OBJECTIVE:--To investigate the association between serum uric acid level and risk of type 2 diabetes. RESEARCH DESIGN AND METHODS--The population for analysis consisted of 4,536 subjects free from ...diabetes at baseline. During a mean of 10.1 years of follow-up, 462 subjects developed diabetes. RESULTS:--The age- and sex-adjusted hazard ratios (HRs) (95% CIs) for diabetes were 1.30 (0.96-1.76) for the second, 1.63 (1.21-2.19) for the third, and 2.83 (2.13-3.76) for the fourth quartile of serum uric acid, in comparison with the first quartile. After adjustment for BMI, waist circumference, systolic and diastolic blood pressure, and HDL cholesterol, the HRs decreased to 1.08 (0.78-1.49), 1.12 (0.81-1.53), and 1.68 (1.22-2.30), respectively. CONCLUSIONS:--The results of this population-based study suggest that serum uric acid is a strong and independent risk factor for diabetes.
Data are scarce for the lifetime risk of developing impaired glucose metabolism, including prediabetes, as are data for the risk of eventual progression from prediabetes to diabetes and for ...initiation of insulin treatment in previously untreated patients with diabetes. We aimed to calculate the lifetime risk of the full range of glucose impairments, from normoglycaemia to prediabetes, type 2 diabetes, and eventual insulin use.
In this prospective population-based cohort analysis, we used data from the population-based Rotterdam Study. We identified diagnostic events by use of general practitioners' records, hospital discharge letters, pharmacy dispensing data, and serum fasting glucose measurements taken at the study centre (Rotterdam, Netherlands) visits. Normoglycaemia, prediabetes, and diabetes were defined on the basis of WHO criteria for fasting glucose (normoglycaemia: ≤6·0 mmol/L; prediabetes: >6·0 mmol/L and <7·0 mmol/L; and diabetes ≥7·0 mmol/L or use of glucose-lowering drug). We calculated lifetime risk using a modified version of survival analysis adjusted for the competing risk of death. We also estimated the lifetime risk of progression from prediabetes to overt diabetes and from diabetes free of insulin treatment to insulin use. Additionally, we calculated years lived with healthy glucose metabolism.
We used data from 10 050 participants from the Rotterdam Study. During a follow-up of up to 14·7 years (between April 1, 1997, and Jan 1, 2012), 1148 participants developed prediabetes, 828 developed diabetes, and 237 started insulin treatment. At age 45 years, the remaining lifetime risk was 48·7% (95% CI 46·2-51·3) for prediabetes, 31·3% (29·3-33·3) for diabetes, and 9·1% (7·8-10·3) for insulin use. In individuals aged 45 years, the lifetime risk to progress from prediabetes to diabetes was 74·0% (95% CI 67·6-80·5), and 49·1% (38·2-60·0) of the individuals with overt diabetes at this age started insulin treatment. The lifetime risks attenuated with advancing age, but increased with increasing BMI and waist circumference. On average, individuals with severe obesity lived 10 fewer years without glucose impairment compared with normal-weight individuals.
Impaired glucose metabolism is a substantial burden on population health, and our findings emphasise the need for more effective prevention strategies, which should be implemented as soon in a person's life as possible. The substantial lifetime risk of prediabetes and diabetes in lean individuals also supports risk factor control in non-obese individuals.
Erasmus MC and Erasmus University Rotterdam; Netherlands Organisation for Scientific Research; Netherlands Organisation for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomics Initiative; Netherlands Ministry of Education, Culture and Science; Netherlands Ministry of Health, Welfare and Sports; European Commission; and Municipality of Rotterdam.
