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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. [ABSTRACT FROM AUTHOR]

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 [β (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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective. With depression being present in approximately 20% of people with type 2 diabetes mellitus (T2DM), we expect equally frequent prescription of antidepressants, anxiolytics, and hypnotics. Nevertheless, prescription data in people with T2DM is missing and the effect of depression on glycaemic control is contradictory. The aim of this study was to assess the prevalence of antidepressants, anxiolytics, and/or hypnotics use in a large, managed, primary care system cohort of people with T2DM and to determine the sociodemographic characteristics, comorbidities, T2DM medication, and metabolic control associated with its use. Method. The prevalence of antidepressants, anxiolytics, and/or hypnotics use in the years 2007–2012 was assessed in the Hoorn Diabetes Care System Cohort from the Netherlands. Results. From the 7016 people with T2DM, 500 people (7.1%) used antidepressants only, 456 people (6.5%) used anxiolytics and/or hypnotics only, and 254 people (3.6%) used a combination. Conclusion. We conclude that in our managed, primary care system 17% of all people with T2DM used antidepressants, anxiolytics, and/or hypnotics. Users of antidepressants, anxiolytics, and/or hypnotics were more often female, non-Caucasian, lower educated, and more often treated with insulin. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To determine whether impaired cardiovascular autonomic function correlates with albuminuria in an age-, sex-, and glucose tolerance-stratified sample of an elderly (50-75 years of age) Caucasian population and to determine whether this association is independent of other determinants of albuminuria.Research Design and Methods: We studied 536 subjects, 256 with normal glucose tolerance, 143 with impaired glucose tolerance (IGT), and 137 with type 2 diabetes. Microalbuminuria was defined as an albumin-to-creatinine ratio of > or =3.0 and < or =30 mg/mmol in an early morning urine sample. We used the deep-breathing test and the lying-to-standing test to obtain 4 measurements of cardiovascular autonomic function: 1) the heart rate (HR) variability during deep breathing, 2) the maximum HR within 15 s after standing up minus the mean HR before standing, 3) the maximum R-R interval between 15 and 30 s after standing up divided by the minimum R-R interval within 15 s after standing up, and 4) the systolic blood pressure in response to standing up. These 4 measurements were summarized in a single cardiovascular autonomic function score (CAFS).Results: A total of 38 subjects with microalbuminuria and 3 subjects with macroalbuminuria (>30 mg/mmol) were grouped as having albuminuria. In bivariate analyses, albuminuria was associated with age, waist-to-hip ratio, systolic and diastolic blood pressure, calculated glomerular filtration rate, and glucose tolerance status. The mean CAFS was higher in subjects with versus without albuminuria (7.5 vs. 5.9, P<0.001). Multiple logistical regression analyses revealed that the CAFS was independently associated with albuminuria in subjects with IGT or type 2 diabetes with an odds ratio (95% CI) of 1.19 (1.02-1.39) per point increase in the CAFS.Conclusions: Impaired cardiovascular autonomic function is independently associated with (and thus a possible contributor to) the presence of albuminuria in subjects with IGT or type 2 diabetes. [ABSTRACT FROM AUTHOR]

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., (© 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.)

Aims: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic β-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., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)

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.

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.

Context: Higher PTH concentrations have been associated with fatal cardiovascular diseases (CVDs), but data in the general population are scarce., Objective: We investigated whether higher PTH concentrations are prospectively associated with all-cause and CVD mortality., Design, Setting, Participants: This study used data from the Hoorn Study, a prospective population-based cohort with baseline measurements between 2000 and 2001. We included 633 participants, mean age 70.1 ± 6.6 years, 51% female. Serum intact PTH was measured using a 2-site immunoassay., Main Outcome Measures: Outcomes were all-cause and CVD mortality based on clinical files and coded according to the International Classification of Diseases, ninth revision. We used Kaplan-Meier plots to estimate survival curves and Cox regression to estimate hazard ratios (HRs) using season-specific PTH quartiles., Results: During a median follow-up of 7.8 years, 112 participants died, of which 26 deaths (23%) were cardiovascular. Survival curves by PTH quartiles differed for all-cause mortality (log-rank P = .054) and CVD mortality (log-rank P = .022). In a multivariate model, the highest PTH quartile was associated with all-cause mortality; HR = 1.98 (1.08, 3.64). Kidney function slightly attenuated the PTH risk association, but risk persisted; HR = 1.93 (1.04, 3.58). The results for CVD mortality showed a similar pattern, although the association was significant only in a threshold model (quartile 4 vs quartile 1-3); HR = 2.56 (1.11, 5.94)., Conclusions: Among a general older population, higher PTH concentrations were associated with higher all-cause mortality risk, mostly explained by fatal CVD events. We suggest to evaluate whether individuals with high PTH concentrations benefit from therapeutic approaches targeted to decrease PTH concentrations.

Background/aims: Markers of vascular disease elsewhere in the body may reflect vascular abnormalities in the brain relevant to age-related cognitive decline and dementia. We examined the association between albuminuria, as a marker of microvascular damage, and cognition in older individuals., Methods: 380 individuals (age 73 ± 6 years), participating in the population-based Hoorn Study, underwent extensive neuropsychological examination in 2005-2008, and urinary albumin-to-creatinine ratios measurements in 2000-2001 (n = 378) and/or 2005-2008 (n = 346). Cognition was expressed in z-scores on 6 domains., Results: In 2000-2001, 42 participants were with and 336 without albuminuria, and in 2005-2008 51 were with and 295 were without. In age-, sex- and premorbid IQ-adjusted analyses, participants with albuminuria 5-7 years earlier had slightly lower z-scores for the domains attention and executive functioning [mean difference: -0.21 (95% CI -0.40 to -0.02)] and language [-0.36 (95% CI -0.63 to -0.09)]. No statistically significant differences in cognition were found between participants with and without albuminuria at the time of neuropsychological testing., Conclusion: Albuminuria predicts future modest cognitive decrements, but concurrent albuminuria is unrelated to cognitive functioning. The link between albuminuria and cognitive dysfunction may convey an etiological message, but because effect sizes were modest its value in prognostic models for cognitive decline may be limited., (Copyright © 2011 S. Karger AG, Basel.)

Objectives: Patients with rheumatoid arthritis (RA) have an increased cardiovascular risk, but the magnitude of this risk is not known precisely. A study was undertaken to investigate the associations between RA and type 2 diabetes (DM2), a well-established cardiovascular risk factor, on the one hand, and cardiovascular disease (CVD) on the other., Methods: The prevalence of CVD (coronary, cerebral and peripheral arterial disease) was determined in 353 randomly selected outpatients with RA (diagnosed between 1989 and 2001, aged 50-75 years; the CARRE study) and in participants of a population-based cohort study on diabetes and CVD (the Hoorn study). Patients with RA with normal fasting glucose levels from the CARRE study (RA, n = 294) were compared with individuals from the Hoorn study with normal glucose metabolism (non-diabetic, n = 258) and individuals with DM2 (DM2, n = 194)., Results: The prevalence of CVD was 5.0% (95% CI 2.3% to 7.7%) in the non-diabetic group, 12.4% (95% CI 7.5% to 17.3%) in the DM2 group and 12.9% (95% CI 8.8% to 17.0%) in those with RA. With non-diabetic individuals as the reference category, the age- and gender-adjusted prevalence odds ratio (OR) for CVD was 2.3 (95% CI 1.1 to 4.7) for individuals with DM2 and 3.1 (95% CI 1.6 to 6.1) for those with RA. There was an attenuation of the prevalences after adjustment for conventional cardiovascular risk factors (OR 2.0 (95% CI 0.9 to 4.5) and 2.7 (95% CI 1.2 to 5.9), respectively)., Conclusions: The prevalence of CVD in RA is increased to an extent that is at least comparable to that of DM2. This should have implications for primary cardiovascular prevention strategies in RA.

