adrie verhoeven - Profile on Academia.edu (original) (raw)
Papers by adrie verhoeven
Atherosclerosis, Aug 1, 2019
showed moderate correlations with PWV: 0.375 (p<0.05) and 0.412 (p<0.0001) in males and 0.468 (p<... more showed moderate correlations with PWV: 0.375 (p<0.05) and 0.412 (p<0.0001) in males and 0.468 (p<0.0001) and 0.389 (p<0.001) in females. Only few biochemical markers demonstrated a significant correlation (p<0.05): TC and TG in males (0.326 and 0.290) and Lp(a) in females (-0.261). The stepwise least squares multiple regression analysis showed an association of PWV only with DBP (p<0.001) in males and with SBP (p<0.001) in females (R¼0.649 and 0.443, R2-adjusted ¼ 0.408 and 0.181). Conclusions: In young Tallinn adults, BP showed an important impact on PWV variability, whereas biochemical markers failed to demonstrate significant association.
Altered Functionality of Lipoprotein(a) Impacts on Angiogenesis in Diabetic Retinopathy
Investigative Opthalmology & Visual Science
Integrative approach reveals specific disturbances in β‐adrenergic signaling in a porcine model of post‐myocardial infarction remodeling
The FASEB Journal, 2011
Clinical Nutrition, 2021
Background & aims: Microalbuminuria is an early sign of vascular complications of type 2 diabetes... more Background & aims: Microalbuminuria is an early sign of vascular complications of type 2 diabetes and predicts cardiovascular disease and mortality. Monomeric and oligomeric flavanols (MOFs) are linked to improved vascular health. The aim of this study was to assess the effect of 3 months MOFs on albuminuria and endothelial function markers in patients with type 2 diabetes and microalbuminuria. Methods: We conducted a double-blind, placebo-controlled trial among patients with type 2 diabetes and microalbuminuria. Patients with type 2 diabetes received either 200 mg MOFs or placebo daily on top of their habitual diet and medication. The primary endpoint was the between-group difference of the change in 24-h Albumin Excretion Rate (AER) over three months. Secondary endpoints were the between-group differences of the change in plasma levels of different markers of endothelial dysfunction. Mixed-modelling was applied for the longitudinal analyses. Results: Participants (n ¼ 97) were 63.0 ± 9.5 years old; diabetes-duration was 15.7 ± 8.5 years. Median baseline AER was 60 (IQR 20e120) mg/24 h. There was no within-group difference in median change of AER from baseline to 3 months in the intervention (0 (-35-21) mg/24 h, p ¼ 0.41) or the control group (0 (-20-10) mg/24 h, p ¼ 0.91). There was no between-group difference in the course of AER over three months (log-transformed data: b ¼ À0.02 (95%CI -0.23-0.20), p ¼ 0.88), nor in the plasma levels of the endothelial dysfunction markers. Conclusion: Daily 200 mg MOFs for three months on top of habitual diet and usual care did not reduce AER and plasma markers of endothelial dysfunction compared to placebo, in patients with long-term type 2 diabetes and microalbuminuria. Clinical trials registration: NTR4669, www.trialregister.nl.
