Routine screening for Coxiella burnetii infection during pregnancy: a clustered randomised controlled trial during an outbreak, the Netherlands, 2010.

Between 2007 and 2010, the Netherlands experienced one of the largest outbreaks of Q fever. Since asymptomatic Coxiella burnetii infection has been associated with maternal and obstetric complications, evidence about the effectiveness of routine screening during pregnancy in outbreak areas is needed. We performed a clustered randomised controlled trial during the Dutch outbreak, in which 55 midwife centres were randomised to recruit pregnant women for an intervention or control strategy. In both groups a serum sample was taken between 20 and 32 weeks of gestation. In the intervention group (n=536), the samples were analysed immediately by indirect immunofluorescence assay for the presence of IgM and IgG (phase I/II) and treatment was given during pregnancy in case of an acute or chronic infection. In the control group (n=693), sera were frozen for analysis after delivery. In both groups 15% were seropositive. In the intervention group 2.2% of the women were seropositive and had an obstetric complication, compared with 1.4% in the control group (Odds ratio: 1.54 (95% confidence interval 0.60-3.96)). During a large Q fever outbreak, routine C. burnetii screening starting at 20 weeks of gestation was not associated with a relevant reduction in obstetric complications and should therefore not be recommended.

Determinants of HbA1c in nondiabetic Dutch adults: genetic loci and clinical and lifestyle parameters, and their interactions in the Lifelines Cohort Study.

OBJECTIVES: Glycated haemoglobin (HbA1c) is associated with cardiovascular disease risk in individuals without diabetes, and its use has been recommended for diagnosing diabetes. Therefore, it is important to gain further understanding of the determinants of HbA1c. The aim of this study was to investigate the effects of genetic loci and clinical and lifestyle parameters, and their interactions, on HbA1c in nondiabetic adults. DESIGN: Population-based cohort study. SETTING: Three northern provinces of the Netherlands. SUBJECTS: A total of 2921 nondiabetic adults participating in the population-based LifeLines Cohort Study. MEASUREMENTS: Body mass index (BMI), waist circumference, HbA1c, fasting plasma glucose (FPG) and erythrocyte indices were measured. Data on current smoking and alcohol consumption were collected through questionnaires. Genome-wide genotyping was performed, and 12 previously identified single-nucleotide polymorphisms (SNPs) were selected for replication and categorized as 'glycaemic' and 'nonglycaemic' SNPs according to their presumed mechanism(s) of action on HbA1c. Genetic risk scores (GRSs) were calculated as the sum of the weighted effect of HbA1c-increasing alleles. RESULTS: Age, gender, BMI, FPG, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, current smoking and alcohol consumption were independent predictors of HbA1c, together explaining 26.2% of the variance in HbA1c, with FPG contributing 10.9%. We replicated three of the previously identified SNPs and the GRSs were also found to be independently associated with HbA1c. We found a smaller effect of the 'nonglycaemic GRS' in females compared with males and an attenuation of the effect of the GRS of all 12 SNPs with increasing BMI. CONCLUSIONS: Our results suggest that a substantial portion of HbA1c is determined by nonglycaemic factors. This should be taken into account when considering the use of HbA1c as a diagnostic test for diabetes.

The influence of maternal and paternal factors on time to pregnancy--a Dutch population-based birth-cohort study: the GECKO Drenthe study.