Background: We hypothesized that acarbose would delay conversion from impaired glucose tolerance (IGT) to type 2 diabetes by alleviating postprandial hyperglycaemia. Our study's main objective was to investigate the effect of acarbose in IGT-persons on their 2-h plasma glucose level and beta-cell function., Subjects and Methods: The study included a random sample of 45-70-year-old residents of Hoorn, Netherlands, with mean fasting plasma glucose < 7.8 mmol/L and mean 2-h plasma glucose of 8.6-11.1 mmol/L (measured by two successive oral glucose tolerance tests). After a qualification period, participants were randomized to acarbose treatment or placebo. Insulin secretion and insulin sensitivity were measured by hyperglycaemic clamp. After a 3-year treatment, analyses were performed of both the intention-to-treat and the per-protocol groups., Results: Of the 12 093 residents who received postal invitations, 118 participants were randomized. The mean difference of the post-load plasma glucose after 3 years, was - 1.16 mmol/L (95% CI: - 2.03; - 0.17). The absolute risk reduction for diabetes was 6% (95% CI: - 9; 21). No effect was seen on insulin secretion and insulin sensitivity., Conclusions: In patients with IGT, treatment with acarbose was associated with beneficial effects on 2-h plasma glucose levels but not with improvement of beta-cell function., (Copyright 2008 John Wiley & Sons, Ltd.)

Objective: To establish whether the Finnish diabetes risk score for predicting the incidence of diabetes (FINDRISK) is also valid in the Netherlands, and to choose cut-off points suitable for the Dutch situation., Design: . Descriptive., Method: The FINDRISK was validated in 3 Dutch cohort studies by means of repeated glucose measurements: the Hoorn study (n=5434), the PREVEND study (n=2713) and part of the Maastricht cohort from the MORGEN study (n=863). The predictive value was evaluated using receiver operating characteristic (ROC) analyses. The risk categories were defined on the basis of sensitivity, specificity and positive predictive value., Results: The predictive value of the FINDRISK was best in the PREVEND cohort (area under the ROC curve 0.77) and was lower for the Hoorn study and the Maastricht cohort (area under the ROC-curve 0.71 for both). The scores were divided into three risk categories: low risk (score lower than 7), slightly increased risk (score 7-9) and increased risk (score so or higher). The percentage of persons with incident diabetes within about 5 years was < 6 in the low risk category, 6-14 in the category with slightly increased risk and 12-26 in the category with increased risk. 16-28% of the Dutch population studied had a score of 10 or higher., Conclusion: The FINDRISK is a reasonably good predictor for incident diabetes in the Netherlands.

Objective: To study the prevalence and risk factors of depressive symptoms, comparing subjects with normal glucose metabolism (NGM), impaired glucose metabolism (IGM) or Type 2 diabetes mellitus (DM2)., Research Design and Methods: Cross-sectional data from a population-based cohort study conducted among 550 residents (276 men and 274 women) of the Hoorn region, the Netherlands. Levels of depressive symptoms were measured using the Centre for Epidemiologic Studies Depression Scale (CES-D score > or = 16). Glucose metabolism status was determined by means of fasting and post-load glucose levels., Results: The prevalence of depressive symptoms in men with NGM, IGM and DM2 was 7.7, 7.0 and 15.0% (P = 0.19) and for women 7.7, 23.1 and 19.7% (P < 0.01), respectively. Depression was significantly more common in women with IGM [odds ratio (OR) = 3.60, 95% confidence interval (CI) = 1.57 to 8.28] and women with DM2 (OR = 3.18, 95% CI = 1.31 to 7.74). In men, depression was not associated with IGM (OR = 0.90, 95% CI = 0.32 to 2.57) and non-significantly more common in DM2 (OR = 2.04, 95% CI = 0.75 to 5.49). Adjustment for cardiovascular risk factors, cardiovascular disease and diabetes symptoms reduced the strength of these associations., Conclusions: Depressive symptoms are more common in women with IGM, but not men. Adjustment for cardiovascular risk factors, cardiovascular disease and diabetes symptoms partially attenuated these associations, suggesting that these variables could be intermediate factors.

Background: Asymptomatic peripheral arterial disease (PAD) is common amongst the elderly and is a risk factor for cardiovascular morbidity and mortality. PAD can be assessed by non-invasive tests such as the ankle/brachial pressure index (ABPI) at rest and Doppler flow velocity (DFV) scanning, but these tests may underestimate the prevalence of PAD. The aim of this study was to estimate the added value, for the detection of PAD, of the one-minute exercise test, defined as positive if the drop of the ankle systolic pressure was more than 30 mmHg. We also investigated whether the combination of the ABPI at rest and the one-minute exercise test could replace DFV scanning., Materials and Methods: We studied this in a random sample (n = 631) of a 50- to 75-year-old population., Results: Of these subjects 11% (66/631) had an abnormal ABPI (< 0.9) and 16% (102/631) had an abnormal DFV curve. Of this sample 72% of the subjects performed a one-minute exercise test. Of all subjects 6% (27/451) had an abnormal ABPI (< 0.9) and 12% (54/451) had an abnormal DFV curve. The one-minute exercise test revealed seven cases of PAD (beyond the 67 already identified) which were not detected by an abnormal ABPI at rest and/or DFV scanning. As a result the prevalence of PAD increased by 2%. All patients with an aortoiliac or femoropopliteal obstruction had an ABPI at rest < 0.9. The sensitivity of the combination of the ABPI at rest and the one-minute exercise test to detect abnormal DFV curves was low for crural obstructions., Conclusion: The one-minute exercise test slightly improves the detection of peripheral arterial disease in the general population.

Aims: Cholesteryl ester transfer protein (CETP) exchanges neutral lipids between lipoproteins. As the role of CETP in the atherogenic process is still not fully clarified, we studied the association of CETP concentration with the prevalence of cardiovascular disease (CVD) and with intima-media thickness of the carotid artery (IMT) in subjects with normal glucose tolerance (NGT), impaird fasting glucose and/or impaired glucose tolerance (IFG/IGT) and Type 2 diabetes mellitus., Methods: Subjects (n = 566) were recruited from the 2000-2001 follow-up examination of the Hoorn study. CETP concentration was determined by immunoassay. CVD was defined as self-reported history of arterial surgery, cerebral vascular event, amputation, angina, claudication, possible infarction, measured ankle-brachial index < 0.90 or ECG abnormalities. The right common carotid artery IMT was measured by ultrasound at 10 mm proximal to the carotid bulb., Results: In men, CETP concentration was not associated with CVD, irrespective of glucose tolerance status. In women with NGT or IGT, there was also no relationship. However, in women with Type 2 diabetes, the risk of CVD was increased in those with high CETP concentration [odds ratio = 3.34 (1.56; 7.14)]. No statistically significant association was found between CETP concentration and IMT in the entire cohort., Conclusions: In an elderly Caucasian population, associations of CETP concentration with CVD were dependent on glucose tolerance status and gender. The finding that high CETP concentration was strongly associated with increased prevalence of CVD in women with Type 2 diabetes warrants further investigation.