Breakfast partly restores the anti-inflammatory function of high-density lipoproteins from patients with type 2 diabetes mellitus
Atherosclerosis Plus, 2021
Abstract Background and aims High-density lipoproteins (HDL) of patients with type 2 diabetes mel... more Abstract Background and aims High-density lipoproteins (HDL) of patients with type 2 diabetes mellitus (T2DM) have impaired anti-inflammatory activities. The anti-inflammatory activity of HDL has been determined ex vivo after isolation by different methods from blood mostly obtained after overnight fasting. We first determined the effect of the HDL isolation method, and subsequently the effect of food intake on the anti-inflammatory function of HDL from T2DM patients. Methods Blood was collected from healthy controls and T2DM patients after an overnight fast, and from T2DM patients 3 h after breakfast (n = 17 each). HDL was isolated by a two-step density gradient ultracentrifugation in iodixanol (HDLDGUC2), by sequential salt density flotation (HDLSEQ) or by PEG precipitation (HDLPEG). The anti-inflammatory function of HDL was determined by the reduction of the TNFα-induced expression of VCAM-1 in human coronary artery endothelial cells (HCAEC) and retinal endothelial cells (REC). Results HDL isolated by the three different methods from healthy controls inhibited TNFα-induced VCAM-1 expression in HCAEC. With apoA-I at 0.7 μM, HDLDGUC2 and HDLSEQ were similarly effective (16% versus 14% reduction; n = 3; p > 0.05) but less effective than HDLPEG (28%, p Conclusions The ex vivo anti-inflammatory activity of HDL is affected by the HDL isolation method. Two-step ultracentrifugation in an iodixanol gradient is a suitable method for HDL isolation when testing HDL anti-inflammatory function. The anti-inflammatory activity of HDL from overnight fasted T2DM patients is significantly impaired in REC but not in HCAEC. The anti-inflammatory function of HDL is partly restored by food intake.
HDL associates with insulin resistance and beta-cell dysfunction in South Asian families at risk of type 2 diabetes
Journal of Diabetes and its Complications, 2021
OBJECTIVE Dyslipidemia precedes type 2 diabetes (T2D) and worsens with increasing glucose intoler... more OBJECTIVE Dyslipidemia precedes type 2 diabetes (T2D) and worsens with increasing glucose intolerance. First degree relatives of T2D patients have an increased risk to develop dyslipidemia and glucose intolerance. The aim of the present study was to assess the relation between the development of dyslipidemia and glucose intolerance in first-degree relatives of T2D patients. RESEARCH DESIGN AND METHODS Fasting lipoprotein profiles were determined by density gradient ultracentrifugation in T2D patients and their first-degree relatives (42 Caucasians and 33 South Asians), and in 29 normoglycemic controls from non-T2D families. Glucose tolerance, insulin sensitivity index (ISI) and insulin disposition index (DI) were assessed by an extended, frequently sampled oral glucose tolerance test (OGTT), and fractional insulin synthesis rate (FSR) was measured by 13C-leucine enrichment in urinary C-peptide during the OGTT. RESULTS Of the first-degree relatives, 40, 16 and 19 had NGT, prediabetes and T2D, respectively. NGT family members had lower plasma HDL-cholesterol (HDLC) (1.34 ± 0.07 vs 1.58 ± 0.06 mmol/L; p = 0.015), HDL2-C (0.41 ± 0.05 vs 0.57 ± 0.05 mmol/L; p = 0.021) and HDL3-C (0.62 ± 0.03 vs 0.72 ± 0.02 mmol/L; p = 0.043) than controls. HDL2-C levels tended to decrease with increasing glucose intolerance state. In South Asians, buoyant LDL-C levels decreased with increasing glucose intolerance state (p = 0.006). In South Asian families, HDL-C correlated with both ISI and DI (β 0.42; p = 0.04 and β 0.53; p = 0.01, respectively), whereas HDL2-C and HDL3-C levels correlated with DI (β 0.64; p = 0.002 and β 0.57; p = 0.005, respectively). HDL2-C and plasma triglyceride correlated with FSR (β 0.48; p = 0.033 and β -0.50; p = 0.029, respectively). CONCLUSIONS Low HDL2-C and HDL3-C levels are present in NGT first-degree relatives of T2D patients, and HDL2-C tend to decrease further with increasing glucose intolerance. In South Asian families HDL2-C and HDL3-C levels linked predominantly to deteriorating beta cell function.
The role of lipoprotein(a) in diabetic retinopathy; pro-inflammatory or pro-angiogenic?
