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Gabriella Gruden,
Federica Barutta,
Nish Chaturvedi, Casper Schalkwijk,
Coen D Stehouwer,
Silvia Pinach,
Maria Manzo,
Maria Loiacono,
Marinella Tricarico,
Giulio Mengozzi,
Daniel R Witte,
John H Fuller,
Paolo Cavallo Perin,
Graziella Bruno
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ABSTRACT: Circulating levels of NH(2)-terminal probrain natriuretic peptide (NT-proBNP), a marker of acute heart failure, are associated with increased risk of cardiovascular disease (CVD) in the general population. However, there is little information on the potential role of NT-proBNP as a biomarker of vascular complications in type 1 diabetic patients. We investigated whether serum NT-proBNP levels were associated with micro- and macrovascular disease in type 1 diabetic subjects.
A cross-sectional nested case-control study from the EURODIAB Prospective Complications Study of 507 type 1 diabetic patients was performed. Case subjects (n = 345) were defined as those with one or more complications of diabetes; control subjects (n = 162) were those with no evidence of any complication. We measured NT-proBNP levels by a two-site sandwich electrochemiluminescence immunoassay and investigated their associations with complications.
Mean NT-proBNP levels were significantly higher in case than in control subjects. In logistic regression analyses, NT-proBNP values >26.46 pg/mL were independently associated with a 2.56-fold increased risk of all complications. Odds ratios of CVD (3.95 [95% CI 1.26-12.35]), nephropathy (4.38 [1.30-14.76]), and distal symmetrical polyneuropathy (4.32 [1.41-13.23]) were significantly increased in patients with NT-proBNP values in the highest quartile (>84.71 pg/mL), independently of renal function and known risk factors. These associations were no longer significant after inclusion of TNF-α into the model.
In this large cohort of type 1 diabetic subjects, we found an association between NT-proBNP and diabetic micro- and macrovascular complications. Our results suggest that the inflammatory cytokine TNF-α may be involved in this association.
Diabetes care 06/2012; 35(9):1931-6. · 8.09 Impact Factor
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ABSTRACT: Frequent episodes of severe hypoglycemia may increase the risk of cardiovascular disease (CVD) in people with diabetes. Our aim was to study the relationship between severe hypoglycemic episodes and CVD incidence in subjects with type 1 diabetes, and further, to assess if markers of inflammation/endothelial injury were enhanced in individuals who experienced hypoglycemic episodes.
The prospective study included 2,181 type 1 diabetic patients from the EURODIAB Prospective Complications Study. At baseline, frequency of self-reported severe hypoglycemia, defined as episodes serious enough to require the help of another person, was assessed based on responses to a patient questionnaire. Both fatal/nonfatal CVD was assessed 7.3 years after baseline examination. At the follow-up visit, data on both severe and nonsevere hypoglycemic episodes in the previous year were collected through a questionnaire and markers of inflammation/stress response/endothelial injury measured by enzyme-linked immunosorbent assays in the 531 subjects of the nested case-control study, including 363 case subjects with one or more complications of diabetes and 168 control subjects with no evidence of any complication.
During the follow-up period, 176 patients had incident CVD. Logistic regression analysis showed that severe hypoglycemia at the baseline examination was not associated with incidence of CVD (adjusted odds ratios [95% CI]: one to two episodes, 0.87 [0.55-1.37]; three or more episodes, 1.09 [0.68-1.75]). Furthermore, follow-up serum levels of markers of endothelial damage/inflammation were not cross-sectionally associated with the frequency of hypoglycemic episodes.
Taken together our data do not support the hypothesis that in type 1 diabetes, severe hypoglycemia increases the risk of CVD.