Aims/hypothesis: The association between depression and insulin resistance has been investigated in only a few studies, with contradictory results reported. The aim of this study was to determine whether the association between symptoms of depression and insulin resistance varies across glucose tolerance status and between men and women., Subjects and Methods: Cross-sectional data from a population-based cohort study in Hoorn, a medium-sized town in the Netherlands, were analysed. The study sample consisted of 541 men and women aged 55-75 years, of whom 260 had NGT, 164 had IGT and 117 had established type 2 diabetes mellitus. Main outcome measures were insulin resistance defined by the homeostasis model assessment for insulin resistance (HOMA-IR) and symptoms of depression using the Centre for Epidemiologic Studies Depression Scale (CES-D)., Results: In the total sample, we found a weak positive correlation between the depressive symptoms CED-D scores and HOMA-IR scores (r (s) = 0.156, p < 0.001). Even weaker associations were found in subjects with NGT (r (s) = 0.041, p=0.509), in subjects with IGT (r (s) = 0.112, p = 0.160) and in subjects with type 2 diabetes (r (s) = 0.007, p = 0.942). The association between depressive symptoms and insulin resistance was similar for men and women., Conclusions/interpretation: We found only weak associations between depressive symptoms and insulin resistance, which did not differ among different glucose metabolism subgroups or between men and women.

Aims/hypothesis: The exact pathogenesis of retinopathy in diabetic and non-diabetic individuals is incompletely understood, but may involve chronic low-grade inflammation and dysfunction of the vascular endothelium. The aim of this study was to investigate the association of inflammation and endothelial dysfunction with prevalent retinopathy in individuals with and without type 2 diabetes., Methods: As part of a population-based cohort study, 625 individuals aged 50-74 years, stratified according to age, sex and glucose tolerance status, underwent an extensive physical examination. Retinopathy was assessed by an ophthalmological examination, including funduscopy and two-field 45 degrees fundus photography with mydriasis in both eyes. Levels of C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1), von Willebrand factor, and soluble vascular adhesion molecule-1 (sVCAM-1) were assessed, together with the urinary albumin : creatinine ratio, and the results were combined to obtain summarising z scores for inflammation and endothelial dysfunction., Results: The prevalence of retinopathy was positively associated with tertiles of CRP and sICAM-1. When compared with the lowest tertile, the highest tertile of the inflammatory z score was associated with retinopathy in all subjects (odds ratio [OR]=2.2, 95% CI 1.2-4.1, adjusted for age, sex and glucose tolerance status). The highest tertile of the endothelial dysfunction z score was associated with retinopathy among diabetic individuals (OR=4.4, 95% CI 1.2-15.9, adjusted for age and sex) but not in non-diabetic individuals. Additional adjustment for other risk factors, such as systolic and diastolic blood pressure, BMI, total cholesterol and triglycerides, or mutual adjustment of the inflammatory and endothelial dysfunction z scores did not change the results., Conclusions/interpretation: In this study, inflammatory activity and endothelial dysfunction were associated with retinopathy, which suggests their involvement in the pathogenesis of retinopathy.

Aims: We investigated whether low subcutaneous thigh fat is an independent risk factor for unfavourable glucose and lipid levels, and whether these associations differ between sexes, and between white and black adults. Our secondary aim was to investigate which body composition characteristics (lean tissue, fat tissue) are reflected by anthropometric measures (waist and thigh circumference)., Methods: Anthropometric measurements and computed tomography of the abdomen and of the thigh were performed for all participants of the Health, Aging and Body Composition Study, who were aged 70-79 years. Fasting glucose, triglycerides and HDL-cholesterol, and 2-h postload glucose were determined., Results: After excluding those already diagnosed with diabetes or dyslipidaemia, we analysed data from 2,106 participants. After adjustment for abdominal subcutaneous and visceral fat, and intermuscular thigh fat, larger thigh subcutaneous fat area was statistically significantly associated with lower ln-transformed triglycerides [standardised beta (95% CI) -0.12 (-0.20 to -0.04) in men and -0.13 (-0.21 to -0.05) in women] and higher ln-HDL-cholesterol [0.10 (0.02 to 0.19) and 0.09 (0.01 to 0.18), respectively]. The associations with lower glucose levels were strong in men [-0.11 (-0.20 to -0.02) for fasting and -0.14 (-0.23 to -0.05) for postload glucose], but not statistically significant in women [-0.02 (-0.10 to 0.07) and -0.04 (-0.13 to 0.05), respectively]. There were no differences in the associations between white and black persons. Waist circumference was more strongly associated with abdominal subcutaneous fat, and this association became stronger with increasing BMI, whereas the association with visceral fat became weaker. Thigh circumference was equally dependent on thigh fat and thigh muscle in men, whereas in women the fat component was the main contributor., Conclusion: Larger subcutaneous thigh fat is independently associated with more favourable glucose (in men) and lipid levels (in both sexes) after accounting for abdominal fat depots, which are associated with unfavourable glucose and lipid levels. Anthropometric measures reflect different fat depots at different levels of BMI at the abdomen, and reflect both fat and lean tissue at the thigh. These results emphasise the importance of accurate measures of regional body composition when investigating potential health risks.

Aims/hypothesis: Coffee contains several substances that may affect glucose metabolism. The aim of this study was to evaluate the relationship between habitual coffee consumption and the incidence of IFG, IGT and type 2 diabetes., Methods: We used cross-sectional and prospective data from the population-based Hoorn Study, which included Dutch men and women aged 50-74 years. An OGTT was performed at baseline and after a mean follow-up period of 6.4 years. Associations were adjusted for potential confounders including BMI, cigarette smoking, physical activity, alcohol consumption and dietary factors., Results: At baseline, a 5 cup per day higher coffee consumption was significantly associated with lower fasting insulin concentrations (-5.6%, 95% CI -9.3 to -1.6%) and 2-h glucose concentrations (-8.8%, 95% CI -11.8 to -5.6%), but was not associated with lower fasting glucose concentrations (-0.8%, 95% CI -2.1 to 0.6%). In the prospective analyses, the odds ratio (OR) for IGT was 0.59 (95% CI 0.36-0.97) for 3-4 cups per day, 0.46 (95% CI 0.26-0.81) for 5-6 cups per day, and 0.37 (95% CI 0.16-0.84) for 7 or more cups per day, as compared with the corresponding values for the consumption of 2 or fewer cups of coffee per day (p=0.001 for trend). Higher coffee consumption also tended to be associated with a lower incidence of type 2 diabetes (OR 0.69, CI 0.31-1.51 for >/=7 vs /=7 vs