Atherosclerosis, 2021
We developed and implemented the software application titled Metabolic Interrelationships as a se... more We developed and implemented the software application titled Metabolic Interrelationships as a selflearning and -teaching tool for intermediary metabolism. It is used by undergraduate medical students in an integrated organ systems-based and disease-oriented core curriculum, which started in our medical faculty in 2001. The computer program provides an interactive environment in which students learn to integrate the major metabolic pathways as well as their hormonal control mechanisms as far as they depend on nutritional status. Students can explore the time-and tissue-dependent changes in mammalian intermediary metabolism during a feeding-fasting cycle. Starting from a whole-body view of interorgan nutrient fluxes, the student can make excursions to individual organs and, from there, to increasing levels of molecular detail and to explanatory animations. The application is well received by students and staff.
Circulation, 2004
Background— We hypothesized that normal and pathological vessel walls display a differential patt... more Background— We hypothesized that normal and pathological vessel walls display a differential pattern of secreted proteins. We have recently set up the conditions for comparing secretomes from carotid atherosclerotic plaques and control arteries using a proteomic approach to assess whether differentially secreted proteins could represent markers for atherosclerosis. Methods and Results— Normal endartery segments and different regions of endarterectomy pieces (noncomplicated/complicated plaques) were incubated in protein-free medium, and the released proteins were analyzed by 2D electrophoresis (2-DE). Among the differently secreted proteins, we have identified heat shock protein-27 (HSP27). Surprisingly, compared with control arteries, HSP27 release was drastically decreased in atherosclerotic plaques and barely detectable in complicated plaque supernatants. HSP27 was expressed primarily by intact vascular cells of normal arteries and carotid plaques (immunohistochemistry). Plasma de...
Additional file 1: of Use of monomeric and oligomeric flavanols in the dietary management of patients with type 2 diabetes mellitus and microalbuminuria (FLAVA trial): study protocol for a randomized controlled trial
SPIRIT 2013 Checklist. (DOC 121 kb)
Journal of Biological Chemistry, 1994
In mammals, an AMP-activated protein kinase (AMPK) phosphorylates both acetyl-coA carboxylase and... more In mammals, an AMP-activated protein kinase (AMPK) phosphorylates both acetyl-coA carboxylase and 3-hydroxy-3-methylglutaryl-CoA reductase in vitro and has been proposed to play a major role in the regulation of lipid metabolism in viuo. W e report here the primary sequence of rat AMPK and show that antibodies raised against synthetic peptides based on the deduced sequence of AMPK immunoprecipitate AMPK activity from rat liver extracts. AMPK has a remarkable degree of sequence identity to the proteins encoded by the yeast SNFl gene and the plant RKINl gene. SNFl protein kinase activity is essential for release of genes from glucose repression in Saccharomyces cerevisiae. Expression of cRKINl in yeast snfl mutants restores SNFl function. These results indicate that AMPK, SNF1, and R K I N l form part of a family of protein kinases that have been highly conserved throughout evolution. Our results suggest that AMPK may be involved in the regulation of a wide range of metabolic pathways. An AMP-activated protein kinase (AMPK)' has been proposed to play an important role in the regulation of mammalian lipid metabolism (
Journal of Physiology and Biochemistry, 2010