Subjects with diabetes mellitus (DM) have an increased risk of arterial thrombosis, to which changes in clot structure and mechanics may contribute. Another contributing factor might be an increased ...formation of neutrophil extracellular traps (NETs) in DM. NETs are mainly formed during the acute phase of disease and form a network within the fibrin matrix, thereby influencing clot properties. Previous research has shown separate effects of NETs and DM on clot properties, therefore our aim was to study how DM affects clot properties in a model resembling an acute phase of disease with NETs formation. Clots were prepared from citrated plasma from subjects with and without DM with the addition of NETs, induced in neutrophils by
bacteria or phorbol myristate acetate (PMA). Structural parameters were measured using scanning electron microscopy, mechanical properties using rheology, and sensitivity to lysis using a fluorescence-based fibrinolysis assay. Plasma clots from subjects with DM had significantly thicker fibers and fewer pores and branch points than clots from subjects without DM. In addition, fibrinolysis was significantly slower, while mechanical properties were similar between both groups. In conclusion, in a model of acute NETs formation, DM plasma shows prothrombotic effects on fibrin clots.
Aims/hypothesis
Microvascular disease in type 2 diabetes is a significant cause of end-stage renal disease, blindness and peripheral neuropathy. The strict control of known risk factors, e.g. ...lifestyle, hyperglycaemia, hypertension and dyslipidaemia, reduces the incidence of microvascular complications, but a residual risk remains. Lipoprotein (a) Lp(a) is a strong risk factor for macrovascular disease in the general population. We hypothesised that plasma Lp(a) levels and the
LPA
gene SNPs rs10455872 and rs3798220 are associated with the incident development of microvascular complications in type 2 diabetes.
Methods
Analyses were performed of data from the DiaGene study, a prospective study for complications of type 2 diabetes, collected in the city of Eindhoven, the Netherlands (
n
= 1886 individuals with type 2 diabetes, mean follow-up time = 6.97 years). To assess the relationship between plasma Lp(a) levels and the
LPA
SNPs with each newly developed microvascular complication (retinopathy
n
= 223, nephropathy
n
= 246, neuropathy
n
= 236), Cox proportional hazards models were applied and adjusted for risk factors for microvascular complications (age, sex, mean arterial pressure, non-HDL-cholesterol, HDL-cholesterol, BMI, duration of type 2 diabetes, HbA
1c
and smoking).
Results
No significant associations of Lp(a) plasma levels and the
LPA
SNPs rs10455872 and rs3798220 with prevalent or incident microvascular complications in type 2 diabetes were found. In line with previous observations the
LPA
SNPs rs10455872 and rs3798220 did influence the plasma Lp(a) levels.
Conclusions/interpretation
Our data show no association between Lp(a) plasma levels and the
LPA
SNPs with known effect on Lp(a) plasma levels with the development of microvascular complications in type 2 diabetes. This indicates that Lp(a) does not play a major role in the development of microvascular complications. However, larger studies are needed to exclude minimal effects of Lp(a) on the development of microvascular complications.
To evaluate the clinical value of metabolic syndrome based on different definitions American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI), International Diabetes Federation ...(IDF) and European Group for the Study of Insulin Resistance (EGIR) in middle-aged and elderly populations.
We studied 8643 participants from the Rotterdam study (1990-2012; mean age 62.7; 57.6 % female), a large prospective population-based study with predominantly elderly participants. We performed cox-proportional hazards models for different definitions, triads within definitions and each separate component for the risk of incident type 2 diabetes mellitus, coronary heart disease, stroke, cardiovascular- and all-cause mortality.
In our population of 8643 subjects, metabolic syndrome was highly prevalent (prevalence between 19.4 and 42.4 %). Metabolic syndrome in general was associated with incident type 2 diabetes mellitus (median follow-up of 6.8 years, hazard ratios 3.13-3.78). The associations with coronary heart disease (median follow-up of 7.2 years, hazard ratios 1.08-1.32), stroke (median follow-up of 7.7 years, hazard ratios 0.98-1.32), cardiovascular mortality (median follow-up of 8.2 years, ratios 0.95-1.29) and all-cause mortality (median follow-up of 8.7 years, hazard ratios 1.05-1.10) were weaker. AHA/NHLBI- and IDF-definitions showed similar associations with clinical endpoints compared to the EGIR, which was only significantly associated with incident type 2 diabetes mellitus. All significant associations disappeared after correcting metabolic syndrome for its individual components.