Objectives: Screening for type 2 diabetes has been recommended and targeted screening might be an efficient way to screen. The aim was to investigate whether diabetic patients identified by a targeted screening procedure differ from newly diagnosed diabetic patients in general practice with regard to the prevalence of macrovascular complications., Design: Cross-sectional population-based study., Setting: Population study, primary care., Subjects: Diabetic patients identified by a population-based targeted screening procedure (SDM patients), consisting of a screening questionnaire and a fasting capillary glucose measurement followed by diagnostic testing, were compared with newly diagnosed diabetic patients in general practice (GPDM patients). Ischaemic heart disease and prior myocardial infarction were assessed by ECG recording. Peripheral arterial disease was assessed by the ankle-arm index. Intima-media thickness of the right common carotid artery was measured with ultrasound., Results: A total of 195 SDM patients and 60 GPDM patients participated in the medical examination. The prevalence of MI was 13.3% (95% CI 9.3-18.8%) and 3.4% (1.0-11.7%) in SDM patients and GPDM patients respectively. The prevalence of ischaemic heart disease was 39.5% (95% CI 32.9-46.5%) in SDM patients and 24.1% (15.0-36.5%) in GPDM patients. The prevalence of peripheral arterial disease was similar in both groups: 10.6% (95% CI 6.9-15.9%) and 10.2% (4.7-20.5%) respectively. Mean intima-media thickness was 0.85 mm (+/-0.17) in SDM patients and 0.90 mm (+/-0.20) in GPDM patients. The difference in intima-media thickness was not statistically significant., Conclusions: Targeted screening identified patients with a prevalence of macrovascular complications similar to that of patients detected in general practice, but with a lower degree of hyperglycaemia.

Aims: To examine the impact of the diagnosis of Type 2 diabetes on psychological well-being and perceived health status in subjects who participated in a targeted population-screening programme., Methods: This study was conducted within the framework of a screening project in the general (aged 50-75 years) Dutch population. The final study population consisted of 259 subjects with a high-risk score on the Symptom Risk Questionnaire; 116 of whom were subsequently detected with Type 2 diabetes and 143 who were non-diabetic. The impact was assessed approximately 2 weeks (shortly) and 6 and 12 months after the diagnosis, using the 12-item Well-Being Questionnaire (W-BQ12) and the Medical Outcomes Study Short Form 36 (SF-36), respectively. Analyses of co-variance (ancova) were used., Results: Approximately 2 weeks after the diagnosis, no significant mean differences were found on either the W-BQ12 or the SF-36, between the screening-detected Type 2 diabetes subjects and the non-diabetic subjects. Six months after the diagnosis, we found lower scores in the screening-detected Type 2 diabetes subjects compared with the non-diabetic subjects on the SF-36 dimensions Role Physical (mean difference (95% CI); -8.2 (-16.2; -0.1); P = 0.046) and Role Emotional (mean difference (95% CI); -7.9 (-15.3; -0.5); P = 0.038). One year after the test results, no significant mean differences were found between both groups on either instrument (W-BQ12; SF-36)., Conclusions: The diagnosis of Type 2 diabetes has no substantial adverse or positive effect on psychological well-being and perceived health status, shortly, and 6 and 12 months after the diagnosis.

The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) is involved in regulation of fatty acid oxidation, skeletal muscle fiber type specificity, and gluconeogenesis. The prevalent Gly482Ser variant in PGC-1 was shown to be associated with type 2 diabetes in some but not all studies. Moreover, it is unclear whether it influences prediabetic subphenotypes in non-diabetic populations. We studied the association of this variant with glucose tolerance (oral glucose tolerance test), insulin sensitivity (euglycemic hyperinsulinemic clamp) of glucose disposal and antilipolysis, insulin secretion (hyperglycemic clamp, 10 mM), maximal oxygen consumption (VO(2)max, bicycle ergometry), and intramyocellular lipids (magnetic resonance spectroscopy, tibialis and soleus muscle) in a normal glucose tolerant German cohort (n = 423) and a normal (n = 65) and impaired glucose tolerant (n = 94) cohort from the Netherlands. No statistically significant association with an examined phenotype was detected in any of the study cohorts. Specifically, VO(2)max and the soleus-to-tibialis ratio of intramyocellular lipid contents as a surrogate parameter of fiber type specificity was not different between the genotype groups. We conclude, that the Gly482Ser variant in PGC-1 is not associated with diabetes-related traits or skeletal muscle fiber type composition in a non-diabetic German and Dutch population.

The prevalence of overweight and obesity in children is increasing significantly. This increase is attended by an increase in diabetes type 2 in children and adolescents. The most important risk factor for the rise of insulin resistance amongst young people is overweight. The diagnostic criteria for diabetes mellitus in young people are: (a) symptoms of diabetes mellitus and a random plasma-glucose concentration of > or = 11.1 mmol/l, or (b) fasting plasma-glucose concentration of > or = 7.0 mmol/l, or (c) 2-hour plasma-glucose levels following an oral glucose-tolerance test > or = 11.1 mmol/l. Treatment involves lowering the glucose concentration by changes in lifestyle such as more physical exercise and dieting. In the US, metformin is registered for use in young people. Insulin is indicated in cases of serious hyperglycaemia or diabetic ketoacidosis. Early detection is very useful in obese children with two additional risk factors: diabetes type 2 in first- and second-degree relatives, members of certain ethnic groups or indications of insulin resistance.

Objective: To estimate the incidence of type-2 diabetes mellitus in the Netherlands, using figures which were observed in a population-based cohort study of diabetes, the Hoorn Study., Design: Descriptive., Method: Age-specific, gender-specific and glucose-status-specific diabetes incidence figures as observed in the Hoorn Study (1989-1998) were applied to the Dutch population structure of January 1, 2000., Results: Based on the fasting glucose diagnostic criteria, as recommended for clinical practice, 312,393 patients with incident type-2 diabetes were expected over 6.4 years in the 50-74 years age category, corresponding to an average of 48,811 patients per year. If data are extrapolated to the > or = 75 years age category, an additional 16,865 patients per year are expected (total: 65,676). If the 2-hour postload glucose values of the oral glucose tolerance test were also used to diagnose diabetes, these figures would be 66,001 new patients per year in the 50-74 years age group, and 22,840 in the > or = 75 years age group.

Aims/hypothesis: Type 2 diabetes is not only associated with hyperglycaemia, but also with disorders of lipid metabolism. The aim of this study was to investigate the association of triglyceride and non-HDL-cholesterol concentrations with cardiovascular disease in subjects with normal and abnormal glucose metabolism., Methods: Subjects were 869 men and 948 women aged 50 to 75 who participated in the Hoorn Study, a population-based cohort study that started in 1989. Glucose metabolism was determined by a 75 g OGTT. High fasting triglyceride and non-HDL-cholesterol concentrations were defined as above the median of the study population., Results: After 10 years of follow-up, the age- and sex-adjusted hazard ratios for cardiovascular disease were 1.35 (1.11-1.64) and 1.71 (1.40-2.08) for high triglycerides and high non-HDL-cholesterol, respectively, after mutual adjustment. After stratification for glucose metabolism status, the hazard ratios for cardiovascular disease for non-HDL-cholesterol were 1.70 (1.31-2.21) in normal glucose metabolism and 1.56 (1.12-2.18) in abnormal glucose metabolism. Triglycerides were not a risk factor in subjects with normal glucose metabolism, with a hazard ratio of 0.94 (0.73-1.22), but in subjects with abnormal glucose metabolism, the hazard ratio for cardiovascular disease was 1.54 (1.07-2.22). In subjects with abnormal glucose metabolism, the hazard ratio for the combined presence of high triglycerides and non-HDL-cholesterol was 2.12 (1.35-3.34)., Conclusion: Our data suggest that in people with abnormal glucose metabolism, but not in those with normal glucose metabolism, high triglyceride concentration could be associated with the risk of cardiovascular disease, particularly in people with high non-HDL-cholesterol.