BACKGROUND: Both maternal and paternal factors have been suggested to influence a couple's fecundity. To investigate this, we examined the role of several maternal and paternal lifestyle and socio-demographic factors as determinants of time to pregnancy (TTP) in a Dutch birth-cohort. METHODS: Groningen Expert Center for Kids with Obesity (GECKO) Drenthe is a population-based birth-cohort study of children born between April 2006 and April 2007 in Drenthe, a province of The Netherlands. Both partners received extensive questionnaires during pregnancy. Univariable and multivariable Cox regression analyses were used to determine the impact of the investigated factors on TTP. RESULTS: A total of 4778 children were born, and the parents of 2997 children (63%) gave their consent to participate. After excluding unintended pregnancies and pregnancies as a result of fertility treatment, the data of 1924 couples were available for analysis. Hazards ratios and 95% confidence intervals of factors influencing TTP in multivariable Cox regression analysis were: maternal age 1.23 (0.98-1.54) for age <25 years, 1.17 (1.03-1.32) for age 25-30 years and 0.72 (0.61-0.85) for age >35 years (reference category: 30-35 years); paternal age: 1.31 (0.94-1.82) for age <25 years, 1.11 (0.97-1.28) for age 25-30 years and 0.91 (0.80-1.04 for age >35 years (reference category: 30-35 years); nulliparity: 0.76 (0.68-0.85) versus multiparity; menstrual cycle length: 1.12 (0.95-1.30) for 3 weeks, 0.72 (0.62-0.83) for 4-6 weeks, 0.68 (0.40-1.16) for >6 weeks and 0.66 (0.54-0.81) for irregular cycle (reference category: 4 weeks); prior contraceptive use: 0.78 (0.67-0.91) for no contraception, 1.68 (1.45-1.95) for condom use, 1.08 (0.89-1.33) for condom use combined with oral contraception, 1.40 (1.16-1.70) for intrauterine device and 0.50 (0.25-1.01) for contraceptive injection (reference category: oral contraception); and maternal educational level 0.75 (0.62-0.92) for low education level and 0.81 (0.73-0.90) for medium educational level (reference category: high educational level). CONCLUSIONS: This population-based birth-cohort study performed in fertile couples who had conceived revealed neither maternal nor paternal modifiable lifestyle factors were significantly associated with TTP after adjustment for confounding by socio-demographic factors. In contrast, several non-modifiable maternal socio-demographic factors are significant predictors of a couple's fecundity.

Maternal and paternal transmission of type 2 diabetes: influence of diet, lifestyle and adiposity.

OBJECTIVE: Transmission of family history of type 2 diabetes to the next generation is stronger for maternal than paternal diabetes in some populations. The aim of the present study was to investigate whether this difference is explained by diet, lifestyle factors and/or adiposity. METHODS: We analysed 35174 participants from the Dutch contribution to the European Prospective Investigation into Cancer and Nutrition, a prospective population-based cohort (aged 20-70 years) with a median follow-up of 10.2 years. Parental history of diabetes was self-reported. Occurrence of diabetes was mainly identified by self-report and verified by medical records. RESULTS: Amongst 35174 participants, 799 incident cases of diabetes were observed. In age- and sex-adjusted analyses, hazard ratio (HR) and 95% confidence intervals (CIs) for diabetes by maternal and paternal diabetes were 2.66 (2.26-3.14) and 2.40 (1.91-3.02), respectively. Maternal transmission of risk of diabetes was explained by diet (9.4%), lifestyle factors including smoking, alcohol consumption, physical activity and educational level (7.8%) and by adiposity, i.e. body mass index and waist and hip circumference (23.5%). For paternal transmission, the corresponding values were 2.9%, 0.0% and 9.6%. After adjustment for diet, lifestyle factors and adiposity, the HRs for maternal (2.20; 95% CI, 1.87-2.60) and paternal (2.23; 95% CI, 1.77-2.80) transmission of diabetes were comparable. CONCLUSIONS: Both maternal and paternal diabetes are associated with increased risk of type 2 diabetes, independently of diet, lifestyle and adiposity. The slightly higher risk conferred by maternal compared to paternal diabetes was explained by a larger contribution of diet, lifestyle factors and adiposity.

Cardiometabolic treatment decisions in patients with type 2 diabetes: the role of repeated measurements and medication burden.

PURPOSE: Clinical guidelines for cardiometabolic risk management indicate a simple threshold-based strategy for treatment, but physicians and their patients may be reluctant to modify drug treatment after a single elevated measurement. We determined how repeated measurements of blood pressure, cholesterol and haemoglobin A1c affect general practitioners' decisions to start or intensify medication in patients with type 2 diabetes. We also evaluated whether medication burden altered these decisions. METHODS: We conducted a cohort study in 3029 patients managed by 62 general practitioners (GPs). We assessed the predictive value of the last risk factor measurement, the number of successive measurements above target level and the percentage change between the last two measurements. Medication burden was assessed as the number of drugs concurrently used. Effects on treatment decisions were estimated by multilevel logistic regression analysis, correcting for clustering at GP level. RESULTS: Repeated high levels of diastolic blood pressure increased the likelihood to start antihypertensive medication (OR=2.08, CI 1.37 to 3.17). Repeated high haemoglobin A1c levels affected intensification of oral glucose-lowering medication (OR=1.71, CI 1.44 to 2.03). Modification of lipid-lowering medication was limited, and only affected by the last total cholesterol level. Starting treatment for all three risk factors, as well as intensifying antihypertensive treatment, was more likely in patients already using more drugs for other chronic diseases. CONCLUSIONS: Waiting for the next measurement before deciding to change medication can explain in part the apparent undertreatment for hypertension and hyperglycaemia, but not for hypercholesterolaemia. Medication burden was not a barrier for treatment modification.

