = 0.01), but not among people with Type 2 diabetes (ß0.46; P = 0.55). These associations between symptom burden and glucose status were attenuated after full adjustment for multiple confounders and remained statistically significant for those with impaired glucose status. Linear mixed models showed significant mean differences in revised Diabetes Symptom Checklist total scores over time when comparing people with Type 2 diabetes with those with normal or impaired glucose metabolism, but not when comparing subjects with impaired vs normal glucose metabolism; these results did not alter after full adjustment. CONCLUSIONS: Symptom burden increased gradually over time in the people with impaired glucose metabolism and those with normal glucose metabolism, but not in patients with Type 2 diabetes over a 7-year follow-up period.

Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and type 2 diabetes susceptibility.

AIMS: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic ß-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to type 2 diabetes in humans. METHODS: Four potentially functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for type 2 diabetes susceptibility in up to 25 000 people (8148 with type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort. In addition, 340 Dutch subjects underwent a 2-h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender-stratified analysis. RESULTS: rs1800497 at the DRD2/ANKK1 locus was associated with a significantly increased risk for type 2 diabetes in women (odds ratio 1.14 (1.06-1.23); P = 4.1*104) but not in men (odds ratio 1.00 (95% CI 0.93-1.07); P = 0.92) or the combined group. Although rs1800497 was not associated with insulin secretion, we did find another single nucleotide polymorphism in this locus, rs6275, to be associated with increased first-phase glucose-stimulated insulin secretion in women (P = 5.5*104) but again not in men (P = 0.34). CONCLUSION: The present data identify DRD2/ANKK1 as a potential sex-specific type 2 diabetes susceptibility gene.

Fasting proinsulin levels are significantly associated with 20 year cancer mortality rates. The Hoorn Study.

AIMS/HYPOTHESIS: Proinsulin is possibly associated with cancer through activation of insulin receptor isoform A. We sought to investigate the associations between proinsulin and 20 year cancer mortality rates. METHODS: The study was performed within the Hoorn Study, a population-based study of glucose metabolism in individuals aged 50-75 years in the Dutch population. Fasting proinsulin levels were measured twice by a double-antibody radioimmunoassay. Participants were continuously followed to register mortality; causes of death were derived from medical records. Cox survival analyses were performed to assess the 20 year risk of death from cancer in relation to proinsulin. All analyses were adjusted for age and sex, with additional adjustments for traditional risk factors. The effect modification of glucose metabolism and sex was tested. RESULTS: Proinsulin levels were measured in 438 individuals (41% normal glucose tolerance, 35.7% impaired glucose metabolism, 23.3% type 2 diabetes). Of these participants, 53 died from cancer. After adjustment for age and sex, proinsulin >16.5 pmol/l (the upper tertile) was significantly associated with a twofold risk of cancer mortality (HR 2.01, 95% CI 1.16, 3.46) compared with individuals with lower proinsulin levels. Additional adjustment for glucose metabolism, BMI and smoking did not substantially change the results (HR 1.91, 95% CI 1.04, 3.52). No interaction with glucose metabolism or sex was observed. CONCLUSIONS/INTERPRETATION: Individuals with fasting proinsulin levels >16.5 pmol/l have a twofold risk of cancer mortality over a 20 year time span. These findings provide population-based evidence for the independent association between high proinsulin levels and cancer mortality rates.

Effects of induced hyperinsulinaemia with and without hyperglycaemia on measures of cardiac vagal control.