Protocols for the extraction of nuclear proteins have been developed for cultured cells and fresh... more Protocols for the extraction of nuclear proteins have been developed for cultured cells and fresh tissue, but sometimes only frozen tissue is available. We have optimized the homogenization procedure and subsequent fractionation protocol for the preparation of nuclear protein extracts from frozen porcine left ventricular (LV) tissue. This method gave a highly reproducible protein yield (6.5±0.7% of total protein; mean±SE, n=9) and a 6-fold enrichment of the nuclear marker protein B23. The nuclear protein extracts were essentially devoid of cytosolic, myofilament, and histone proteins. Compared to nuclear extracts from fresh LV tissue, some loss of nuclear proteins to the cytosolic fraction was observed. Using this method, we studied the distribution of tyrosinephosphorylated signal transducer and activator of transcription 3 (PY-STAT3) in LV tissue of animals treated with the β-agonist dobutamine. Upon treatment , PY-STAT3 increased 30.2±8.5-fold in total homogenates, but only 6.9±2.1-fold (n=4, P=0.03) in nuclear protein extracts. Of all PY-STAT3 formed, only a minor fraction appeared in the nuclear fraction. This simple and reproducible protocol yielded nuclear protein extracts that were highly enriched in nuclear proteins with almost complete removal of cytosolic and myofilament proteins. This nuclear protein extraction protocol is therefore well-suited for nuclear proteome analysis of frozen heart tissue collected in biobanks. Keywords Nuclear extract. Frozen tissue. Transcription factors. Heart tissue Abbreviations DPBS Dulbecco's phosphate-buffered saline ECL Enhanced chemiluminescence GAPDH Glyceraldehyde-3-phosphate dehydrogenase LV Left ventricle LV dP/dt max Maximum rate of rise of left ventricular pressure PY-STAT3 Tyrosine-phosphorylated signal transducer and activator of transcription 3 SERCA2 Sarcoplasmic/endoplasmic reticulum Ca 2+-ATPase 2 SR Sarcoplasmic reticulum TF Transcription factor
XIth International Congress on Thrombosis and Haemostasis
Signal processing in platelets seems to involve polyphosphoinositide (PPI) metabolism, although d... more Signal processing in platelets seems to involve polyphosphoinositide (PPI) metabolism, although direct coupling between PPI metabolism and responses has not been proved. Neomycin binds tightly to PPIs and has been used to probe the involvement of PPI metabolism and responses in platelets. Neomycin(SO4)3 powerfully inhibited ADP- and adrenaline-induced aggregation of platelets in PRP. This was partly due to the sulphate anion; the chloride form was therefore prepared. Platelets were prelabelled in PRP with 32P-Pi. and transferred by gel filtration to a calcium-free Tyrode’s solution (GFP). Increasing concentrations (2-5 mM) of neomycinCl6 caused progressive inhibition of thrombin-induced aggregation, dense granule secretion, acid hydrolase secretion and formation of 32P-phosphatidic acid (PA); the inhibition was immediate, not affected by aspirin and counteracted by increasing thrombin concentrations. Incubation of neomycin (up to 5 mM) with this GFP or with P-Pi. On GFP prepared fro...
Atherosclerosis
High levels of Lp(a) may contribute to the residual cardiovascular risk in statin-treated dyslipi... more High levels of Lp(a) may contribute to the residual cardiovascular risk in statin-treated dyslipidemic patients. • Reported data on modulatory effects of statins on plasma Lp(a) levels are inconsistent. • Statin treatment increases Lp(a) levels in patients with dyslipidemia, exclusively in those with the LMW apo(a) phenotype. • The increase in Lp(a) levels upon statin treatment was not associated with common LPA SNPs or change in LDL cholesterol.
Trials, Jan 16, 2018
Patients with type 2 diabetes mellitus (T2D) are prone to micro- and macro-vascular complications... more Patients with type 2 diabetes mellitus (T2D) are prone to micro- and macro-vascular complications. Monomeric and oligomeric flavanols (MOF) isolated from grape seeds (Vitis vinifera) have been linked to improved endothelial function and vascular health. The aim of this study is to determine the effect of a daily supplementation of 200 mg MOF on renal endothelial function of patients with T2D and microalbuminuria. For this double-blind, placebo-controlled, randomized, multicenter trial 96 individuals (ages 40-85 years) with T2D and microalbuminuria will be recruited. Participants will be randomly assigned to the intervention group, receiving 200 mg of MOF daily for 3 months, or to the control group, receiving a placebo. The primary endpoint is the evolution over time in albumin excretion rate (AER) until 3 months of intervention as compared with placebo. Secondary endpoints are the evolution over time in established plasma markers of renal endothelial function-asymmetric dimethylargi...