Non-alcoholic fatty liver disease is associated with cardiovascular disease risk markers.

Recognition of the link between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) has boosted research in this area. The main objective of this paper is to review the literature on NAFLD in the context of CVD, focussing on underlying mechanisms and treatment. Besides excessive fatty acid influx, etiologic factors may include components of the metabolic syndrome, cytokines and mitochondrial dysfunction. NAFLD is associated with both hepatic and systemic insulin resistance. In the case of NAFLD, the liver overproduces several atherogenic factors, notably inflammatory cytokines, glucose, lipoproteins and coagulation factors, and factors increasing blood pressure. Intervention studies on diet and laparoscopic surgery revealed improvements of hepatic fat content and CVD risk profile. Pharmacological approaches with potential benefit have been developed as well, but effects are often confounded by weight change. NAFLD is associated with an increased CVD risk profile (and hepatic risk). In order to improve CVD risk profile, prevention and treatment of NAFLD seem advisable. However, well-designed intervention studies, randomized clinical trials and long-term follow-up studies are scarce.

Acute lymphoblastic leukemia and obesity: increased energy intake or decreased physical activity?

BACKGROUND: Obesity is a well-known problem in children with acute lymphoblastic leukemia (ALL), and it might be the result of an excess in energy intake, reduced energy expenditure, or both. The aim of this study is to describe energy intake and physical activity during treatment for ALL with intermittent dexamethasone (DEXA). METHODS: Body mass index (BMI), energy intake, and physical activity were measured in 16 ALL patients on maintenance treatment and in 17 healthy controls. ALL patients were measured during ("on DEXA") and in between ("off DEXA") DEXA treatments. RESULTS: In patients, the mean increase in BMI z-score was 1.4 +/- 1.1. Energy intake on DEXA was higher (2,125.9 +/- 476.0 vs 1,775.1 +/- 426.1 kcal/24 h, p < 0.05) and energy intake off DEXA was lower (1,305.0 +/- 249.4 vs 1,775.1 +/- 426.1 kcal/24 h, p < 0.05), compared to healthy controls. Physical activity on DEXA was lower compared to healthy controls (30.0 +/- 3.9 vs 40.0 +/- 6.0 kcal kg(-1) 24 h(-1), p < 0.001 and 7,303.1 +/- 4,622.9 vs 13,927.2 +/- 3,822.7 steps, p < 0.05). Physical activity off DEXA was not different compared to healthy controls. CONCLUSION: Weight gain in patients on ALL treatment might be owing to increased energy intake and decreased physical activity during treatment with DEXA.

Low yield of population-based screening for Type 2 diabetes in the Netherlands: the ADDITION Netherlands study.

BACKGROUND: About 10 years ago, it was estimated that half of all people with diabetes were unrecognized. Since then, according to the national guidelines, case finding for diabetes in general practice has become common in the Netherlands, resulting in a substantial increase of the prevalence of known diabetes. Nevertheless, the need for population-based screening is advocated, especially by the national federation of diabetes patients. OBJECTIVE: To evaluate the efficiency of population-based screening for Type 2 diabetes. METHODS: From 2002 to 2004, we performed a four-step screening procedure [questionnaire, random glucose measurement, fasting glucose measurement and oral glucose tolerance test (OGTT)] and a three-step procedure (without random glucose measurement) in 79 general practices in the southwestern region of the Netherlands. RESULTS: A total of 56 978 non-diabetic subjects, aged 50-70 years, were asked to complete the questionnaire. Those with a score above threshold underwent further glucose testing. Eventually, 586 participants (1.0%) were diagnosed with Type 2 diabetes (in four-step procedure 285 subjects and in three-step procedure 301). Impaired glucose regulation was assessed in 1011 participants (1.8%). Dropout rate in the screening programme among participants who should undergo an OGTT was 23.4%. The risk score was higher if glucose metabolism was more disturbed. CONCLUSION: In the Netherlands, the yield of population-based screening is low. The dropout among high-risk individuals was high. Given the decreasing prevalence of undiagnosed diabetes and the possibility of opportunistic screening on a continuous basis, opportunistic screening for diabetes might be more appropriate than population-based screening. Further research on this topic is needed.