Large variability exists between and within definitions of the metabolic syndrome with respect to risk of clinical events and mortality. In a relatively old population the metabolic syndrome did not show an additional predictive value on top of its individual components. So, besides as a manner of easy identification of high risk patients, the metabolic syndrome does not seem to add any predictive value for clinical practice.
Aims
Type 2 diabetes mellitus is a major cause of death and disability due to its long-term macro- and microvascular diseases. Although women with type 2 diabetes have more macrovascular diseases, it ...is unclear whether there are sex differences in the occurrence of microvascular disease. The aim of our study was to investigate sex differences in the incidence of microvascular complications in type 2 diabetes.
Methods
Analyses were performed in the DiaGene study, a prospective cohort study for complications of type 2 diabetes, collected in the city of Eindhoven, the Netherlands (
n
= 1886, mean follow-up time = 6.93 years). Cox proportional hazard models adjusted for risk factors for complications (age, smoking, hypertension, dyslipidemia, HbA1c and duration of type 2 diabetes) were used to analyze the incidence of microvascular complications in men and women.
Results
The incidence of microalbuminuria was significantly higher in men (HR microalbuminuria 1.64 CI 1.21–2.24,
p
= 0.002). Additionally, men are more likely to develop two or three microvascular complications compared to women (OR 2.42 CI 1.69–3.45,
p
< 0.001).
Conclusions
This study shows that men with type 2 diabetes are more likely to develop microvascular complications, especially microalbuminuria. Furthermore, men seem to have a higher chance of developing multiple microvascular complications. Our results highlight that men and women may not benefit to a similar extent from current treatment approaches to prevent diabetes-related microvascular diseases.
Chronic obstructive pulmonary disease (COPD) and asthma associate with high morbidity and mortality. High levels of advanced glycation end products (AGEs) were found in tissue and plasma of COPD ...patients but their role in COPD and asthma is unclear.
In the Rotterdam Study (n = 2577), AGEs (by skin autofluorescence (SAF)), FEV
and lung diffusing capacity (D
c and D
c /alveolar volume V
) were measured. Associations of SAF with asthma, COPD, GOLD stage, and lung function were analyzed using logistic and linear regression adjusted for covariates, followed by interaction and stratification analyses. sRAGE and EN-RAGE associations with COPD prevalence were analyzed by logistic regression.
SAF associated with COPD prevalence (OR = 1.299 1.060, 1.591) but not when adjusted for smoking (OR = 1.106 0.89, 1.363). SAF associated with FEV
% predicted (β=-3.384 -4.877, -1.892), D
c (β=-0.212 -0.327, -0.097) and GOLD stage (OR = 4.073, p = 0.001, stage 3&4 versus 1). Stratified, the association between SAF and FEV
%predicted was stronger in COPD (β=-6.362 -9.055, -3.670) than non-COPD (β=-1.712 -3.306, -0.118). Association of SAF with D
c and D
c/V
were confined to COPD (β=-0.550 -0.909, -0.191; β=-0.065 -0.117, -0.014 respectively). SAF interacted with former smoking and COPD prevalence for associations with lung function. Lower sRAGE and higher EN-RAGE associated with COPD prevalence (OR = 0.5750.354, 0.931; OR = 1.7781.142, 2.768, respectively).
Associations between SAF, lung function and COPD prevalence were strongly influenced by smoking. SAF associated with COPD severity and its association with lung function was more prominent within COPD. These results fuel further research into interrelations and causality between SAF, smoking and COPD.
Skin AGEs associated with prevalence and severity of COPD and lung function in the general population with a stronger effect in COPD, calling for further research into interrelations and causality between SAF, smoking and COPD.
Inflammation is important in the development of type 2 diabetes complications. The N-glycosylation of IgG influences its role in inflammation. To date, the association of plasma IgG N-glycosylation ...with type 2 diabetes complications has not been extensively investigated. We hypothesised that N-glycosylation of IgG may be related to the development of complications of type 2 diabetes.