Diabetologia, 2018
Weight-loss programmes for adults with type 2 diabetes are less effective in the long term owing ... more Weight-loss programmes for adults with type 2 diabetes are less effective in the long term owing to regain of weight. Our aim was to determine the 2 year effectiveness of a cognitive behavioural group therapy (group-CBT) programme in weight maintenance after diet-induced weight loss in overweight and obese adults with type 2 diabetes, using a randomised, parallel, non-blinded, pragmatic study design. We included 158 obese adults (median BMI 36.3 [IQR 32.5-40.0] kg/m) with type 2 diabetes from the outpatient diabetes clinic of Erasmus MC, the Netherlands, who achieved ≥5% weight loss on an 8 week very low calorie diet. Participants were randomised (stratified by weight loss) to usual care or usual care plus group-CBT (17 group sessions). The primary outcomes were the between-group differences after 2 years in: (1) body weight; and (2) weight regain. Secondary outcomes were HbA levels, insulin dose, plasma lipid levels, depression, anxiety, self-esteem, quality of life, fatigue, physi...
Diet-induced weight loss and markers of endothelial dysfunction and inflammation in treated patients with type 2 diabetes
Clinical Nutrition ESPEN
s u m m a r y Background & aims: Overweight and obesity increase cardiovascular mortality... more s u m m a r y Background & aims: Overweight and obesity increase cardiovascular mortality in patients with type 2 diabetes (T2D). In a recent trial, however, diet-induced weight loss did not reduce the cardiovascular risk of patients with T2D, possibly due to the parallel intensive medical treatment. We investigated the effect of diet-induced weight loss on cardiovascular risk factors in overweight and obese patients with T2D, and whether this effect was influenced by the use of statins, ACE inhibitors, metformin and duration of T2D. Methods: Patients with T2D and BMI >27 were subjected to an energy-restricted diet during 4 months. Before and after intervention, plasma levels of sICAM-1, sVCAM-1, hsCRP, vWF and classical biomarkers were measured. The association of the change in biomarker levels with medication use and T2D history, corrected for age, sex and change in insulin dose, was tested by matched linear regression analyses.
The anti-inflammatory function of high-density lipoprotein in type II diabetes: A systematic review
Journal of Clinical Lipidology
Soluble LR11 associates with aortic root calcification in asymptomatic treated male patients with familial hypercholesterolemia
Atherosclerosis
Despite statin treatment, a high prevalence of severe vascular calcification is found in patients... more Despite statin treatment, a high prevalence of severe vascular calcification is found in patients with familial hypercholesterolemia (FH). We assessed the relation between the circulating soluble form of low-density lipoprotein receptor relative with 11 ligand-binding repeats (sLR11), a risk factor for cardiovascular disease, and vascular calcification in asymptomatic statin-treated heterozygous FH patients. In 123 asymptomatic heterozygous FH patients (age 40-69 years), aortic root (ARC), aortic valve (AVC) and coronary artery calcification (CAC) were determined with CT-based calcium scoring expressed in Agatston units. Plasma sLR11 levels were measured by sandwich ELISA. Seventy-three patients displayed ARC, 48 had AVC and 96 CAC. Plasma sLR11 levels were positively correlated with the presence of ARC (r = 0.2, p = 0.03), but not with AVC or CAC. The correlation between sLR11 levels and ARC was restricted to male FH patients (r = 0.31, p = 0.006). Multivariate logistic analyses showed that the association of plasma sLR11 with the presence of ARC was independent of other determinants (Adjusted Odds Ratio, 2.01 (95% CI = 1.28-3.16) p = 0.002). Plasma sLR11 is associated with ARC in male FH patients and may be mechanistically involved in the differential distribution of atherosclerotic lesions in the vasculature.