Angiographic distribution of lower extremity atherosclerosis in patients with and without diabetes.

AIMS: To determine differences in the anatomic site of atherosclerosis in the lower extremity between patients with and patients without diabetes. DESIGN: Cross-sectional study of patients who underwent angiography of both legs because of symptoms of intermittent claudication, rest and/or night pain, ulceration or gangrene. METHODS: The angiographies of 37 patients with diabetes and 37 patients without diabetes, matched for age, sex and smoking behaviour, were evaluated using the Bollinger scoring system. RESULTS: The mean (sd) Bollinger score in the upper leg (from the abdominal aorta to and including the superficial femoral artery) was higher (P = 0.01) for patients without diabetes (35.3 (22.8)) than for patients with diabetes (23.3 (16.1)). In the lower leg (from the popliteal artery to the posterior tibial artery) patients with diabetes tended to have a higher score than patients without diabetes: 47.4 (34.2) and 37.6 (32.9), respectively (P = 0.22). CONCLUSION: This angiographic study confirms the clinical notion that lower limb atherosclerosis in diabetes is more severe in distal segments of the lower extremity, while the proximal segments remain less attenuated compared with patients without diabetes.

Primary and secondary prevention in cardiovascular disease: an old-fashioned concept?

OBJECTIVE: Is the concept of primary and secondary cardiovascular prevention an old-fashioned concept that needs to be re-defined? DESIGN: Discussion paper. RESULTS: Cardiovascular prevention means reduction of absolute risk for cardiovascular disease (CVD), irrespective of clinical stage. CONCLUSION: For the calculation of an individual probability to develop CVD all factors that contribute to the risk must be taken into account, including previous CVD events.

Cytokine secretion is impaired in women with diabetes mellitus.

BACKGROUND: As women with diabetes mellitus (DM) have an increased prevalence of asymptomatic bacteriuria (ASB) and it is known that a correlation exists between the increased prevalence of genitourinary tract infection and impaired cytokine production in women infected with Human Immunodeficiency Virus (HIV), we studied urinary cytokine excretion in diabetic women and compared it with that of nondiabetic controls. MATERIALS AND METHODS: To evaluate the cytokine secretion capacity of women with DM, both whole blood and isolated monocytes of women with and without DM were stimulated in vitro with lipopolysaccharide (LPS). RESULTS: Lower urinary interleukin-8 (IL-8) and interleukin-6 (IL-6) concentrations (P = 0.1 and P < 0.001, respectively) were found in diabetic women than in nondiabetic controls. A lower urinary leukocyte cell count correlated with lower urinary IL-8 and IL-6 concentrations (P < 0.05). Lower tumour necrosis factor-alpha (TNF-alpha) and IL-6, but comparable interleukin-10 (IL-10) concentrations were found in whole blood (P < 0.04) and isolated monocytes (P = 0.03) of women with DM type 1 compared to women without DM. CONCLUSIONS: Diabetic women with ASB have lower urinary IL-6 concentrations than nondiabetic bacteriuric controls. In addition, monocytes of women with DM type 1 secrete lower pro-inflammatory cytokines after stimulation with LPS than monocytes of women without DM. This is not due to an inhibitory effect of the anti-inflammatory cytokine IL-10. This can have important consequences for both host defense, endothelial cell functioning and atherogenesis.

Management of type 2 diabetes: a challenge for patient and physician.