AIMS/HYPOTHESIS: We examined the effects of serum insulin levels on vagal control over the heart and tested the hypothesis that higher fasting insulin levels are associated with lower vagal control. We also examined whether experimentally induced increases in insulin by beta cell secretagogues, including glucagon-like peptide-1 (GLP-1), will decrease vagal control. METHODS: Respiration and ECGs were recorded for 130 healthy participants undergoing clamps. Three variables of cardiac vagal effects (the root mean square of successive differences [rMSSD] in the interbeat interval of the heart rate [IBI], heart-rate variability [HRV] caused by peak-valley respiratory sinus arrhythmia [pvRSA], and high-frequency power [HF]) and heart rate (HR) were obtained at seven time points during the clamps, characterised by increasing levels of insulin (achieved by administering insulin plus glucose, glucose only, glucose and GLP-1, and glucose and GLP-1 combined with arginine). RESULTS: Serum insulin level was positively associated with HR at all time points during the clamps except the first-phase hyperglycaemic clamp. Insulin levels were negatively correlated with variables of vagal control, reaching significance for rMSSD and log10HF, but not for pvRSA, during the last four phases of the hyperglycaemic clamp (hyperglycaemic second phase, GLP-1 first and second phases, and arginine). These associations disappeared when adjusted for age, BMI and insulin sensitivity. Administration of the beta cell secretagogues GLP-1 and arginine led to a significant increase in HR, but this was not paired with a significant reduction in HRV measures. CONCLUSION/INTERPRETATION: Experimentally induced hyperinsulinaemia is not correlated with cardiac vagal control or HR when adjusting for age, BMI and insulin sensitivity index. Our findings suggest that exposure to a GLP-1 during hyperglycaemia leads to a small acute increase in HR but not to an acute decrease in cardiac vagal control.

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes.

AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. RESULTS: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.

Common carotid intima-media thickness does not add to Framingham risk score in individuals with diabetes mellitus: the USE-IMT initiative.

AIMS/HYPOTHESIS: The aim of this work was to investigate whether measurement of the mean common carotid intima-media thickness (CIMT) improves cardiovascular risk prediction in individuals with diabetes. METHODS: We performed a subanalysis among 4,220 individuals with diabetes in a large ongoing individual participant data meta-analysis involving 56,194 subjects from 17 population-based cohorts worldwide. We first refitted the risk factors of the Framingham heart risk score on the individuals without previous cardiovascular disease (baseline model) and then expanded this model with the mean common CIMT (CIMT model). The absolute 10 year risk for developing a myocardial infarction or stroke was estimated from both models. In individuals with diabetes we compared discrimination and calibration of the two models. Reclassification of individuals with diabetes was based on allocation to another cardiovascular risk category when mean common CIMT was added. RESULTS: During a median follow-up of 8.7 years, 684 first-time cardiovascular events occurred among the population with diabetes. The C statistic was 0.67 for the Framingham model and 0.68 for the CIMT model. The absolute 10 year risk for developing a myocardial infarction or stroke was 16% in both models. There was no net reclassification improvement with the addition of mean common CIMT (1.7%; 95% CI -1.8, 3.8). There were no differences in the results between men and women. CONCLUSIONS/INTERPRETATION: There is no improvement in risk prediction in individuals with diabetes when measurement of the mean common CIMT is added to the Framingham risk score. Therefore, this measurement is not recommended for improving individual cardiovascular risk stratification in individuals with diabetes.

Gender-specific differences in carotid intima-media thickness and its progression over three years: a multicenter European study.

BACKGROUND AND AIMS: This multicentre European study evaluated, in a young-to-middle-aged healthy population without carotid atherosclerosis, the gender-related differences in carotid intima-media thickness (IMT) and its short-term (3-year) progression, and whether these differences are related to different vascular ageing rate, cardiovascular risk profile or different susceptibility to family predisposition to cardiovascular diseases (CVD). METHODS AND RESULTS: 366 men and 422 women (age between 30 and 60 years) underwent B-mode carotid ultrasound at baseline and after 3-year follow-up period. IMT in 3 carotid segments was higher in men than in women (p < 0.0001 for all segments). When evaluated according to age decade, differences between men and women disappeared in the 6th decade, as in this decade a 3-year IMT progression rate accelerated in women (p < 0.05 as compared to the 4th and 5th age decade). Age was a major determinant of baseline all-segment IMT in women; in men all-segment IMT was influenced by age and LDL-cholesterol. IMT progression did not correlate with established cardiovascular risk factors, their short-term changes or family predisposition to CVD. Yet, a 3-year IMT progression in common carotid artery (CCA) was higher in men (p = 0.01) and women (p < 0.01) in whom relative Framingham risk increased during the corresponding period. CONCLUSION: This study provides reference values on IMT and its short-term progression in healthy young-to-middle-aged population, and demonstrates gender-related differences in the susceptibility of carotid wall to ageing and LDL-cholesterol. Increase in Framingham risk accelerated a short-term CCA IMT progression rate in both genders, whereas family predisposition to CVD did not influence carotid IMT.