Atherosclerosis, Aug 1, 2019
showed moderate correlations with PWV: 0.375 (p<0.05) and 0.412 (p<0.0001) in males and 0.468 (p<... more showed moderate correlations with PWV: 0.375 (p<0.05) and 0.412 (p<0.0001) in males and 0.468 (p<0.0001) and 0.389 (p<0.001) in females. Only few biochemical markers demonstrated a significant correlation (p<0.05): TC and TG in males (0.326 and 0.290) and Lp(a) in females (-0.261). The stepwise least squares multiple regression analysis showed an association of PWV only with DBP (p<0.001) in males and with SBP (p<0.001) in females (R¼0.649 and 0.443, R2-adjusted ¼ 0.408 and 0.181). Conclusions: In young Tallinn adults, BP showed an important impact on PWV variability, whereas biochemical markers failed to demonstrate significant association.
Altered Functionality of Lipoprotein(a) Impacts on Angiogenesis in Diabetic Retinopathy
Investigative Opthalmology & Visual Science
Integrative approach reveals specific disturbances in β‐adrenergic signaling in a porcine model of post‐myocardial infarction remodeling
The FASEB Journal, 2011
Clinical Nutrition, 2021
Background & aims: Microalbuminuria is an early sign of vascular complications of type 2 diabetes... more Background & aims: Microalbuminuria is an early sign of vascular complications of type 2 diabetes and predicts cardiovascular disease and mortality. Monomeric and oligomeric flavanols (MOFs) are linked to improved vascular health. The aim of this study was to assess the effect of 3 months MOFs on albuminuria and endothelial function markers in patients with type 2 diabetes and microalbuminuria. Methods: We conducted a double-blind, placebo-controlled trial among patients with type 2 diabetes and microalbuminuria. Patients with type 2 diabetes received either 200 mg MOFs or placebo daily on top of their habitual diet and medication. The primary endpoint was the between-group difference of the change in 24-h Albumin Excretion Rate (AER) over three months. Secondary endpoints were the between-group differences of the change in plasma levels of different markers of endothelial dysfunction. Mixed-modelling was applied for the longitudinal analyses. Results: Participants (n ¼ 97) were 63.0 ± 9.5 years old; diabetes-duration was 15.7 ± 8.5 years. Median baseline AER was 60 (IQR 20e120) mg/24 h. There was no within-group difference in median change of AER from baseline to 3 months in the intervention (0 (-35-21) mg/24 h, p ¼ 0.41) or the control group (0 (-20-10) mg/24 h, p ¼ 0.91). There was no between-group difference in the course of AER over three months (log-transformed data: b ¼ À0.02 (95%CI -0.23-0.20), p ¼ 0.88), nor in the plasma levels of the endothelial dysfunction markers. Conclusion: Daily 200 mg MOFs for three months on top of habitual diet and usual care did not reduce AER and plasma markers of endothelial dysfunction compared to placebo, in patients with long-term type 2 diabetes and microalbuminuria. Clinical trials registration: NTR4669, www.trialregister.nl.
Breakfast partly restores the anti-inflammatory function of high-density lipoproteins from patients with type 2 diabetes mellitus
Atherosclerosis Plus, 2021
Abstract Background and aims High-density lipoproteins (HDL) of patients with type 2 diabetes mel... more Abstract Background and aims High-density lipoproteins (HDL) of patients with type 2 diabetes mellitus (T2DM) have impaired anti-inflammatory activities. The anti-inflammatory activity of HDL has been determined ex vivo after isolation by different methods from blood mostly obtained after overnight fasting. We first determined the effect of the HDL isolation method, and subsequently the effect of food intake on the anti-inflammatory function of HDL from T2DM patients. Methods Blood was collected from healthy controls and T2DM patients after an overnight fast, and from T2DM patients 3 h after breakfast (n = 17 each). HDL was isolated by a two-step density gradient ultracentrifugation in iodixanol (HDLDGUC2), by sequential salt density flotation (HDLSEQ) or by PEG precipitation (HDLPEG). The anti-inflammatory function of HDL was determined by the reduction of the TNFα-induced expression of VCAM-1 in human coronary artery endothelial cells (HCAEC) and retinal endothelial cells (REC). Results HDL isolated by the three different methods from healthy controls inhibited TNFα-induced VCAM-1 expression in HCAEC. With apoA-I at 0.7 μM, HDLDGUC2 and HDLSEQ were similarly effective (16% versus 14% reduction; n = 3; p > 0.05) but less effective than HDLPEG (28%, p Conclusions The ex vivo anti-inflammatory activity of HDL is affected by the HDL isolation method. Two-step ultracentrifugation in an iodixanol gradient is a suitable method for HDL isolation when testing HDL anti-inflammatory function. The anti-inflammatory activity of HDL from overnight fasted T2DM patients is significantly impaired in REC but not in HCAEC. The anti-inflammatory function of HDL is partly restored by food intake.