Type 2 diabetes mellitus is a chronic disease, associated with serious complications and co-morbidity and considerable costs. The number of people with diabetes mellitus is expected to increase with 40% in the next decade, due to prolonged life expectancy, the ageing of the population and developments in the health care sector, including more active screening strategies. The majority (40-60%) of type 2 diabetes patients in routine GP practice have a poor metabolic control (HbA1c > 8% or fasting blood glucose > 11 mmol/l). In this paper the obstacles in routine clinical practice for optimal type 2 diabetes care are discussed. Long-term complications are the major cause of morbidity and mortality in type 2 diabetes patients. Therefore, the primary aim of type 2 diabetes management is the prevention of complications, by lowering blood glucose levels and reducing the cardiovascular risk profile. An important component of type 2 diabetes management is an active role of the patient: diet, smoking habits, physical exercise and self-care behavior often need to change. In addition, the patient has to adhere to life long medical therapy. Motivating the patient for this active role is the challenge for health care providers. A complicating factor is that changes in lifestyle do not give immediate benefit for the patient, as the effects are seen in the reduction of the development of long-term complications. The cornerstones of health care to support active patient participation are: to guarantee the continuity of care, to integrate education in health care and to encourage the patient's attendance. It is the challenge for physicians to give type 2 diabetes patients the tools for active participation in the management of the disease.

Incidence and determinants of mortality and cardiovascular events in diabetes mellitus: a meta-analysis.

Patients with diabetes mellitus are at increased risk of developing atherosclerotic disease. The extent of this additional risk and its determinants are not well known, but this information is needed for sample-size estimations in intervention studies. Therefore, a meta-analysis of epidemiologic studies on this subject was performed. Medline was searched from 1966 onwards, including the reference lists of all relevant publications. A total of 27 prospective follow-up studies in the English language that allowed calculation of the unadjusted incidence of one of the predefined outcome events were included. The influence of age, sex, type of diabetes, duration of diabetes, year of study, HbA1c, cholesterol level, blood pressure and smoking on these incidences was studied by means of univariate Poisson regression analysis. Overall total mortality was 2.9% per year (95% CI 2.8-3.0; 27 studies), and for death from all vascular causes was 1.4% per year (95% CI 1.3-1.4; 16 studies). Only two studies were found that reported on the incidence of the composite outcome 'event death from all vascular causes, non-fatal myocardial infarction, or non-fatal stroke'. In univariate analysis, age, year of study, total cholesterol and systolic blood pressure were positively related to total mortality and death from all vascular causes. After adjustment for age, or limiting the analyses to studies in patients with type 2 diabetes only (n = 11), these relationships remained statistically significant. In conclusion, the overall yearly total mortality in diabetes mellitus is 2.9% and for death from all vascular causes is 1.4%. There are few data on the incidence of composite cardiovascular outcome events.

Physical activity in elderly subjects with impaired glucose tolerance and newly diagnosed diabetes mellitus.

The authors carried out a study to investigate the association between different indicators of physical activity and the prevalence of impaired glucose tolerance (IGT) and newly diagnosed diabetes (nDM) in a population-based cohort of elderly men and women in the Netherlands. A sample of participants of the Rotterdam Study (n = 1,016) aged 55-75 years who were not known to have diabetes mellitus underwent an oral glucose tolerance test. Physical activity was assessed by means of a self-administered questionnaire and expressed as time spent on activities per week. Associations with the prevalence of IGT and nDM were assessed by logistic regression analysis after adjustment for age, body mass index, waist-hip ratio, family history of diabetes, and smoking. A total of 745 subjects had normal glucose tolerance, 153 IGT, and 118 nDM. The total amount of time spent on physical activity decreased with increasing glucose intolerance. Adjusted for main confounders, vigorous activities such as bicycling (men: odds ratio (OR) = 0.26, 95% confidence interval (CI) 0.14-0.49; women: OR = 0.37, 95% CI 0.18-0.78) and sports (men: OR = 0.28, 95% CI 0.11-0.74) showed an inverse association with the presence of nDM. For IGT, the associations pointed in the same direction but did not reach statistical significance. These results indicate that physical inactivity and glucose intolerance are associated among older adults similar to the way they are associated among middle-aged adults.

Discontinuation of prophylaxis for Pneumocystis carinii pneumonia in HIV-1-infected patients treated with highly active antiretroviral therapy.