Effect of coercive measures on treatment outcome in involuntarily admitted patients in Amsterdam.

Objective: The prevalence of involuntary admissions rose the last forty years in European countries, including the Netherlands. Involuntary admissions result in seclusion, physical restraint and forced medication in approximately 40% of patients. We looked at whether treatment outcomes differ in patients with and without coercive measures. Methods: Using The Health of the Nation Outcome Scales (HoNOS) to measure treatment outcomes, we studied the files of 786 patients admitted involuntarily to an Amsterdam clinic. We applied Generalised Linear Models to determine whether the use, or not, of coercive measures during treatment was associated with a difference in outcomes. Results: 19% of the cohort were secluded in a High Security Room (HSR); 24% were secluded in their own room and/or received forced medication. After adjustment for the influence of diagnosis, disorder severity (initial HoNOS score) and treatment duration, the HSR group had, on average, a HoNOS difference score that was 2.4 points lower than patients without coercive measures (CI -4.0 to -0.8.; p 0.003). In the seclusion in own room group, this score was 2.6 points lower (CI -4.0 to -1.1; p 0.001), corresponding to an effect size of 0.35 and 0.40, respectively. Conclusion: Seclusion, whether or not in combination with forced medication, was applied to two-fifths of patients. The HoNOS scores of the group without coercion improved by nearly two and a half points more on average than those of the two groups with coercion. A causal relationship between coercion and treatment outcome could neither be confirmed nor excluded on the basis of our results.

A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts.

AIMS/HYPOTHESIS: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. METHODS: Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) ≤ 7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. RESULTS: In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p = 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10(-6), respectively). CONCLUSIONS/INTERPRETATION: A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.

Plasma sCD36 is associated with markers of atherosclerosis, insulin resistance and fatty liver in a nondiabetic healthy population.

OBJECTIVES: Insulin resistance is associated with increased CD36 expression in a number of tissues. Moreover, excess macrophage CD36 may initiate atherosclerotic lesions. The aim of this study was to determine whether plasma soluble CD36 (sCD36) was associated with insulin resistance, fatty liver and carotid atherosclerosis in nondiabetic subjects. METHODS: In 1296 healthy subjects without diabetes or hypertension recruited from 19 centres in 14 European countries (RISC study), we determined the levels of sCD36, adiponectin, lipids and liver enzymes, insulin sensitivity (M/I) by euglycaemic-hyperinsulinaemic clamp, carotid atherosclerosis as intima-media thickness (IMT) and two estimates of fatty liver, the fatty liver index (FLI) and liver fat percentage (LF%). RESULTS: IMT, FLI, LF%, presence of the metabolic syndrome, impaired glucose regulation, insulin and triglycerides increased across sCD36 quartiles (Q2-Q4), whereas adiponectin and M/I decreased (P ≤ 0.01). sCD36 was lower in women than in men (P = 0.045). Log sCD36 showed a bimodal distribution, and amongst subjects with sCD36 within the log-normal distribution (log-normal population, n = 1029), sCD36 was increased in subjects with impaired glucose regulation (P = 0.045), metabolic syndrome (P = 0.006) or increased likelihood of fatty liver (P < 0.001). sCD36 correlated significantly with insulin, triglycerides, M/I and FLI (P < 0.05) after adjustment for study centre, gender, age, glucose tolerance status, smoking habits and alcohol consumption. In the log-normal population, these relationships were stronger than in the total study population and, additionally, sCD36 was significantly associated with LF% and IMT (P < 0.05). CONCLUSIONS: In this cross-sectional study of nondiabetic subjects, sCD36 was significantly associated with indices of insulin resistance, carotid atherosclerosis and fatty liver. Prospective studies are needed to further evaluate the role of sCD36 in the inter-relationship between atherosclerosis, fatty liver and insulin resistance.