Diabetes care 05/2012; 35(7):1598-604. · 8.09 Impact Factor
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Lian Engelen,
Søren Lund,
Isabel Ferreira,
Lise Tarnow,
Hans-Henrik H. Parving,
Jørgen Gram,
Kaj Winther,
Oluf Pedersen,
Tom Teerlink,
Rob Barto,
Coen Stehouwer,
Allan Vaag, Casper Schalkwijk
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ABSTRACT: Metformin has been reported to reduce alpha-dicarbonyls, which are known to contribute to diabetic complications. It is unclear whether this is due to direct quenching of alpha-dicarbonyls or to an improvement in glycaemic control. We therefore compared the effects of metformin vs. repaglinide, an anti-hyperglycaemic agent with an insulin-secreting mechanism, on the levels of the alpha-dicarbonyl 3-deoxyglucosone (3DG). We conducted a single-centre, double-blind, double-dummy, crossover study involving 96 non-obese patients with type 2 diabetes. After a one-month run-in on diet-only treatment, patients were randomised to either repaglinide (6 mg daily) followed by metformin (2 g daily) or vice versa each during four months with a 1-month washout between interventions. 3DG levels decreased after both metformin [-19.3% (95%CI:-23.5;-14.8)] and repaglinide [-20.8% (-24.9;-16.3)] treatments, but no difference was found between treatments [1.8% (-3.8;7.8)]. Regardless of treatment, changes in glycaemic variables were associated with changes in 3DG. Specifically, 3DG decreased by 22.7% (19.0;26.5) per SD decrease in fasting plasma glucose (PG), by 20.0% (16.2;23.9) per SD decrease in 7-point MPG, by 22.5% (18.6;26.6) per SD decrease in AUC-PG, by 17.2% (13.8;20.6) per SD decrease in HbA1c and by 10.9% (6.4;15.5) per SD decrease in Amadori albumin. In addition, decreases in 3DG were associated with decreases in AGEs and endothelial markers. Improved glycaemic control induced by both metformin and repaglinide is associated with a reduction in 3DG levels in non-obese individuals with type 2 diabetes. This may constitute a shared metabolic pathway through which both treatments have a beneficial impact on the cardiovascular risk.
European journal of endocrinology / European Federation of Endocrine Societies. 01/2011;
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ABSTRACT: Diabetes mellitus (DM) is a multifactorial chronic metabolic disease characterized by hyperglycaemia. Several different mechanisms have been implicated in the development of the disease, including endoplasmic reticulum (ER) stress. ER stress is increasingly acknowledged as an important mechanism in the development of DM, not only for beta-cell loss but also for insulin resistance. Accumulating evidence suggests that ER stress-induced apoptosis may be an important mode of beta-cell loss and therefore important in the development of diabetes. Recent data also suggest a role of ER stress-induced apoptosis in liver and adipose tissue in relation to diabetes, but more extensive studies on human adipocyte and hepatocyte (patho)physiology and ER stress are needed to identify the exact interactions between environmental signals, ER stress and apoptosis in these organs.
Apoptosis 09/2009; 14(12):1424-34. · 4.07 Impact Factor
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ABSTRACT: We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination.
This was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. The primary end point was a change in albuminuria. Secondary measures included change in 24-h blood pressure and glomerular filtration rate (GFR).
Placebo geometric mean albuminuria was 258 mg/day (range 84-2,361), mean +/- SD 24-h blood pressure was 140/73 +/- 15/8 mmHg, and GFR was 89 +/- 27 ml/min per 1.73 m(2). Aliskiren treatment reduced albuminuria by 48% (95% CI 27-62) compared with placebo (P < 0.001), not significantly different from the 58% (42-79) reduction with irbesartan treatment (P < 0.001 vs. placebo). Combination treatment reduced albuminuria by 71% (59-79), more than either monotherapy (P < 0.001 and P = 0.028). Fractional clearances of albumin were significantly reduced (46, 56, and 67% reduction vs. placebo). Twenty-four-hour blood pressure was reduced 3/4 mmHg by aliskiren (NS/P = 0.009), 12/5 mmHg by irbesartan (P < 0.001/P = 0.002), and 10/6 mmHg by the combination (P = 0.001/P < 0.001). GFR was significantly reduced 4.6 (95% CI 0.3-8.8) ml/min per 1.73 m(2) by aliskiren, 8.0 (3.6-12.3) ml/min per 1.73 m(2) by irbesartan, and 11.7 (7.4-15.9) ml/min per 1.73 m(2) by the combination.
The combination of aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with albuminuria than monotherapy.