Aims/hypothesis: There is accumulating evidence that depression is common in people with Type 2 diabetes. However, most prevalence-studies are uncontrolled and could also be inaccurate from selection-bias, as they are conducted in specialized treatment settings. We studied the prevalence and risk factors of co-morbid depression in a community-based sample of older adults, comparing Type 2 diabetic patients with healthy control subjects., Methods: A large (n=3107) community-based study in Dutch adults (55-85 years of age) was conducted. Pervasive depression was defined as a CES-D score greater than 15. Diagnosis of Type 2 diabetes was obtained from self-reports and data from general practitioners., Results: A number of 216 patients (7%) were identified as having Type 2 diabetes. The prevalence of pervasive depression was increased in people with Type 2 diabetes and co-morbid chronic disease (20%) but not in patients with Type 2 diabetes only (8%), compared with the healthy control subjects (9%). Regression analyses in diabetic patients yielded that being single, being female, having functional limitations, receiving instrumental support and having an external locus of control were associated with higher levels of depression., Conclusions/interpretation: The Results suggest that the prevalence of pervasive depression is increased in patients with Type 2 diabetes and co-morbid disease(s), but not in patients with Type 2 diabetes only. Functional limitations that often accompany co-morbid chronic disease could play an essential role in the development of depression in Type 2 diabetes. These findings can enable clinicians and researchers to identify high-risk groups and set up prevention and treatment programs.

Aims/hypothesis: Currently, three categories of cardiovascular autonomic nervous function measures are used: classic Ewing-test measures, measures of heart-rate variability (HRV), and measures of baroreflex sensitivity (BRS). Little is known about the agreement between these measures, and reference and reproducibility values for these measures have not been reported within the same group., Methods: As part of the Hoorn Study, 631 subjects aged 50 to 75 participated in a study of autonomic nervous function. Cardiac cycle duration (RR interval) and continuous finger arterial pressure were measured under three conditions: during spontaneous breathing, during six deep breaths over 1 min, and during an active change in position from lying to standing. From these readings, ten measures of autonomic function were assessed (mean heart rate, three Ewing test measures, five HRV measures and one BRS measure)., Results: Regression analysis in a healthy subgroup (n=191) showed sex differences for two of the ten measures and seven measures decreased with age. Therefore, appropriate age-specific and sex-specific reference values were calculated. Reproducibility (n=39) of most measures was moderate, with a reliability coefficient of around 50%. Agreement between the measures of autonomic nervous function varied greatly, between 0% and 87%. The HRV-power ratio measure and the blood pressure changes in the lying-to-standing test showed the lowest agreement with all other measures., Conclusion/interpretation: This study provides age-specific and sex-specific reference values for a wide range of different autonomic function measures in an elderly population. Agreement among the different measures varied widely and reproducibility was only moderate.

Aim: To explore the psychological impact of a stepwise population-screening project for Type 2 diabetes., Methods: As part of a stepwise population screening project for Type 2 diabetes in the Hoorn region, The Netherlands, an explorative interview study was conducted. The psychological impact of screening was studied using semistructured interviews in 40 subjects: 20 who were diagnosed with Type 2 diabetes, and 20 subjects who were at increased risk of having diabetes but who did not meet criteria for diabetes. Transcripts were analysed using techniques of content analysis., Results: Newly diagnosed subjects reported limited understanding of their elevated blood glucose levels. None, with the exception of one, was alarmed by the diagnosis. Having Type 2 diabetes was not experienced as severe and no concerns were expressed. Adjusting diet was perceived as a major change by some. All newly diagnosed subjects had informed close relatives and friends of the diabetes, who were in general not alarmed by the news. Both groups positively judged the screening procedure. In general the screening procedure was considered as useful and not experienced as burdensome., Conclusions: This explorative study suggests that the psychological impact of screening in newly diagnosed subjects is limited. Both those who were and those who were not diagnosed with Type 2 diabetes judged the screening procedure positively.

Context: Persons with impaired glucose tolerance (IGT) are known to have an elevated risk of developing diabetes mellitus. Less is known about diabetes risk among persons with impaired fasting glucose (IFG) or with normal glucose levels., Objective: To determine the incidence of diabetes in relation to baseline fasting and postload glucose levels and other risk factors., Design, Setting, and Participants: Population-based cohort study conducted from October 1989 to February 1992 among 1342 nondiabetic white residents of Hoorn, the Netherlands, aged 50 to 75 years at baseline, in whom fasting plasma glucose (FPG) levels and glucose levels 2 hours after a 75-g oral glucose tolerance test were measured at baseline and at follow-up in 1996-1998., Main Outcome Measures: Cumulative incidence of diabetes, defined according to the diagnostic criteria of the World Health Organization (WHO-1985 and WHO-1999) and the American Diabetes Association (ADA-1997), during a mean follow-up of 6.4 years, compared among participants with IFG, IGT, and normal glucose levels at baseline., Results: The cumulative incidence of diabetes was 6.1%, 8.3%, and 9.9% according to the WHO-1985, ADA, and WHO-1999 criteria, respectively. The cumulative incidence of diabetes (WHO-1999 criteria) for participants with both IFG and IGT was 64.5% compared with 4.5% for those with normal glucose levels at baseline. The odds ratios for diabetes (WHO-1999 criteria), adjusted for age, sex, and follow-up duration, were 10.0 (95% confidence interval [CI], 6.1-16.5), 10.9 (95% CI, 6.0-19.9), and 39.5 (95% CI, 17.0-92.1), respectively, for those having isolated IFG, isolated IGT, and both IFG and IGT. In addition to FPG and 2-hour postload glucose levels (P<.001 for both), the waist-hip ratio also was an important risk factor for developing diabetes (P =.002)., Conclusion: In this study, the cumulative incidence of diabetes was strongly related to both IFG and IGT at baseline and, in particular, to the combined presence of IFG and IGT.