Discontinuation of statins among patients with type 2 diabetes.

BACKGROUND: Statins play an important role in the prevention of cardiovascular disease in type 2 diabetes. Several studies have reported low adherence with statins among patients with type 2 diabetes. Studies comparing discontinuation of statins compared with discontinuation of oral anti-diabetics within the same individuals before and after initiation of oral anti-diabetic drugs are not available. The aim of this study was to describe discontinuation among patients with type 2 diabetes prescribed statins prior to and after initiation of oral anti-diabetics and to compare statin discontinuation with discontinuation of oral anti-diabetics. METHODS: We report an observational cohort study among patients initiating treatment with statins prior to or after initiation of oral anti-diabetics between 1999 and 2007. Patients were classified as starting statins prior to initiation (Prior users) or after initiation (After users) of anti-diabetics. Discontinuation was defined as an interval of 180 days or more between the theoretical end date of a statin/anti-diabetic prescription and the dispensing date of the next statin/anti-diabetic prescription. RESULTS AND CONCLUSIONS: We included 3323 starters with oral anti-diabetic drugs in our study; 2072 patients initiated statins in the period of observation. Discontinuation rates for statins were higher compared with oral anti-diabetics (52.1 vs 15.0%). After users discontinued statin therapy more frequently compared to prior users (62.8 vs 48.2%). Discontinuation of statins is higher compared with anti-diabetic discontinuation. Patients starting statins after the initiation of oral anti-diabetic treatment are more likely to discontinue treatment than patients who initiate statins before the start of oral anti-diabetics.

Glucocorticoid receptor gene polymorphisms are associated with reduced first-phase glucose-stimulated insulin secretion and disposition index in women, but not in men.

AIM: Glucocorticoids are efficacious anti-inflammatory agents, but, in susceptible individuals, these drugs may induce glucose intolerance and diabetes by affecting ß-cell function and insulin sensitivity. We assessed whether polymorphisms in the glucocorticoid receptor gene NR3C1 associate with measures of ß-cell function and insulin sensitivity derived from hyperglycaemic clamps in subjects with normal or impaired glucose tolerance. METHODS: A cross-sectional cohort study was conducted in four academic medical centres in the Netherlands and Germany. Four hundred and forty-nine volunteers (188 men; 261 women) were recruited with normal glucose tolerance (n=261) and impaired glucose tolerance (n=188). From 2-h hyperglycaemic clamps, first- and second-phase glucose-stimulated insulin secretion, as well as insulin sensitivity index and disposition index, were calculated. All participants were genotyped for the functional NR3C1 polymorphisms N363S (rs6195), BclI (rs41423247), ER22/23EK (rs6189/6190), 9ß A/G (rs6198) and ThtIIII (rs10052957). Associations between these polymorphisms and ß-cell function parameters were assessed. RESULTS: In women, but not in men, the N363S polymorphism was associated with reduced disposition index (P=1.06 10(-4) ). Also only in women, the ER22/23EK polymorphism was associated with reduced first-phase glucose-stimulated insulin secretion (P=0.011) and disposition index (P=0.003). The other single-nucleotide polymorphisms were not associated with ß-cell function. Finally, none of the polymorphisms was related to insulin sensitivity. CONCLUSION: The N363S and ER22/23EK polymorphisms of the NR3C1 gene are negatively associated with parameters of ß-cell function in women, but not in men.