Diabetes care 08/2009; 32(10):1873-9. · 8.09 Impact Factor
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Lian Engelen,
Isabel Ferreira,
Olaf Brouwers,
Ronald M A Henry,
Jacqueline M Dekker,
Giel Nijpels,
Robert J Heine,
Marleen M J van Greevenbroek,
Carla J H van der Kallen,
Ellen E Blaak,
Edith J M Feskens,
Hugo ten Cate,
Coen D A Stehouwer, Casper G Schalkwijk
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ABSTRACT: Methylglyoxal is a major precursor in the formation of advanced glycation endproducts (AGEs), which are known to contribute to vascular complications such as hypertension and arterial stiffness. Methylglyoxal can be detoxified by glyoxalase 1 (GLO1). Because genetic variation in the GLO1 gene may alter the expression and/or the activity of GLO1, we investigated whether single nucleotide polymorphisms (SNPs) in the GLO1 gene are associated with vascular complications.
The study entailed cross-sectional data analyses of the Cohort study of Diabetes and Atherosclerosis Maastricht (CoDAM) study and the Hoorn study, comprising a total of 1289 participants, aged 64.5 +/- 8.58 years, of whom 43.5% had normal glucose metabolism, 23.2% had impaired glucose metabolism and 33.3% had type 2 diabetes mellitus. Nine tag SNPs that cover the common GLO1 gene variation were genotyped. Levels of blood pressure and markers of atherosclerosis, arterial stiffness, renal function and AGEs were compared across genotypes.
All genotyped SNPs were in Hardy-Weinberg equilibrium. Prevalence of hypertension and markers of atherosclerosis, arterial stiffness, renal function and AGEs did not differ across genotypes of the nine SNPs. In additive models, SNP18 (rs2736654) was associated with pulse pressure [-1.20 mmHg (95% confidence interval: -2.26;-0.14)] and SNP40 (rs10484854) was associated with systolic blood pressure [-1.77 mmHg (-3.40;-0.14)].
Polymorphisms in the GLO1 gene are not associated with the prevalence of hypertension, markers of atherosclerosis, renal function and AGEs and are weakly associated with pulse pressure and systolic blood pressure (possibly due to chance) in two Dutch cohorts of patients with normal glucose metabolism, impaired glucose metabolism and type 2 diabetes mellitus.
Journal of hypertension 05/2009; 27(7):1399-403. · 4.02 Impact Factor
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ABSTRACT: To assess whether serum anti-heat shock protein 27 (HSP27) antibody levels are associated with micro- and macrovascular complications of type 1 diabetes.
Anti-HSP27 IgG antibody levels were measured in 531 type 1 diabetic subjects recruited as part of the cross-sectional analysis of the EURODIAB Prospective Complications Study. Case subjects (n = 363) were defined as individuals with one or more diabetes complications and control subjects (n = 168) as individuals with no evidence of any diabetes complication.
Anti-HSP27 levels were comparable in case and control subjects (19.6 arbitrary units/ml [11.3-32.7] vs. 20.4 arbitrary units/ml [11.7-35.3], geometric mean [interquartile range]), and there was no correlation between HSP27 and anti-HSP27 levels (r = 0.01, P = 0.81). In logistic regression analysis, anti-HSP27 was not associated with the presence of complications, even after adjustment for main risk factors.
Anti-HSP27 antibody levels are not a marker of vascular complications in type 1 diabetes.
Diabetes care 05/2009; 32(7):1269-71. · 8.09 Impact Factor
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ABSTRACT: Heat shock protein 27 (HSP27) is a member of the small heat shock protein family of proteins. HSP27 expression is enhanced in target tissues of diabetic microvascular complications, and changes in circulating serum HSP27 levels (sHSP27) have been reported in patients with macrovascular disease. We investigated whether sHSP27 levels were associated with micro- and macrovascular complications in type 1 diabetic patients.
A cross-sectional, nested, case-control study from the EURODIAB Prospective Complications Study of 531 type 1 diabetic patients was performed. Case subjects (n = 363) were defined as those with one or more complications of diabetes; control subjects (n = 168) were defined as those with no evidence of any complication. We measured sHSP27 levels and investigated their associations with diabetes complications.
