Microalbuminuria is strongly associated with NIDDM and hypertension, but not with the insulin resistance syndrome: the Hoorn study

Microalbuminuria is a strong predictor of cardiovascular disease. The aim of this study was to investigate whether microalbuminuria is part of a cluster of risk factors, the insulin resistance syndrome (IRS), or whether it is only associated with, and presumably a complication of, hypertension and non-insulin-dependent diabetes mellitus (NIDDM). An age-, sex- and glucose tolerance-stratified random sample from a 50-75 year old general population (n = 622) was investigated. The urinary albumin-to-creatinine ratio was measured in an early morning spot urine sample. Microalbuminuria was defined as an albumin-to-creatinine ratio greater than 2.0 mg/mmol. We considered, as IRS-related variables, fasting hyperinsulinaemia, insulin resistance (IR; calculated from the formula of the homeostasis model assessment), dyslipidaemia, glucose intolerance, hypertension and waist-to-hip ratio (WHR). Dyslipidaemia was defined as levels of HDL-cholesterol in the lowest and/or levels of triglyceride in the highest tertile. Fasting insulin levels, IR and WHR were divided into tertiles; the highest tertiles were compared to the lowest tertiles. Age-, sex- and glucose tolerance-adjusted analyses showed microalbuminuria to be significantly associated with hypertension, NIDDM and WHR. In multiple logistic regression analyses, microalbuminuria showed independent associations with hypertension, NIDDM and WHR, with odds ratios (ORs [95% confidence interval]) of 3.33 (1.86-5.96), 2.26 (1.14-4.48) and 2.49 (1.09-5.70), respectively. No associations were found with impaired glucose tolerance, hyperinsulinaemia, IR or dyslipidaemia. Multiple logistic regression analyses in diabetic and non-diabetic subjects separately showed that microalbuminuria was independently associated only with hypertension (ORs 4.31 and 2.69). In this Caucasian population, microalbuminuria was associated with hypertension, NIDDM and WHR and not with other variables of the IRS. It is therefore likely that microalbuminuria is a complication of hypertension and NIDDM, and not an integral part of the IRS

Endothelial LRP1 transports amyloid-β1-42 across the blood-brain barrier

According to the neurovascular hypothesis, impairment of low-density lipoprotein receptor-related protein-1 (LRP1) in brain capillaries of the blood-brain barrier (BBB) contributes to neurotoxic amyloid-beta (A beta) brain accumulation and drives Alzheimer's disease (AD) pathology. However, due to conflicting reports on the involvement of LRP1 in A beta transport and the expression of LRP1 in brain endothelium, the role of LRP1 at the BBB is uncertain. As global Lrp1 deletion in mice is lethal, appropriate models to study the function of LRP1 are lacking. Moreover, the relevance of systemic A beta clearance to AD pathology remains unclear, as no BBB-specific knockout models have been available. Here, we developed transgenic mouse strains that allow for tamoxifen-inducible deletion of Lrp1 specifically within brain endothelial cells (Slo1c1-CreER(Tz) Lrp1(fl/fl) mice) and used these mice to accurately evaluate LRP1-mediated A beta BBB clearance in vivo. Selective deletion of Lrp1 in the brain endothelium of C57BL/6 mice strongly reduced brain efflux of injected [I-125] A beta(1-42). Additionally, in the 5xFAD mouse model of AD, brain endothelial-specific Lrp1 deletion reduced plasma A beta levels and elevated soluble brain A beta, leading to aggravated spatial learning and memory deficits, thus emphasizing the importance of systemic AD elimination via the BBB. Together, our results suggest that receptor-mediated A beta BBB clearance may be a potential target for treatment and prevention of A beta brain accumulation in AD

Cardiovascular events in type 2 diabetes: comparison with nondiabetic individuals without and with prior cardiovascular disease - 10-year follow-up of the Hoorn Study

Aims: We questioned whether prior cardiovascular disease has the same impact on risk of cardiovascular events as type 2 diabetes, and whether this differed between men and women. Methods and results: To address these issues we compared the 10-year risk of cardiovascular events among 208 Caucasian individuals with diabetes to that of 2253 Caucasian individuals without diabetes, in a population-based cohort study. Gender significantly modified the association between type 2 diabetes and cardiovascular events (p=0.01). The hazard ratio of cardiovascular events associated with the presence of diabetes was higher in women (adjusted hazard ratio, 1.8; 95% CI, 1.2 to 2.7) than in men (adjusted hazard ratio, 1.3; 0.9 to 2). As compared to men without diabetes but with prior cardiovascular disease, risk of cardiovascular events was significantly lower in men with diabetes but without prior cardiovascular disease (adjusted hazard ratio, 0.5; 0.3 to 0.9). In contrast, this risk was equal in women with diabetes but without prior cardiovascular disease and women without diabetes but with prior cardiovascular disease (adjusted hazard ratio, 1.0; 0.6 to 1.7; P for interaction between gender and diabetes=0.05). Conclusions: Women with diabetes but without prior cardiovascular disease have a risk of cardiovascular events that is similar to that of women without diabetes but with prior cardiovascular disease, whereas in men the presence of prior cardiovascular disease conferred a higher risk. These data emphasise the necessity of aggressive treatment of cardiovascular risk factors in women with type 2 diabetes. © 2003 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved

Vitality, perceived social support and disease activity determine the performance of social roles in recently diagnosed multiple sclerosis: a longitudinal analysis.