BACKGROUND: Prophylactic drugs for Pneumocystis carinii pneumonia (PCP) are strongly recommended for HIV-1-infected patients with CD4 cell counts of less than 200 cells/microL. Because of the highly active antiretroviral therapy (HAART) currently available, we speculated that prophylaxis can be discontinued in patients with CD4 cell counts of more than 200 cells/microL. METHODS: In this prospective observational study, PCP prophylaxis (primary or secondary) was discontinued in HIV-1-infected patients whose CD4 cell count had increased above 200 cells/microL (documented twice with an interval of at least 1 month) as a result of HAART. Patients and their CD4 cell counts were monitored every 3 months. The primary endpoint of the study was the occurrence or reoccurrence of PCP. FINDINGS: 78 patients were enrolled: 62 patients were receiving prophylaxis for primary prevention of PCP and 16 patients for secondary prevention of PCP. At the time of discontinuation of prophylaxis, the mean CD4 cell count was 347 cells/microL, and HIV-1-RNA was not detectable in 61 patients. The lowest mean CD4 cell count during prophylaxis was 79 cells/microL. Patients stopped prophylaxis 9.8 (SD 6.4) months after they started HAART. The mean follow-up after discontinuation of prophylaxis was 12.7 (SD 7.6) months, and none of the patients developed PCP (97.5% one-sided CI 0-4.4%). INTERPRETATION: The preliminary results of this study indicate that PCP prophylaxis can be stopped safely in HIV-1-infected patients whose CD4 cell counts have increased above 200 cells/microL after treatment with HAART.

[What are the consequences of the new American guidelines for the diagnosis of diabetes mellitus in The Netherlands?]. / Wat zijn de gevolgen van nieuwe Amerikaanse richtlijnen voor de diagnostiek van diabetes mellitus voor Nederland?

The American Diabetes Association (ADA) recently issued new guidelines for classification and diagnosis of diabetes mellitus. The main change is the decrease of the liminal value of the fasting plasma glucose level from 7.8 to 7.0 mmol/l. A fasting level of 6.1-6.9 mmol/l indicates impaired glucose tolerance (which eliminates the category 'impaired glucose tolerance', which was established on the basis of a slightly increased 2-hour glucose level after ingestion of 75 g glucose). Consequently, the ADA criteria render the oral glucose tolerance test (GTT) redundant for clinical practice. Given these criteria, the prevalence of diabetes mellitus among the general Dutch population will change only slightly, but the number of persons to be classified in a different category after their introduction is considerable: 39.2% of the ADA diabetics are not diabetics according to the current WHO classification, while 38.1% of the WHO diabetics are not diabetics according to the ADA criteria. The criteria established by the ADA accommodate clinical practice, in which the GTT is hardly used anymore. The WHO still has to decide about whether or not accepting the ADA guidelines.

A polymorphism in the glucocorticoid receptor gene may be associated with and increased sensitivity to glucocorticoids in vivo.

We investigated whether a polymorphism at nucleotide position 1220, resulting in an asparagine-to-serine change at codon 363 in the glucocorticoid receptor (GR) gene is associated with an altered sensitivity to glucocorticoids. In a group of 216 elderly persons, 13 heterozygotes for the N363S polymorphism were identified by PCR/single strand conformation polymorphism analysis. In 2 dexamethasone (DEX) suppression tests (DSTs), using 1 and 0.25 mg DEX, the circulating cortisol and insulin concentrations were compared between N363S carriers and controls. In the 1-mg DST, there were no differences between N363S carriers and controls, with respect to adrenal suppression, but there was a significantly higher (P < 0.05) insulin response in N363S carriers. In the 0.25-mg DST, a significantly larger (P < 0.05) cortisol suppression and higher (P < 0.05) insulin response were seen in N363S carriers. Comparison of blood pressure, body mass index (BMI), and bone mineral density (BMD) between the N363S carriers and controls showed that N363S carriers had a higher (P < 0.05) BMI but normal blood pressure. There was an obvious trend towards lower age-, BMI-, and sex-adjusted BMD in the lumbar spine in N363S carriers. GR characteristics measured in 41 controls and 9 N363S carriers in peripheral mononuclear leucocytes showed no differences between N363S carriers and controls, with respect to GR number and ligand binding affinity. However, there was a trend towards greater sensitivity to DEX in the carriers' lymphocytes, in a mitogen-induced cell proliferation assay. In transfection assays, the capacity of the codon 363 variant to activate mouse mammary tumor virus promotor-mediated transcription in COS-1 cells was unaltered, when compared with the wild-type GR. We conclude that in 6.0% of our study population, a polymorphism in codon 363 of the GR gene was found. Individuals carrying this polymorphism seemed healthy at clinical examination but had a higher sensitivity to exogenously administered glucocorticoids, with respect to both cortisol suppression and insulin response. Life-long exposure to the mutated allele may be accompanied by an increased BMI and a lowered BMD in the lumbar spine but does not affect blood pressure.

