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OBJECTIVE Methylglyoxal (MGO) is a reactive dicarbonyl compound and a potential key player in diabetic cardiovascular disease (CVD). Whether plasma MGO levels are associated with CVD in type 2 diabetes is unknown. RESEARCH DESIGN AND METHODS We included 1,003 individuals (mean ± SD age 59.1 ± 10.5 years, 69.3% male, and 61.6% with prior CVD) with type 2 diabetes from the Second Manifestations of ARTerial disease cohort (SMART). We measured plasma MGO levels and two other dicarbonyls (glyoxal [GO] and 3-deoxyglucosone [3-DG]) at baseline with mass spectrometry. Median follow-up of CVD events was 8.6 years. Data were analyzed with Cox regression with adjustment for sex, age, smoking, systolic blood pressure, total cholesterol, HbA1c, BMI, prior CVD, and medication use. Hazard ratios are expressed per SD Ln-transformed dicarbonyl. RESULTS A total of 287 individuals suffered from at least one CVD event (n = 194 fatal events, n = 146 myocardial infarctions, and n = 72 strokes); 346 individuals died, and 60 individuals underwent an amputation. Higher MGO levels were associated with total (hazard ratio 1.26 [95% CI 1.11–1.42]) and fatal (1.49 [1.30–1.71]) CVD and with all-cause mortality (1.25 [1.11–1.40]), myocardial infarction (1.22 [1.02–1.45]), and amputations (1.36 [1.05–1.76]). MGO levels were not apparently associated with stroke (1.03 [0.79–1.35]). Higher GO levels were significantly associated with fatal CVD (1.17 [1.00–1.37]) but not with other outcomes. 3-DG was not significantly associated with any of the outcomes. CONCLUSIONS Plasma MGO and GO levels are associated with cardiovascular mortality in individuals with type 2 diabetes. Influencing dicaronyl levels may therefore be a target to reduce CVD in type 2 diabetes.

OBJECTIVE To investigate risk of a recurrent cardiovascular event and its predictors in a population-based cohort. RESEARCH DESIGN AND METHODS Participants of the Hoorn Study who had experienced a first cardiovascular event after baseline (n = 336) were followed with respect to a recurrent event. Absolute risk of a recurrent event was calculated for individuals with normal glucose metabolism, intermediate hyperglycemia, and type 2 diabetes. Cox regression models were used to investigate which variables, measured before the first vascular event, predicted a recurrent event using the stepwise backward procedure. RESULTS During a median follow-up of 4.1 years, 44% (n = 148) of the population developed a recurrent vascular event. The rate of recurrent events per 100 person-years was 7.2 (95% CI 5.8–8.7) in individuals with normal glucose metabolism, compared with 9.8 (6.6–14.0) in individuals with intermediate hyperglycemia and 12.5 (8.5–17.6) in individuals with type 2 diabetes. Higher age (hazard ratio 1.02 [95% CI 1.00–1.04]), male sex (1.56 [1.08–2.25]), waist circumference (1.02 [1.02–1.03]), higher systolic blood pressure (1.01 [1.01–1.02]), higher HbA1c (%, 1.13 [0.97–1.31]/ mmol/mol, 1.01 [1.00–1.03]), and family history of myocardial infarction (1.38 [0.96–2.00]) predicted a recurrent cardiovascular event. CONCLUSIONS Individuals with type 2 diabetes, but not individuals with intermediate hyperglycemia, are at increased risk for a recurrent vascular event compared with individuals with normal glucose metabolism. In people with a history of cardiovascular disease, people at increased risk of a recurrent event can be identified based on the patient’s risk profile before the first event.

OBJECTIVE Heart failure is common in individuals with type 2 diabetes, and early detection of individuals at risk may offer opportunities for prevention. We aimed to explore 1) prospective associations of B-type natriuretic peptide (BNP) levels in a non–heart failure range with changes in markers of left ventricular (LV) function and 2) possible effect modification by type 2 diabetes in a population-based cohort. RESEARCH DESIGN AND METHODS Echocardiographic measurements were performed at baseline (2000–2001) and follow-up (2007–2009), together with standardized physical examinations and BNP measurements on 300 individuals (mean age 66 years, 32% with type 2 diabetes) of the longitudinal Hoorn Study. Multivariate linear regression analyses were performed to investigate associations of baseline BNP (