Mean sHSP27 levels were significantly higher in case subjects with distal symmetrical polyneuropathy (DSP) than in control subjects, even after adjustment for age and albumin excretion rate (AER) (785.9 vs. 574.7 pg/ml, P = 0.03). In logistic regression analysis, sHSP27 levels in the upper quartile were associated with a twofold increased odds ratio (OR) of DSP, independently of conventional risk factors, markers of inflammation, and AER (OR 2.41 [95% CI 1.11-5.24]).
In this large cohort of type 1 diabetic subjects, we found an independent association between sHSP27 and DSP. This suggests that sHSP27 levels may be a novel marker for diabetic neuropathy.
Diabetes 08/2008; 57(7):1966-70. · 8.29 Impact Factor
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ABSTRACT: To evaluate risk factors for progression from persistent microalbuminuria to diabetic nephropathy in the Irbesartan in Patients with Type 2 diabetes and Microalbuminuria (IRMA 2) study, including biomarkers of endothelial dysfunction, chronic low-grade inflammation, growth factors and advanced glycation end products (AGE peptides).
IRMA 2 was a 2-year multicentre, randomized, double-blind trial comparing irbesartan (150 and 300 mg once daily) versus placebo. The primary end-point was time to onset of diabetic nephropathy. Samples from a subgroup from the placebo and the 300 mg irbesartan treatment group were used in this post-hoc analysis (n = 269, 68 %). Nine biomarkers were analysed: high sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), fibrinogen, von Willebrand Factor (vWf), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin, transforming growth factor-beta (TGF-beta) and AGE peptides. Mean standard deviation scores (Z-scores) were used to combine biomarker information.
In a Cox enter model with combined Z-scores for biomarkers of endothelial dysfunction (vWf, sVCAM-1, sICAM-1, sE-selectin) and for biomarkers of inflammation (hs-CRP, IL-6, fibrinogen), endothelial dysfunction (hazard ratio for a 28 % increase ( = 1 SD) in Z-score) 3.20 (1.56 to 6.56), p = 0.001) and UAER (HR for a 75 % increase ( = 1 SD) in UAER) 2.61 (1.30 to 5.23), p = 0.007) were found as independent predictors. Independently, IL-6 and vWf predicted the end-point. In addition, endothelial Z-score was associated with progression of albuminuria (p = 0.038).
Endothelial dysfunction and possibly inflammation are novel predictors of progression to diabetic nephropathy in patients with type 2 diabetes and microalbuminuria independently of traditional risk factors. ClinicalTrials.gov ID: NCT00317915.
Scandinavian journal of clinical and laboratory investigation 07/2008; 68(8):731-8. · 1.38 Impact Factor
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ABSTRACT: Advanced glycation end products (AGEs) are associated with hypertension. Whether N(epsilon)-(carboxymethyl)lysine (CML) contributes to the development of hypertension in young spontaneously hypertensive rats (SHR) remains to be established compared to WKY. We determined blood pressure, renal function, marker for oxidative stress (OS), and CML in young WKY rats and SHR. We found blood pressure was increased in SHR with no difference in renal function and OS compared to WKY. CML was elevated in plasma (2.3 +/- 0.3 vs. 1.3 +/- 0.2 micromol/L) and kidney (1.0 +/- 0.1 vs. 0.5 +/- 0.1 micromol/L) compared to WKY. Early CML accumulation may contribute to the development of hypertension potentially by inducing early renal inflammation independent of glomerular dysfunction or oxidative stress.
Annals of the New York Academy of Sciences 05/2008; 1126:201-4. · 3.15 Impact Factor
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ABSTRACT: We assessed the impact of sample storage conditions on soluble vascular cell adhesion molecules (sVCAM), soluble intracellular adhesion molecules (sICAM-1), soluble (s)E-selectin, C-reactive protein (CRP), and sP-selectin.
Markers were measured by ELISA in venous blood from 10 healthy volunteers on aliquots stored as plasma or whole blood at 4, 21, or 30 degrees C for 1-5 days and after 1-5 freeze-thaw cycles. We compared results on these samples to results for samples processed immediately and stored at -80 degrees C. Statistical models assessed time-related effects and effects of postprocessing conditions.