Objective: The aim of this study was to identify the principal determinants that are longitudinally associated with the performance of social roles in the first 3 years following a diagnosis of multiple sclerosis. Design: Inception cohort with 5 measurements over 3 years. Patients: A total of 156 patients recently diagnosed with multiple sclerosis. Method: Performance of social roles was measured using the 2 role functioning and the social sub-scales of the Medical Outcome Study Short Form 36. Potential determinants (n = 43) were divided into the following clusters: patient and disease characteristics (n = 12), psychosocial characteristics (n= 10), basic functions (n= 18) and basic activities (n= 3). Multivariate longitudinal regression analyses were performed with generalized estimating equations. A backwards selection procedure for every cluster per outcome reduced the large number of potential determinants. In order to determine whether longitudinal associations are present the selected determinants were entered into an overall regression model. Results: Twenty-three candidate determinants were selected. Vitality, measured with the SF36 sub-scale vitality, the T2-weighted supratentorial lesion load and the perceived amount of social support, measured with the Social Support List Discrepancies, were longitudinally associated with the performance of social roles in 2 or 3 of the models. Conclusion: Vitality, the perceived amount of social support, and disease activity, i.e. the T2-weighted supratentorial lesion load, determine the performance of social roles in the early stages of multiple sclerosis. © 2007 The Authors. Journal Compilation © 2007 Foundation of Rehabilitation Information

Relation of impaired fasting and postload glucose with incident type 2 diabetes in a Dutch population - The Hoorn study

Item does not contain fulltextCONTEXT: 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

Improvement of glycaemic control in type 2 diabetes: favourable changes in blood pressure, total cholesterol and triglycerides, but not in HDL cholesterol, fibrinogen, von Willebrand factor and (pro)insulin

Background: Diabetes mellitus causes a substantial increase in cardiovascular risk, which can only partly be reduced by antihyperglycaemic treatment. We were interested in whether improvement in glycaemic control is associated with improvement of other cardiovascular risk factors. Therefore, we studied among type 2 diabetic patients the association between on the one hand changes in glycaemic control and on the other hand within-subject changes of both classic cardiovascular risk factors and less conventional cardiovascular risk indicators that are typically associated with type 2 diabetes (proinsulin, insulin, fibrinogen, von Willebrand factor and the urinary albumin-creatinine ratio). Methods: The 214 type 2 diabetic patients were randomly assigned to either a strict fasting capillary glucose target level (<6.5 mmol/l) or a less strict target (<8.5 mmol/l). Duration of follow-up was two years. Since the interventions did not yield statistically significant differences between the treatment arms, we reanalysed the data focusing on within-subject changes of cardiovascular risk factors and indicators across tertiles of average HbAIC. Results: Individuals in whom HbAIC decreased had significant favourable concurrent changes in triglycerides, total cholesterol, blood pressure, and in the albumin-creatinine ratio in those who were normoalbuminuric at baseline. In contrast, these individuals had unfavourable, although not statistically significant, changes in HDL cholesterol, proinsulin, insulin, fibrinogen and von Willebrand factor. In the whole group, fibrinogen increased more than could be expected on the basis of the relationship between fibrinogen and age, namely from 3.5 ± 0.8 to 3.9 ± 0.9 g/l (p value <0.01). Conclusions: Our results suggest that improvement in glycaemia in type 2 diabetes is associated with significant favourable changes in triglycerides, total cholesterol, blood pressure and, in normoalbuminuric individuals, albumin-creatinine ratio. In contrast, it is not consistently associated with favourable changes in some cardiovascular risk indicators typically associated with diabetes, which may in part explain why antihyperglycaemic treatment does not clearly lower atherothrombotic disease risk

Endothelial dysfunction contributes to renal function-associated cardiovascular mortality in a population with mild renal insufficiency: The Hoorn study

Mildly impaired renal function is associated with cardiovascular morbidity and mortality. There are indications that endothelial dysfunction and/or chronic inflammation, which play an important role in atherothrombosis, are present in early stages of renal insufficiency. This study investigated whether and to which extent endothelial dysfunction and inflammation were related to renal function and contributed to renal function-associated cardiovascular mortality in a population-based cohort (n = 613), aged 50 to 75 yr, that was followed with a median duration of 12.5 yr. During follow-up, 192 individuals died (67 of cardiovascular causes). At baseline, renal function was estimated with serum creatinine, the Cockcroft-Gault formula, and the Modification of Diet in Renal Disease equation of GFR (eGFR). Endothelial function was estimated by plasma von Willebrand factor, soluble vascular cell adhesion molecule-1, and the urinary albumin-creatinine ratio. Inflammatory activity was estimated by plasma C-reactive protein and soluble intercellular adhesion molecule-1. Renal function was mildly impaired (mean eGFR 68 ± 12 ml/min per 1.73