Insulin and cognitive function in an elderly population. The Rotterdam Study.

OBJECTIVE: To examine the association between insulin and cognitive function in the population-based Rotterdam Study. RESEARCH DESIGN AND METHODS: Serum insulin was measured 2 h after an oral glucose load, while global cognitive function was assessed by the Mini Mental State Examination in 5,510 subjects, aged 55 years and over. RESULTS: An increase in postload insulin only in women was associated with a decrease in cognitive function (age-adjusted regression coefficient -0.10 per 50 mU/l insulin; 95% CI -0.16 to -0.04). The association between insulin resistance, assessed by the ratio of postload insulin over glucose, and cognitive function was not statistically significant. Further adjustment for the individual risk factors of serum glucose, BMI, HDL, systolic blood pressure, smoking, or use of estrogen did not change the results. The association was present in women with and without cardiovascular disease and present after excluding subjects with diabetes. Women with dementia, the extreme of cognitive dysfunction, had increased age-adjusted insulin levels (76.3 +/- 4.9 vs. 66.8 +/- 1.0 mU/l [means +/- SE], P = 0.06). CONCLUSIONS: The results of this study suggest that increased serum insulin may be associated with decreased cognitive function and dementia in women. These findings are more compatible with a direct effect of insulin on the brain than with an effect through an increase in cardiovascular risk factors.

Lack of association between five polymorphisms in the human glucocorticoid receptor gene and glucocorticoid resistance.

Glucocorticoid resistance due to mutations in the gene for the glucocorticoid receptor has been suggested to be more common than is thought at present, owing to the relative mildness of its symptoms and the difficulty of its diagnosis. To investigate the prevalence of mutations in the glucocorticoid receptor gene responsible for relative insensitivity to glucocorticoids, we carried out polymerase chain reaction/single-strand conformation analysis of the glucocorticoid receptor gene in a group of 20, otherwise healthy, persons with a reduced response in a dexamethasone suppression test and in 20 controls. We did not find mutations or polymorphisms associated with a reduced sensitivity to glucocorticoids. However, we identified five novel polymorphisms in the gene for the human glucocorticoid receptor, which may be useful in analyzing whether loss of (part of) the glucocorticoid receptor gene plays a role in glucocorticoid-resistant malignancies. Although relative resistance to glucocorticoids seems to be rather frequent in otherwise healthy persons, it is not usually associated with mutations or polymorphisms in the glucocorticoid receptor gene.

Diabetes mellitus, impaired glucose tolerance, and hyperinsulinemia in an elderly population. The Rotterdam Study.

To estimate the prevalence of glucose intolerance in the elderly, oral glucose tolerance tests were performed as part of the Rotterdam Study, a population-based study in subjects aged 55 years and over. The study population consisted of 2,668 men and 3,950 women. Diabetes mellitus was defined as the use of antidiabetes medication, or a random or post-load serum glucose level of > or = 11.1 mmol/liter. Impaired glucose tolerance was defined as a post-load serum glucose between 7.8 and 11.1 mmol/liter. In men, the frequency of diabetes mellitus ranged from 5.9% in ages < 60 years to 19.8% in ages > 85 years, and in women from 3.8% in ages < 60 years to 18.9% in ages > 85 years; more than half of the subjects with diabetes were newly diagnosed. The prevalence of impaired glucose tolerance ranged from 8.8% and 11.0% in men and women aged < 60 years to 24.3% and 34.7% in men and women aged > 85 years. The prevalence of diabetes mellitus in the total Rotterdam Study population of 7,439 elderly men and women was estimated to be 11.3% (95% confidence interval (CI) 10.5-12.0). Waist/hip ratio, systolic blood pressure, hypertension, and number of cigarettes smoked increased with a worsening of the glucose tolerance from normal, hyperinsulinemia, impaired glucose tolerance to diabetes in both men and women (p < 0.01, adjusted for age). Body mass index was higher in subjects with glucose intolerance, but the frequency of obesity showed a relative decrease with worsening of glucose tolerance. These results show that glucose intolerance, especially impaired glucose tolerance and undetected diabetes mellitus, is common in the elderly. Moreover, not only subjects with diabetes mellitus but also subjects with hyperinsulinemia and impaired glucose tolerance have an increase of cardiovascular risk factors.