Using an upper limit of 10% variation from baseline with P >0.05, we found that stability duration in plasma was 5 days for sVCAM-1 and sICAM-1 and at least 2 days for sE-selectin at 4, 21, and 30 degrees C and 5 days for CRP at 4 and 21 degrees C and 1 day at 30 degrees C. Stability duration in whole blood was 5 days for sVCAM-1 and sICAM-1 and at least 2 days for sE-selectin at 4, 21, and 30 degrees C and 5 days for CRP at 4 and 21 degrees C and 2 days at 30 degrees C. sP-selectin was not stable in plasma or whole blood. sICAM-1, sVCAM-1, CRP, and sE-selectin were stable after 5 freeze-thaw cycles.
sVCAM-1, sICAM-1, and CRP are stable in plasma or whole blood at 4 and 21 degrees C for at least 3 days and sE-selectin for 2 days. sP-selectin is not stable and therefore requires immediate assay.
Clinical Chemistry 10/2007; 53(10):1858-60. · 7.91 Impact Factor
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ABSTRACT: The impact of irbesartan treatment on biomarkers of low-grade inflammation, endothelial dysfunction, growth factors, and advanced glycation end products (AGEs) during the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study was evaluated. IRMA 2 was a 2-year multicenter, randomized, double-blind trial in patients comparing irbesartan (150 or 300 mg once daily) versus placebo. The primary end point was onset of overt nephropathy. A subgroup (n = 269, 68%) was analyzed for biomarkers at baseline and after 1 and 2 years. High-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, fibrinogen, adhesion molecules, transforming growth factor-beta, and AGE peptides were assessed. Irbesartan treatment yielded significant changes in hs-CRP (based on generalized estimating equation regression coefficient) with a 5.4% decrease per year versus a 10% increase per year in the placebo group (P < 0.001). Fibrinogen decreased 0.059 g/l per year from baseline versus placebo's 0.059 g/l increase per year (P = 0.027). IL-6 showed a 1.8% increase per year compared with placebo's 6.5% increase per year (P = 0.005). Changes in IL-6 were associated with changes in albumin excretion (P = 0.04). There was no treatment effect on the other biomarkers. Irbesartan (300 mg once daily) reduces low-grade inflammation in this high-risk population, and this may reduce the risk of micro- and macrovascular disease.
Diabetes 01/2007; 55(12):3550-5. · 8.29 Impact Factor
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ABSTRACT: Patients with renal insufficiency have an increased risk of cardiovascular disease that is not fully explained by the presence of known cardiovascular risk factors. In patients with end-stage renal disease, increased serum concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), has been linked to excess cardiovascular morbidity. We investigated, in patients with mild-to-moderate renal failure, the relationship between plasma ADMA and three surrogate markers of atherosclerosis that have been shown to have prognostic value, namely carotid intima-media thickness (IMT), plasma soluble vascular cell adhesion molecule-1 (sVCAM-1), and plasma C-reactive protein (CRP).
We used baseline data of an ongoing randomized trial in which the effects of oxidative stress-lowering treatment on vascular function and structure are studied in patients with chronic nondiabetic renal failure without clinical evidence of atherosclerosis (GFR 15 to 70 mL/min/per 1.73 m(2) according to the Cockcroft-Gault equation; ATIC study).
Data from 93 patients were used. Creatinine clearance was inversely related to plasma ADMA concentration (standardized beta after adjustment = -0.342, P = 0.023). Plasma ADMA was strongly related to carotid IMT in univariate (beta = 0.459, P < 0.0001) and multivariate analysis (beta= 0.444, P < 0.0001). Plasma ADMA was also significantly related with plasma soluble vascular cell adhesion molecule-1 (sVCAM-1) in univariate (beta = 0.260, P = 0.010) and multivariate (beta = 0.242, P = 0.022) analysis. Plasma ADMA was not significantly related to C-reactive protein (beta = -0.134, P = 0.204).
In patients with mild-to-moderate renal failure, renal function is inversely associated with plasma ADMA, which, in turn, is positively associated with carotid IMT and plasma sVCAM-1 concentration. Increased plasma ADMA may be a link between renal function and cardiovascular disease in patients with mild-to-moderate renal failure.