OBJECTIVE—We investigated stroke mortality in individuals in different categories of glycemia and compared hazard ratios (HRs) corresponding to a 1-SD increase in 2-h plasma glucose and fasting plasma glucose (FPG) criteria. RESEARCH DESIGN AND METHODS—We examined data from 2-h 75-g oral glucose tolerance tests taken from 13 European cohorts comprising 11,844 (55%) men and 9,862 (45%) women who were followed up for a median of 10.5 years. A multivariate adjusted Cox proportional hazards model was used to estimate HRs for stroke mortality. RESULTS—In men and women without a prior history of diabetes, multivariate adjusted HRs for stroke mortality corresponding to a 1-SD increase in FPG were 1.02 (95% CI 0.83–1.25) and 1.52 (1.22–1.88) and those in 2-h plasma glucose 1.21 (1.06–1.38) and 1.31 (1.06–1.61), respectively. Addition of 2-h plasma glucose to the model with FPG significantly improved prediction of stroke mortality in men (χ2 = 10.12; P = 0.001) but not in women (χ2 = 0.01; P = 0.94), whereas addition of FPG to 2-h plasma glucose improved stroke mortality in women (χ2 = 4.08; P = 0.04) but not in men (χ2 = 3.29; P = 0.07). CONCLUSIONS—Diabetes defined by either FPG or 2-h plasma glucose increases the risk of stroke mortality. In individuals without a history of diabetes, elevated 2-h postchallenge glucose is a better predictor than elevated fasting glucose in men, whereas the latter is better than the former in women.

We evaluated the association of biomarkers of endothelial dysfunction and inflammation with all-cause mortality and cardiovascular mortality and morbidity and decline in glomerular filtration rate (GFR) in type 1 diabetic patients.We prospectively followed 199 type 1 diabetic patients with diabetic nephropathy and 192 patients with persistent normoalbuminuria. Biomarkers were measured at baseline.We constructed two Z scores: the mean inflammatory Z score combined C-reactive protein, interleukin-6, soluble intercellular adhesion molecule (sICAM-1), and secreted phospholipase A2 and the mean Z score for endothelial dysfunction combined soluble vascular cell adhesion molecule 1, plasminogen activator inhibitor-1, and sICAM-1. The mean Z score of inflammatory biomarkers was associated with mortality and the combined end point in patients with diabetic nephropathy after multivariate adjustment (hazard ratio 1.7 [95% CI 1.1-2.6]; P = 0.025 and 1.5 [1.1-2.2]; P = 0.017). The mean Z score for endothelial dysfunction biomarkers was associated with mortality in a model adjusting for age and sex in patients with diabetic nephropathy (1.6 [1.0-2.3]; P = 0.031). The mean Z score for endothelial dysfunction correlated with decline in GFR (r = -0.243; P = 0.001); the correlation persisted after multivariate adjustment (coefficient -1.38 [95% CI -2.27 to -0.50]; P = 0.002).Mean Z scores of inflammatory biomarkers are significantly associated with all-cause mortality and cardiovascular morbidity and mortality in patients with nephropathy after multivariate adjustment. These data suggest that the high risk of cardiovascular disease in type 1 diabetes may be explained in part by inflammatory activity. Mean Z score of endothelial dysfunction correlated after multivariate adjustment with the rate of decline in GFR.

To optimize identification of future diabetic patients, the American Diabetes Association (ADA) introduced criteria for impaired fasting glucose (IFG) in 1997 (IFG 6.1 mmol/l [IFG6.1]) and lowered the threshold from 6.1 to 5.6 mmol/l (IFG5.6) in 2003. Our aim was to assess the consequences of lowering the IFG cutoff on the risk of cardiovascular disease (CVD) mortality and to evaluate whether this risk is explained by a conversion to type 2 diabetes within 6.4 years.In a population-based cohort, the Hoorn Study, plasma glucose was determined in 1989 and 1996 (n = 1,428). Subjects were classified in 1989 according to 1997 and 2003 ADA criteria. Subjects with IFG in 1989 were further classified according to diabetes status in 1996. Hazard ratios for CVD mortality (n = 81) in the period 1996-2005 were adjusted for age and sex.Subjects with IFG6.1, but not IFG5.6, had a significantly higher CVD mortality risk than normal fasting glucose (NFG) subjects. Subjects who converted from IFG to diabetes (IFG6.1: 42%; IFG5.6: 21%) had a more than twofold risk of CVD mortality (IFG6.1: 2.47 [1.17-5.19]; IFG5.6: 2.14 [1.12-4.10]) than subjects with NFG. IFG subjects who did not develop diabetes did not have significantly higher CVD mortality risks (IFG6.1: 1.50 [0.72-3.15]; IFG5.6: 1.15 [0.69-1.93]).The lower cutoff for IFG (ADA 2003 criteria) results in a category of IFG that no longer represents a high-risk state of CVD. Furthermore, only subjects who convert from IFG to diabetes have a high risk of CVD mortality.