HDL associates with insulin resistance and beta-cell dysfunction in South Asian families at risk of type 2 diabetes
Journal of Diabetes and its Complications, 2021
OBJECTIVE Dyslipidemia precedes type 2 diabetes (T2D) and worsens with increasing glucose intoler... more OBJECTIVE Dyslipidemia precedes type 2 diabetes (T2D) and worsens with increasing glucose intolerance. First degree relatives of T2D patients have an increased risk to develop dyslipidemia and glucose intolerance. The aim of the present study was to assess the relation between the development of dyslipidemia and glucose intolerance in first-degree relatives of T2D patients. RESEARCH DESIGN AND METHODS Fasting lipoprotein profiles were determined by density gradient ultracentrifugation in T2D patients and their first-degree relatives (42 Caucasians and 33 South Asians), and in 29 normoglycemic controls from non-T2D families. Glucose tolerance, insulin sensitivity index (ISI) and insulin disposition index (DI) were assessed by an extended, frequently sampled oral glucose tolerance test (OGTT), and fractional insulin synthesis rate (FSR) was measured by 13C-leucine enrichment in urinary C-peptide during the OGTT. RESULTS Of the first-degree relatives, 40, 16 and 19 had NGT, prediabetes and T2D, respectively. NGT family members had lower plasma HDL-cholesterol (HDLC) (1.34 ± 0.07 vs 1.58 ± 0.06 mmol/L; p = 0.015), HDL2-C (0.41 ± 0.05 vs 0.57 ± 0.05 mmol/L; p = 0.021) and HDL3-C (0.62 ± 0.03 vs 0.72 ± 0.02 mmol/L; p = 0.043) than controls. HDL2-C levels tended to decrease with increasing glucose intolerance state. In South Asians, buoyant LDL-C levels decreased with increasing glucose intolerance state (p = 0.006). In South Asian families, HDL-C correlated with both ISI and DI (β 0.42; p = 0.04 and β 0.53; p = 0.01, respectively), whereas HDL2-C and HDL3-C levels correlated with DI (β 0.64; p = 0.002 and β 0.57; p = 0.005, respectively). HDL2-C and plasma triglyceride correlated with FSR (β 0.48; p = 0.033 and β -0.50; p = 0.029, respectively). CONCLUSIONS Low HDL2-C and HDL3-C levels are present in NGT first-degree relatives of T2D patients, and HDL2-C tend to decrease further with increasing glucose intolerance. In South Asian families HDL2-C and HDL3-C levels linked predominantly to deteriorating beta cell function.
The role of lipoprotein(a) in diabetic retinopathy; pro-inflammatory or pro-angiogenic?
Atherosclerosis, 2021
We developed and implemented the software application titled Metabolic Interrelationships as a se... more We developed and implemented the software application titled Metabolic Interrelationships as a selflearning and -teaching tool for intermediary metabolism. It is used by undergraduate medical students in an integrated organ systems-based and disease-oriented core curriculum, which started in our medical faculty in 2001. The computer program provides an interactive environment in which students learn to integrate the major metabolic pathways as well as their hormonal control mechanisms as far as they depend on nutritional status. Students can explore the time-and tissue-dependent changes in mammalian intermediary metabolism during a feeding-fasting cycle. Starting from a whole-body view of interorgan nutrient fluxes, the student can make excursions to individual organs and, from there, to increasing levels of molecular detail and to explanatory animations. The application is well received by students and staff.