Kidney International 11/2005; 68(5):2230-6. · 6.61 Impact Factor
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ABSTRACT: SU6668 is a tyrosine kinase inhibitor which targets platelet-derived growth factor receptor-beta, fibroblast growth factor receptor-1, vascular endothelial growth factor receptor-2, and KIT. We did a phase I study to define the maximum tolerated dose and to assess the pharmacokinetics of SU6668 administered orally thrice daily with food.
Patients with histologically proven, advanced, and progressive solid tumors were included at a starting dose level of 400 mg/m2 thrice daily. The early onset of dose-limiting toxicities (DLT) required dose reductions to 100 and 200 mg/m2 thrice daily. Pharmacokinetics was done on days 1, 28, and 56.
Sixteen patients were included. Two of the first three patients developed DLTs, which consisted of grade 4 fatigue and grade 3 serositis-like pains. Six patients at dose level 100 mg/m2 thrice daily experienced no DLT. At dose level 200 mg/m2 thrice daily, two out of seven patients experienced DLTs consisting of grade 3 abdominal pain, grade 4 anorexia and grade 3 nausea/vomiting. Increasing doses resulted in a disproportional increase in area under the curve and C(max) (peak plasma concentration). Both variables, however, decreased significantly on days 28 and 56 compared with day 1 (P < 0.05). No objective responses were observed. Acute phase response, probably mediated by interleukin-6, was observed in serial blood samples.
The maximum tolerated dose of SU6668 given orally, thrice daily under fed conditions, is 100 mg/m2. Because of the low plasma levels reached at this dose level, the efficacy of SU6668 as a single agent is not to be expected.
Clinical Cancer Research 10/2005; 11(17):6240-6. · 7.74 Impact Factor
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ABSTRACT: Inflammatory activity is increased in type 1 diabetes and may predispose to vascular disease. Its origin is not clear. We therefore investigated determinants of inflammation in type 1 diabetes.
We performed a nested case-control study from the EURODIAB Prospective Complications Study of 543 European individuals having type 1 diabetes (278 men), diagnosed at <36 years of age. Case subjects (n = 348) were those with one or more complications of diabetes; control subjects (n = 195) were all those with no evidence of any complication. We determined levels of C-reactive protein, interleukin-6, and tumor necrosis factor-alpha, combined them in a "general score of inflammatory markers," and investigated their associations with vascular risk factors and markers of endothelial dysfunction by use of multiple linear regression analysis.
Measures of inflammation were associated with sex, diabetes duration, glycemic control, the advanced glycation end product pentosidine, BMI, HDL cholesterol, triglycerides, and systolic blood pressure (standardized betas with the general score of inflammatory markers 0.15 [P = 0.002], 0.15 [P = 0.006], 0.18 [P < 0.0001], 0.12 [P = 0.005], 0.10 [P = 0.057], -0.15 [P = 0.001], 0.16 [P < 0.0001], and 0.09 [P = 0.042], respectively). In addition, measures of inflammation were strongly associated with markers of endothelial dysfunction, soluble vascular cell adhesion molecule-1, and soluble E-selectin (standardized betas with the general score of inflammatory markers 0.28 [P < 0.0001] and 0.19 [P < 0.0001]).
We have shown that conventional risk factors for vascular disease and endothelial adhesion molecules are important determinants of inflammation in type 1 diabetic individuals, suggesting that strategies to decrease inflammatory activity in type 1 diabetes should focus not only on control of conventional risk factors, but also on improvement of endothelial function.