High proinsulin concentration may be a better predictor for cardiovascular disease (CVD) mortality than insulin concentration. Previous observations may have been confounded by glucose tolerance status or lack of precision because of high intraindividual variability. We investigated the longitudinal relation of means of duplicate measurements of insulin and proinsulin with all-cause and CVD mortality in a population-based cohort taking glucose tolerance status into account.Fasting and post-75-g glucose-load (2-h) glucose, insulin, and proinsulin values were determined in duplicate on separate days in 277 participants with normal glucose metabolism, 208 participants with impaired glucose metabolism, and 119 newly detected patients with type 2 diabetes of the Hoorn Study. Insulin resistance and beta-cell function were estimated by homeostasis model assessment (HOMA-IR and HOMA-B, respectively), and the fasting proinsulin-to-insulin ratio was calculated. Subjects were followed with respect to mortality until January 2003.Fasting proinsulin levels were significantly associated with all-cause and CVD mortality. The hazard ratios (HRs) per increase in interquartile range adjusted for age and sex were 1.21 (95% CI 1.04-1.42) for all-cause mortality and 1.33 (1.06-1.66) for CVD mortality. Adjustment for glucose tolerance status and HOMA-IR did not substantially change the associations.Fasting proinsulin was associated with all-cause and CVD mortality, independent of glucose tolerance status and insulin resistance and largely independent of other CVD risk factors. Proinsulin might play a role in the relationship between insulin resistance and CVD.

Waist and hip circumferences have been shown to have independent and opposite associations with glucose levels. Waist circumference is positively associated with glucose levels, whereas hip circumference is negatively associated. It is unclear which tissues are involved in the pathophysiological mechanism causing these associations. The main goal was to determine which tissue in the trunk and legs, fat or lean tissue, is associated with measures of glucose metabolism.In 623 participants of the third examination of the Hoorn Study, whole-body dual-energy X-ray absorptiometry was performed to determine fat and lean soft-tissue mass in the trunk and legs. Fasting and 2-h postload glucose levels after 75-g oral glucose tolerance test (OGTT) were determined. After exclusion of known diabetic patients, cross-sectional analyses were performed in 275 men aged 60-87 years (140 with normal glucose metabolism, 92 with impaired glucose metabolism; and 43 with diabetes) and in 281 women (148 with normal glucose metabolism, 90 with impaired glucose metabolism, and 43 with diabetes).Greater trunk fat mass was associated with higher glucose levels after adjustment for age, trunk lean mass, leg lean mass, and leg fat mass. Standardized beta (95% CI) in men were 0.44 (0.25-0.64) for fasting and 0.41 (0.22-0.60) for postload glucose. For women, these values were 0.49 (0.35-0.63) and 0.47 (0.33-0.61), respectively. In contrast, in the same regression models, a larger leg fat mass was associated with lower glucose levels. Standardized beta in men were -0.24 (-0.43 to -0.05) and -0.12 (-0.31 to 0.07) and in women -0.24 (-0.37 to -0.10) and -0.27 (-0.40 to -0.13) for fasting and postload glucose, respectively. In these models, larger leg lean mass was also associated with lower glucose levels but was only statistically significant in men.If trunk fat is taken into account, accumulation of fat in the legs seems to be protective against a disturbed glucose metabolism, particularly in women. Further research is needed to unravel underlying pathophysiological mechanisms.