Objective: To compare the risks of all-cause and cardiovascular disease (CVD) mortality in the American Diabetes Association (ADA) and World Health Organization (WHO) glucose tolerance categories after 9 years of follow-up in the Hoorn Study and to study the test-retest reproducibility of those categories., Research Design and Methods: In this population-based cohort study of 2,468 elderly men and women, subjects were classified according to both the WHO and the ADA criteria. Causes of death were extracted from the medical records. Age- and sex-adjusted relative risks were estimated by Cox's proportional hazards model. Reproducibility of the diagnostic criteria was assessed in a sample of 1,109 subjects with duplicate oral glucose tolerance tests., Results: Subjects with known diabetes had a four to five times higher risk of all-cause and CVD mortality compared with normal subjects (P<0.05). The relative risks of all-cause mortality were 1.67 (95% CI 1.09-2.57) and 1.56 (1.00-2.43) for newly diagnosed diabetic subjects according to the WHO and ADA criteria, respectively. The WHO and ADA criteria had similar levels of reproducibility The overall K was 0.59 (0.54-0.64) for WHO criteria and 0.61 (0.56-0.66) for ADA criteria. For the category of newly diagnosed diabetes according to WHO or ADA, the percentages of agreement for the second test compared with the first test were 77% (85/110) and 74% (74/100), respectively., Conclusions: Both sets of diagnostic criteria identify criteria-specific diabetic subjects with an increased mortality risk compared with normal subjects, and the reproducibility of both criteria is similar.

Aims/hypothesis: The degree of glycaemia has been shown to be associated with all-cause and cardiovascular mortality in diabetic subjects. Whether this association also exists in the general population is still controversial. We studied the predictive value of fasting plasma glucose, 2-hour post-load glucose and HbA1c in a population-based cohort of 2363 older (50-75 years) subjects, without known diabetes., Methods: Relative risks (RR) of all-cause and cardiovascular mortality were estimated by Cox proportional hazards model, adjusting for age and sex, and additionally for known cardiovascular risk factors., Results: During 8 years of follow-up, 185 subjects died; 98 of cardiovascular causes. Fasting plasma glucose was only predictive in the diabetic range, although the risks started to increase at about 6.1 mmol/l. Post-load glucose and HbA1c values were, even within the non-diabetic range, associated with an increased risk (p for linear trend < 0.05). These increased risks were mostly, but not completely, attributable to known cardiovascular risk factors. After exclusion of subjects with newly diagnosed diabetes or with pre-existent cardiovascular disease (n = 551), a 5.8 mmol/l increase of post-load glucose (corresponding to two standard deviations of the population distribution) was associated with a higher age-adjusted and sex-adjusted risk of all-cause (RR 2.24) and cardiovascular mortality (RR 3.40) (p < 0.05). After additional adjustment for known cardiovascular risk factors, these relative risks were still statistically significant, with values of 2.20 and 3.00 respectively (p < 0.05)., Conclusion/interpretation: High glycaemic variables, especially 2-h post-load glucose concentrations and to a lesser extent HbA1c values, indicate a risk of all-cause and cardiovascular mortality in a general population without known diabetes.

Objective: Leptin is thought to play a key role in the control of body weight. There is a complex interrelationship between leptin and insulin or insulin resistance, but it is unknown how leptin is regulated. We therefore explored, in a large population-based study of 2,484 Caucasian subjects aged 50-74 years, the relationship between leptin and variables of body adiposity, energy balance, and insulin resistance., Research Design and Methods: Leptin was measured by means of a radioimmunoassay. Multiple linear regression analyses were performed with leptin as dependent variable and age, sex, BMI, waist circumference, daily energy intake, physical activity, smoking, hypertension, fasting triglyceride concentrations, HDL cholesterol, fasting plasma glucose, and fasting plasma insulin concentrations as independent variables (determinants), Results: Leptin concentrations were found to be four times higher in women than in men. Effect modification between sex and potential determinants was expected, and the analyses were performed separately for women and men. BMI was the strongest determinant of leptin in women and waist circumference the strongest determinant in men. BMI, waist circumference, insulin, and triglyceride concentrations were independently and significantly (P < 0.05) associated with leptin, while inverse associations were shown for smoking and daily energy intake (borderline significance)., Conclusions: This study confirms the relationship between insulin and leptin and, in addition, suggests a relationship between triglyceride concentrations and leptin independent of sex, BMI, waist circumference, and insulin.

Aims/hypothesis: We have analysed to what extent two previously reported single nucleotide polymorphisms in the sulphonylurea receptor gene (SUR1) are associated with Type II (non-insulin-dependent) diabetes mellitus in The Netherlands. Furthermore, we estimated haplotype frequencies in control and diabetic populations, including data extracted from three other studies., Methods: Subjects with Type II diabetes (n = 388) and normoglycaemic subjects (n = 336) were randomly selected from two population-based studies, the Hoorn and Rotterdam studies. DNA was typed for variants in exon 16 (-3c-->t variant in the splice acceptor site) and exon 18 (Thr759Thr, ACC-->ACT)., Results: The genotype frequencies in both populations were similar. We observed an association of the exon 16-3t variant with Type II diabetes (allele frequencies 0.41 % vs 0.48 % in NGT and Type II diabetes, respectively, p = 0.01). There was no association between Type II diabetes and the variant in exon 18 or the combination of both variants (p > 0.5). A strong linkage disequilibrium between the exon 16 and exon 18 variants was observed in the diabetic groups but not, or less pronounced, in the control groups from the different studies. Haplotype estimation shows that several different risk haplotypes exist in different Caucasian populations., Conclusion/interpretation: The exon 16-3t allele of the SUR1 gene is associated with Type II diabetes in the Netherlands. Based on estimated haplotype frequencies in different Caucasian populations we conclude that multiple haplotypes on the SUR1 gene seem to confer a risk for developing Type II diabetes in Caucasians.

We have analyzed the association of variants in the genes for amylin, insulin receptor, insulin receptor substrate-1 (IRS-1), and coagulation factor V with type 2 diabetes mellitus. Random samples of subjects with type 2 diabetes and controls were taken from two population-based studies, the Hoorn and Rotterdam studies, to reduce the risk of artifactual associations. No association was found for variants in the genes for amylin, IRS-1, and coagulation factor V, nor was there any evidence for epistatic interactions between these gene variants. A significant difference in the frequency of the Arg972 allele of the IRS-1 gene was observed between control subjects from Hoorn and Rotterdam (9.4% vs. 18.6%; P < 0.05). The insulin receptor Met985 variant was found at frequencies of 4.4% and 1.8%, respectively, in type 2 diabetic (n = 433) and normoglycemic patients (n = 799; P < 0.02). Inclusion of data from two other studies yielded a summarized odds ratio of 1.87 (95% confidence interval, 1.06-3.29; P = 0.03). We conclude that the association between the Met985 variant in the insulin receptor gene and type 2 diabetes, which we previously reported in the Rotterdam study, is supported by thejoint analysis with a second population-based study and other studies. The large regional differences in allele frequency of the Arg972 allele of IRS-1 gene makes genetic association studies of this gene less reliable.