Diabetes Care 07/2003; 26(7):2165-73. · 8.09 Impact Factor
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ABSTRACT: The transmigration of leukocytes across the endothelium is a prerequisite for the inflammatory process. Leukocyte-endothelium interaction is regulated by several endothelial adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Their expression is enhanced by inflammatory mediators, such as TNalpha. In vivo a small part of these adhesion molecules is shed by proteases, and can be detected in the circulation. In this study, the time course of the TNalpha-induced accumulation in the blood of three circulating soluble adhesion molecules, sE-selectin, sICAM-1 and sVCAM-1, was studied in plasma samples of tumor patients enrolled in a phase I trial receiving TNalpha. Two different cohorts were studied. Eleven patients received a continuous 24-hour TNalpha infusion while 10 other patients received a 5-day continuous TNalpha infusion. After 24 hours of TNalpha infusion sE-selectin levels increased by 1985 +/- 312 %, sVCAM-1 by 301 +/- 19 % and sICAM-1 by 445 +/- 82 %. Differences in accumulation patterns were observed after 5 days of continuous TNalpha infusion. sVCAM-1 and sICAM-1 levels showed an increase during the infusion with a maximum at 3 to 5 days and stayed elevated after discontinuation of the TNalpha infusion. In contrast, sE-selectin reached its peak at day 1 and declined thereafter. In conclusion, sVCAM-1 and sICAM-1 show a different accumulation pattern upon TNalpha infusion as compared to sE-selectin in man.
Thrombosis and Haemostasis 07/2003; 89(6):1052-7. · 5.04 Impact Factor
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ABSTRACT: In 196 type 1 diabetic subjects and 195 nondiabetic subjects aged 30-55 years, we examined whether C-reactive protein (CRP) is elevated in diabetes and whether CRP is associated with coronary artery calcification (CAC).
CRP was measured with a highly sensitive immunoassay. CAC was measured using electron beam computed tomography.
CRP was elevated in diabetic women compared with nondiabetic women (median 1.62 vs. 0.85 mg/l, P < 0.001) independently of other factors, but was similar in diabetic and nondiabetic men (median 0.82 vs. 0.81 mg/l). Insulin dose per day was positively correlated with CRP in diabetic women (Spearman's rho = 0.36, P = 0.0003) but much less so in men (rho = 0.16, P = 0.09). Being in the top tertile for CRP was associated with CAC in diabetic and nondiabetic men even after adjustment for other risk factors (adjusted odds ratio [OR] = 4.6 and 4.3, respectively, P = 0.02 for both). In nondiabetic women, being in the top tertile for CRP was associated with CAC (OR 3.1, P = 0.04), but not independently of BMI (OR = 1 after adjustment). Among diabetic women the association was not significant even before adjustment for BMI (OR = 2.6, P = 0.07).
Elevated CRP in diabetic women might reflect a particular sensitivity to insulin levels or might reflect insulin resistance. In general, CRP is an important marker of subclinical atherosclerosis, but the clinical significance of elevated CRP in diabetic women needs to be addressed in prospective studies, since CRP was not clearly associated with CAC in this group.
Diabetes Care 11/2002; 25(10):1813-7. · 8.09 Impact Factor
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ABSTRACT: OBJECTIVE—In 196 type 1 diabetic subjects and 195 nondiabetic subjects aged 30–55 years, we examined whether C-reactive protein (CRP) is elevated in diabetes and whether CRP is associated with coronary artery calcification (CAC). RESEARCH DESIGN AND METHODS—CRP was measured with a highly sensitive immunoassay. CAC was measured using electron beam computed tomography. RESULTS—CRP was elevated in diabetic women compared with nondiabetic women (median 1.62 vs. 0.85 mg/l, P < 0.001) independently of other factors, but was similar in diabetic and nondiabetic men (median 0.82 vs. 0.81 mg/l). Insulin dose per day was positively correlated with CRP in diabetic women (Spearman’s ρ = 0.36, P = 0.0003) but much less so in men (ρ = 0.16, P = 0.09). Being in the top tertile for CRP was associated with CAC in diabetic and nondiabetic men even after adjustment for other risk factors (adjusted odds ratio [OR] = 4.6 and 4.3, respectively, P = 0.02 for both). In nondiabetic women, being in the top tertile for CRP was associated with CAC (OR 3.1, P = 0.04), but not independently of BMI (OR = 1 after adjustment). Among diabetic women the association was not significant even before adjustment for BMI (OR = 2.6, P = 0.07). CONCLUSIONS—Elevated CRP in diabetic women might reflect a particular sensitivity to insulin levels or might reflect insulin resistance. In general, CRP is an important marker of subclinical atherosclerosis, but the clinical significance of elevated CRP in diabetic women needs to be addressed in prospective studies, since CRP was not clearly associated with CAC in this group. British Heart Foundation