To investigate whether screening-detected diabetic patients differ from diabetic patients newly diagnosed in general practice with regard to the presence of microvascular complications.Diabetic patients, identified by a population-based targeted screening procedure consisting of a screening questionnaire and a fasting capillary whole-blood glucose measurement followed by diagnostic testing, were compared with patients newly diagnosed with diabetes in general practice. Retinopathy was assessed with fundus photography, impaired foot sensitivity was assessed with Semmes-Weinstein monofilaments, and the presence of microalbuminuria was measured by means of the albumin-to-creatinine ratio (ACR).A total of 195 screening-detected type 2 diabetic patients and 60 patients newly diagnosed in general practice participated in the medical examination. The prevalence of retinopathy was higher in screening-detected type 2 diabetic patients than in patients newly diagnosed in general practice, but not significantly higher. The prevalence of retinopathy was 7.6% (95% CI 4.6-12.4) in screening-detected type 2 diabetic patients and 1.9% (0.3-9.8) in patients newly diagnosed in general practice. The prevalence of impaired foot sensitivity was similar in both groups, 48.1% (40.9-55.3) and 48.3% (36.2-60.7), respectively. The ACR was 0.61 (interquartile range 0.41-1.50) in screening-detected type 2 diabetic patients and 0.99 (0.53-2.49) in patients newly diagnosed in general practice. The difference in prevalence of microalbuminuria was not statistically significant. The prevalence of microalbuminuria was 17.2% (95% CI 12.5-23.2) and 26.7% (17.1-39.0) in screening-detected type 2 diabetic patients and patients newly diagnosed in general practice, respectively.Targeted screening for type 2 diabetes (with a screening questionnaire as a first step) resulted in the identification of previously undiagnosed diabetic patients with a considerable prevalence of microvascular complications.

Transforming growth factor (TGF)-beta1 is overexpressed in diabetes as a consequence of hyperglycemia and the creation of early glycated end products and may be responsible for the characteristic structural renal changes associated with diabetes. We sought to examine the role of both urinary and circulating TGF-beta1 and its promoter Amadori albumin in the vascular complications of type 1 diabetes.The present article reports on a nested case-control study from the EURODIAB Prospective Complications Study of Europeans with type 1 diabetes. Case subjects (n = 356) were all individuals with one or more complications of diabetes; control subjects (n = 185) were all individuals with no evidence of complications.Urinary TGF-beta1 and Amadori albumin were elevated in patients with micro- or macroalbuminuria. Standardized regression effects (SREs) for macroalbuminuria versus normoalbuminuria were 2.45 (95% CI 1.88-3.18, P = 0.0001 for urinary TGF-beta1) and 1.67 (1.34-2.07, P = 0.001 for Amadori albumin). The SRE for urinary TGF-beta1 remained statistically significant when adjusted for HbA(1c), Amadori albumin, and blood pressure. Circulating TGF-beta1 was elevated in individuals with proliferative retinopathy compared with individuals without retinopathy (SRE 1.29 [1.07-1.550], P = 0.007). This result was attenuated to 1.16 (0.95-1.43, P = 0.2) in the multivariate model, largely because of HbA(1c).Elevated levels of urinary TGF-beta1 in macroalbuminuria were associated with elevations in Amadori albumin and HbA(1c) and also in blood pressure. In contrast, only circulating TGF-beta1 was related to proliferative retinopathy, and HbA(1c) largely accounted for this. These findings may indicate novel pathways for understanding mechanisms and therapeutic interventions.

To study potential risk factors for retinopathy in diabetic and nondiabetic individuals.The Hoorn Study is a population-based study including 2,484 50- to 74-year-old Caucasians. A subsample of 626 individuals stratified by age, sex, and glucose tolerance underwent extensive measurements during 1989-1992, including ophthalmologic examination and two-field 45-degree fundus photography. The prevalence of (diabetic) retinopathy was assessed among individuals with normal glucose metabolism (NGM) and impaired glucose metabolism (IGM) and individuals with newly diagnosed diabetes mellitus (NDM) and known diabetes mellitus (KDM) (new World Health Organization 1999 criteria).The prevalence of retinopathy was 9% in NGM, 11% in IGM, 13% in NDM, and 34% in KDM. Retinopathy worse than minimal nonproliferative diabetic retinopathy was present in 8% in KDM and 0-2% in other glucose categories. The prevalence of retinopathy was positively associated with elevated blood pressure, BMI, cholesterol, and triglyceride serum levels in all glucose categories. The age-, sex-, and glucose metabolism category-adjusted odds ratios were 1.5 (95% CI 1.2-1.9), 1.3 (1.0-1.7), and 1.3 (1.0-1.6) per SD increase of systolic blood pressure, BMI, and total cholesterol concentration, respectively, and 1.2 (1.0-1.5) per 50% increase of triglyceride level. Elevated blood pressure and plasma total and LDL cholesterol levels showed associations with retinal hard exudates.Retinopathy is a multifactorial microvascular complication, which, apart from hyperglycemia, is associated with blood pressure, lipid concentrations, and BMI.