Objective: To develop a predictive model to identify individuals with an increased risk for undiagnosed diabetes, allowing for the availability of information within the health care system., Research Design and Methods: A sample of participants from the Rotterdam Study (n = 1,016), aged 55-75 years, not known to have diabetes completed a questionnaire on diabetes-related symptoms and risk factors and underwent a glucose tolerance test. Predictive models were developed using stepwise logistic regression analyses with the absence or presence of newly diagnosed diabetes as the dependent variable and various items with a plausible connection to diabetes as the independent variables. The models were evaluated in another Dutch population-based study, the Hoorn Study (n = 2,364), in which the participants were aged 50-74 years. Performances of the predictive models were compared by using receiver-operator characteristics (ROC) curves., Results: We developed three predictive models (PMs), PM1 contained information routinely collected by the general practitioner, while PM2 also contained variables obtainable by additional questions. The third predictive model, PM3, included variables that had to be obtained from a physical examination. These latter variables did not have additive predictive value, resulting in a PM3 similar to PM2. The area under the ROC curve was higher for PM2 than for PM1, but the 95% Cls overlapped (0.74 [0.70-0.78] and 0.68 [0.64-0.72], respectively)., Conclusions: Using only information normally present in the files of a general practitioner, a predictive model was developed that performed similarly to one supplemented by information obtained from additional questions. The simplicity of PM1 makes it easy to implement in the current health care setting.

Objective: Recently, the American Diabetes Association (ADA) introduced new diagnostic criteria. These new criteria are based on fasting plasma glucose levels, avoiding the burdensome oral glucose tolerance test (OGTT). We compared the 1997 ADA criteria with the 1985 World Health Organization (WHO) criteria with respect to the prevalence of diabetes and the cardiovascular risk profile in the population of the Hoorn Study, Research Design and Methods: The Hoorn Study is a population-based survey of 2,484 men and women, aged 50-75 years. An OGTT was performed and cardiovascular risk factors were determined in 2,378 subjects without known diabetes. Subjects were categorized according to both sets of diagnostic criteria., Results: Although the prevalence of diabetes was similar for both sets of criteria, 47 of 120 (39.2%) subjects who were diagnosed with diabetes according to the 1997 ADA criteria were not classified as having diabetes when using the 1985 WHO criteria. Similarly, of 285 subjects diagnosed with impaired fasting glucose by the 1997 ADA criteria, 195 (68.4%) were classified as having normal glucose tolerance by the 1985 WHO criteria. The overall agreement was poor (kappa 0.33; 95% CI 0.28-0.38). Subjects who were diagnosed as having diabetes by either set of criteria had an adverse cardiovascular risk profile, which was between the cardiovascular risk profiles of concordant normal and concordant diabetic subjects., Conclusions: In this study both sets of criteria diagnosed a similar number of diabetic subjects, but many of the subjects shifted between glucose intolerance categories. With either set of criteria, a considerable number of subjects at risk of developing diabetes and subjects carrying an increased risk of cardiovascular disease, as reflected by an adverse cardiovascular risk profile, will be missed.

Low heart rate variability is associated with high risk of sudden death in myocardial infarction patients. This has been attributed to unfavorable autonomic cardiac control. In the present study, the predictive value of heart rate variability for sudden death, mortality from coronary heart disease, and from all causes was investigated in the general population, using brief electrocardiographic recordings. From 1960 to 1985, 878 middle-aged Dutch men, aged 40-60 years, were followed and repeatedly examined as part of the Zutphen Study. In 1985 the remaining cohort was extended to 885 elderly men, aged 65-85 years, and followed until 1990. Heart rate variability (standard deviation of duration of normal RR intervals) was determined from the resting 12-lead electrocardiogram. The 5-year age-adjusted relative rate of total mortality of men with heart rate variability of < 20 milliseconds (msec) compared with men with heart rate variability of 20-39 msec was 2.1 (95 percent confidence interval 1.4-3.0) in middle-aged men and 1.4 (95% confidence interval 0.9-2.2) in elderly men. Death from noncoronary causes, especially cancer, contributed significantly to this elevated risk. The association of low heart rate variability with sudden death or coronary heart disease mortality was less consistent. In conclusion, in middle-aged men and probably in elderly men, low heart rate variability is predictive of mortality from all causes. This suggests that low heart rate variability is an indicator of compromised health in the general population.

Prolongation of heart rate-adjusted QT length (corrected QT interval [QTc]) is associated with elevated risk of coronary heart disease and sudden death. This may have to do with autonomic cardiac control. Because insulin is known to stimulate sympathetic activity, we studied the association of insulin level and glucose tolerance with QTc. In 1990, 383 elderly men 70-89 years of age without previous myocardial infarctions or known diabetes had a 12-lead electrocardiogram recorded and glucose tolerance determined in the frame of an ongoing follow-up study. QTc was significantly associated with fasting glucose, insulin, and C-peptide and glucose levels 60 and 120 min after an oral glucose load. For fasting C-peptide and the area under the glucose curve (AUGC), this association could not be explained by the concomitant occurrence of other risk factors of coronary heart disease. Furthermore, fasting C-peptide and the AUGC were independently additive predictors of QTc duration. The difference in QTc between men in the extreme quintiles of both variables was 22 ms. QTc prolongation seems to be part of the insulin resistance syndrome. The association may be explained by increased sympathetic activity induced by high insulin levels. An additional explanation could be an effect of high insulin, impaired glucose utilization, or both on membrane activity of myocardial cells.

The Cardiac Infarction Injury Score (CIIS), based on electrocardiographic characteristics, was developed as a measure to determine the presence of myocardial infarctions. In the present study the association of the CIIS with coronary morbidity and mortality was investigated among middle-aged and elderly men. A cohort of 877 men, born between 1900 and 1919, was followed and repeatedly examined from 1960 onwards. In 1985 the remaining cohort was extended to 836 elderly men from the same birth cohort, and followed until 1990. In both middle-aged and elderly men with high CIIS the prevalence of (silent) previous myocardial infarction and the occurrence of ST-T abnormalities were increased. Five-year relative risks of men with CIIS 20 or more relative to men with CIIS < 5 were 2.2 (95% confidence interval: 1.2-4.1) for angina pectoris, 2.4 (1.4-4.0) for myocardial infarction and 5.8 (3.4-9.9) for coronary heart disease death. Thus, the CIIS is associated with risk of coronary heart disease in apparently healthy middle-aged as well as elderly men.

Objectives: This study evaluated the predictive value of T wave amplitude and ST segment level on lead I for angina pectoris, a first myocardial infarction, sudden death and coronary heart disease death in middle-aged and elderly men., Background: Certain ST-T wave characteristics may reflect favorable autonomic cardiac control. Slight ST segment elevation has been reported to indicate a low risk of coronary heart disease mortality., Methods: A total of 876 men, born between 1900 and 1920, participated in periodic medical examinations and were followed up with respect to morbidity and mortality from 1960 to 1985. In 1985, the remaining cohort was extended to 836 elderly men from the same birth cohort who were followed up until 1990. Relative risks in categories of T wave amplitude and ST segment level were estimated by survival analysis., Results: Both middle-aged and elderly men with T wave amplitudes > or = 0.15 mV had a lower risk of myocardial infarction, coronary heart disease death and sudden death than men with T wave amplitudes 0.05 to 0.15 mV. The adjusted relative risk of coronary heart disease death was 0.5 (95% confidence interval [CI] 0.2 to 1.0); in men with T wave amplitude < or = 0.05 mV, relative risk was 2.0 (95% CI 1.3 to 3.1). Slight ST segment elevation was also associated with decreased risk: relative risk 0.5 (95% CI 0.3 to 1.0) compared with the isoelectric ST segment level. In men with ST segment depression, relative risk was 2.2 (95% CI 1.4 to 3.4). The association of T wave amplitude and ST segment level were independent of each other., Conclusions: In addition to the elevated risk of coronary heart disease that is associated with ST-T wave abnormalities, we observed that normal variations in repolarization characteristics are predictive of future heart disease.