In three independent type 2 diabetes cohorts, plasma IgG N-glycosylation was measured using ultra performance liquid chromatography (DiaGene n = 1815, GenodiabMar n = 640) and mass spectrometry (Hoorn Diabetes Care Study n = 1266). We investigated the associations of IgG N-glycosylation (fucosylation, galactosylation, sialylation and bisection) with incident and prevalent nephropathy, retinopathy and macrovascular disease using Cox- and logistic regression, followed by meta-analyses. The models were adjusted for age and sex and additionally for clinical risk factors.
IgG galactosylation was negatively associated with prevalent and incident nephropathy and macrovascular disease after adjustment for clinical risk factors. Sialylation was negatively associated with incident diabetic nephropathy after adjustment for clinical risk factors. For incident retinopathy, similar associations were found for galactosylation, adjusted for age and sex.
We showed that IgG N-glycosylation, particularly galactosylation and to a lesser extent sialylation, is associated with a higher prevalence and future development of macro- and microvascular complications of diabetes. These findings indicate the predictive potential of IgG N-glycosylation in diabetes complications and should be analysed further in additional large cohorts to obtain the power to solidify these conclusions.
Background Inflammation is a pathophysiological factor in diabetes and its cardiovascular complications. High-density lipoprotein (HDL) suppresses inflammation in healthy individuals. The ...relationship of HDL with diabetes and cardiovascular disease may be explained by HDL function rather than by HDL cholesterol level. In diabetes, HDL seems to become dysfunctional. Objective We performed a systematic review to answer the following research questions: Is the anti-inflammatory function of HDL diminished in individuals with diabetes and if so, what causes this? Methods We systematically searched Medline and Embase and included original research articles on the anti-inflammatory effects of HDL or HDL-based interventions in diabetes or diabetes models. We assessed the risk of bias of all included studies. Results Fourteen studies were included. These showed great heterogeneity in methodology, study populations, and diabetes models. Overall, HDL from subjects with type II diabetes displayed a reduced ability to suppress inflammatory processes and inflammation markers. However, the mechanisms and the in vivo effects remain largely unknown. No studies reported on HDL from individuals with other types of diabetes. In most studies, the risk of bias was high or could not be assessed. Conclusions HDL isolated from individuals with type II diabetes showed a decreased ability to suppress inflammation. However, the direction of causality and the underlying mechanisms are unknown and should be investigated. For development of treatments directed at restoring HDL anti-inflammatory function in diabetes, a standardized method for assessing HDL anti-inflammatory function needs to be developed and in vivo biomarkers must be identified.
Aims/hypothesis
ADAMTS13 is a protease that breaks down von Willebrand factor (VWF) multimers into smaller, less active particles. VWF has been associated with an increased risk of incident type 2 ...diabetes mellitus. Here, we determine whether ADAMTS13 activity and VWF antigen are associated with incident diabetes.
Methods
This study included 5176 participants from the Rotterdam Study, a prospective population-based cohort study. Participants were free of diabetes at baseline and followed up for more than 20 years. Cox proportional hazards models were used to examine the association of ADAMTS13 activity and VWF antigen with incident diabetes.
Results
ADAMTS13 activity was associated with an increased risk of incident diabetes (HR 1.17 95% CI 1.08, 1.27) after adjustment for known risk factors and VWF antigen levels. Although ADAMTS13 activity was positively associated with fasting glucose and insulin, the association with incident diabetes did not change when we adjusted for these covariates. ADAMTS13 activity was also associated with incident prediabetes (defined on the basis of both fasting and non-fasting blood glucose) after adjustment for known risk factors (HR 1.11 95% CI 1.03, 1.19), while the VWF antigen level was not. VWF antigen was associated with incident diabetes, but this association was attenuated after adjustment for known risk factors.
Conclusions/interpretation
ADAMTS13 activity appears to be an independent risk factor for incident prediabetes and type 2 diabetes. As the association between ADAMTS13 and diabetes did not appear to be explained by its cleavage of VWF, ADAMTS13 may have an independent role in the development of diabetes.
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