Background: Heart-rate-adjusted QT-interval (QTc) is prognostic of sudden death in myocardial infarction patients. So far, population studies have yielded conflicting results on the predictive value of QTc for coronary heart disease morbidity and mortality. Therefore, we investigated this in a longitudinal study of middle-aged and elderly men., Methods and Results: From 1960 to 1985, 877 middle-aged men were followed and repeatedly examined in the Zutphen Study. In 1985 the remaining cohort was extended to 835 elderly men from the same birth cohort and followed until 1990. Men with prolonged QTc (420 ms1/2 or more) had a higher risk of myocardial infarction and coronary heart disease death relative to men with QTc less than 385 ms1/2. Age-adjusted coronary heart disease mortality rate ratios were 4.3 (95% confidence interval, 1.3 to 13.8) in middle-aged men and 3.3 (95% confidence interval, 1.0 to 11.6) in elderly men. These associations could not be attributed to prevalent heart disease and were independent of other cardiovascular risk factors., Conclusions: These results indicate that within the normal range of QTc in the general population, men with long QTc are at higher risk for coronary heart disease. Because QTc is easily determined, it may provide a valuable contribution to risk stratification.

Multivariate analysis in case-base designs depends on approximate methods. In the present study, new pseudo-likelihood methods are developed for this design. With these methods, the case-cohort risk ratio and rate ratio as well as their standard errors are easily estimated using logistic regression and Poisson regression, respectively. This is illustrated by the association between hypertension and cardiovascular mortality in a cohort, estimated by case-cohort analysis, using samples of several sizes. The estimates are compared with those obtaining in full-cohort and nested case-control designs. The results indicate that these methods, which require nothing but widely available computer software, are valid. The case-cohort design, therefore, is a good, sometimes even advantageous alternative to the nested case-control design, in studying a disease that is not very rare. Application of the risk ratio method to the full cohort, using a 'sample' of 100 per cent follows logically; whenever the true risk ratio is desired instead of the odds ratio, a multivariate model for its estimation is therefore available.

The association between serum total cholesterol and cancer mortality was investigated in a 28-year follow-up study of 3,091 Dutch civil servants aged 40-65 years and their spouses. After adjustment for age, body mass index, and smoking, an inverse association between serum total cholesterol and all-cancer mortality was observed in men during the first 15 years of follow-up, excluding the first 2 years: The multivariate rate ratio of those in the lowest cholesterol quintile compared with those in the highest quintile was 2.1 (95% confidence interval (Cl) 1.1-4.0); this association was accounted for mainly by gastrointestinal cancers (RR = 4.2, 95% Cl 1.4-12.9). For follow-up years 16-28, the multivariate rate ratio for all-cancer mortality was 0.8 (95% Cl 0.5-1.40. In women, no consistent association between serum total cholesterol and cancer was observed. After the first 5 years of follow-up were excluded, the significant inverse association in men still persisted. These results suggest that in this study population, low serum cholesterol seems not to be attributable to undetected cancer, but might be a risk factor for cancer mortality in men.

Objective: To investigate the prognostic value of frequently occurring slight variations in the ST segment for cardiovascular mortality in healthy subjects., Design: Follow up study of mortality in relation to variations in ST segment level in a cohort over the 28 years from 1953 to 1981. A case-cohort sampling design was applied to limit the number of electrocardiograms that had to be coded by hand., Setting: General health examination carried out in 1953 of civil servants in Amsterdam and assessment of subsequent mortality., Subjects: Apparently healthy civil servants aged 40 to 65 years: 1583 men and 1508 women., Main Outcome Measures: Relative risk of variations in ST segment level for mortality from all causes, cardiovascular disease, and coronary heart disease., Results: In men the multivariate relative risks of 15 year mortality from cardiovascular disease and coronary heart disease of slight ST elevation at 80 ms past the J point (compared with isoelectric ST segment) were 0.5 (95% confidence interval 0.3 to 0.9) and 0.4 (0.2 to 0.8), respectively. As expected, ST segment depression (greater than 0.25 mm) was associated with increased risk: 1.9 (1.1 to 3.0) and 2.2 (1.2 to 3.9), respectively. In women associations were weaker. The full 28 year period showed a similar pattern of somewhat weaker associations for men; among women, however, no predictive value was apparent., Conclusion: These results are empirical evidence for the intuitive opinion among doctors that a curved, upward sloping ST segment, resulting in slight ST elevation at 80 ms, indicates low risk compared with the isoelectric flat, stretched ST segment.

Data obtained from a general health examination in 1953-1954 of 2605 middle-aged Dutch civil servants were analysed to investigate the relation between dietary calcium and cardiovascular (CVD) and coronary heart disease (CHD) mortality. Calcium intake was assessed at baseline by a 1-week food frequency recall. Multivariate adjusted odds ratios (OR) were calculated using the highest quintile of calcium intake as the reference. No statistically significant associations were observed for low calcium intake in 15 and 28 years of follow-up in both men and women. For men, multivariate adjusted OR for the lowest quintile of calcium intake were 1.3 (95% confidence interval (CI): 0.8-1.9) and 0.9 (95% CI: 0.6-1.6) for 28-year CVD and CHD mortality, respectively. For women, corresponding OR were 1.1 (95% CI: 0.6-2.0) and 1.1 (95% CI: 0.5-2.5). Although an inverse association between calcium intake and CVD and CHD mortality, possibly mediated by blood pressure, might be hypothesized, no clear association was observed. Because dietary patterns in the 1950s were quite stable, and major calcium sources were addressed, misclassification of calcium intake may not be fully responsible for this finding.

Background: In myocardial infarction patients, heart rate-adjusted QT interval (QTc), an electrocardiographic indicator of sympathetic balance, is prognostic for survival., Methods and Results: In a 28-year follow-up, the association between QTc and all-cause, cardiovascular, and ischemic heart disease mortality was studied in a population of 3,091 apparently healthy Dutch civil servants and their spouses, aged 40-65 years, who participated in a medical examination during 1953-1954. Moderate (QTc, 420-440 msec) and extensive (QTc, more than 440 msec) QTc prolongations significantly predict all-cause mortality during the first 15 years among men (adjusted respective relative risks [RRs], 1.5 and 1.7) and among women (RRs, 1.7 and 1.6). In men, cardiovascular (RRs, 1.6 and 1.8) and ischemic heart disease mortality (RRs, 1.8 and 2.1) mainly account for this association. In women, the association cannot be attributed specifically to cardiovascular and ischemic heart disease mortality. RRs for a subpopulation without any sign of heart disease at baseline are similar. The same is observed for QTc prolongation after light exercise, although in this situation most associations are not statistically significant, probably because of smaller numbers in the QTc prolongation categories., Conclusions: Our results suggest that QTc contributes independently to cardiovascular risk. If autonomic imbalance is an important mechanism, it might be speculated that changes in life-style (e.g., with regard to physical exercise and smoking) may have a preventive impact.