Circulation, 2004
Background— We hypothesized that normal and pathological vessel walls display a differential patt... more Background— We hypothesized that normal and pathological vessel walls display a differential pattern of secreted proteins. We have recently set up the conditions for comparing secretomes from carotid atherosclerotic plaques and control arteries using a proteomic approach to assess whether differentially secreted proteins could represent markers for atherosclerosis. Methods and Results— Normal endartery segments and different regions of endarterectomy pieces (noncomplicated/complicated plaques) were incubated in protein-free medium, and the released proteins were analyzed by 2D electrophoresis (2-DE). Among the differently secreted proteins, we have identified heat shock protein-27 (HSP27). Surprisingly, compared with control arteries, HSP27 release was drastically decreased in atherosclerotic plaques and barely detectable in complicated plaque supernatants. HSP27 was expressed primarily by intact vascular cells of normal arteries and carotid plaques (immunohistochemistry). Plasma de...
Additional file 1: of Use of monomeric and oligomeric flavanols in the dietary management of patients with type 2 diabetes mellitus and microalbuminuria (FLAVA trial): study protocol for a randomized controlled trial
SPIRIT 2013 Checklist. (DOC 121 kb)
Journal of Biological Chemistry, 1994
In mammals, an AMP-activated protein kinase (AMPK) phosphorylates both acetyl-coA carboxylase and... more In mammals, an AMP-activated protein kinase (AMPK) phosphorylates both acetyl-coA carboxylase and 3-hydroxy-3-methylglutaryl-CoA reductase in vitro and has been proposed to play a major role in the regulation of lipid metabolism in viuo. W e report here the primary sequence of rat AMPK and show that antibodies raised against synthetic peptides based on the deduced sequence of AMPK immunoprecipitate AMPK activity from rat liver extracts. AMPK has a remarkable degree of sequence identity to the proteins encoded by the yeast SNFl gene and the plant RKINl gene. SNFl protein kinase activity is essential for release of genes from glucose repression in Saccharomyces cerevisiae. Expression of cRKINl in yeast snfl mutants restores SNFl function. These results indicate that AMPK, SNF1, and R K I N l form part of a family of protein kinases that have been highly conserved throughout evolution. Our results suggest that AMPK may be involved in the regulation of a wide range of metabolic pathways. An AMP-activated protein kinase (AMPK)' has been proposed to play an important role in the regulation of mammalian lipid metabolism (
Journal of Physiology and Biochemistry, 2010
Protocols for the extraction of nuclear proteins have been developed for cultured cells and fresh... more Protocols for the extraction of nuclear proteins have been developed for cultured cells and fresh tissue, but sometimes only frozen tissue is available. We have optimized the homogenization procedure and subsequent fractionation protocol for the preparation of nuclear protein extracts from frozen porcine left ventricular (LV) tissue. This method gave a highly reproducible protein yield (6.5±0.7% of total protein; mean±SE, n=9) and a 6-fold enrichment of the nuclear marker protein B23. The nuclear protein extracts were essentially devoid of cytosolic, myofilament, and histone proteins. Compared to nuclear extracts from fresh LV tissue, some loss of nuclear proteins to the cytosolic fraction was observed. Using this method, we studied the distribution of tyrosinephosphorylated signal transducer and activator of transcription 3 (PY-STAT3) in LV tissue of animals treated with the β-agonist dobutamine. Upon treatment , PY-STAT3 increased 30.2±8.5-fold in total homogenates, but only 6.9±2.1-fold (n=4, P=0.03) in nuclear protein extracts. Of all PY-STAT3 formed, only a minor fraction appeared in the nuclear fraction. This simple and reproducible protocol yielded nuclear protein extracts that were highly enriched in nuclear proteins with almost complete removal of cytosolic and myofilament proteins. This nuclear protein extraction protocol is therefore well-suited for nuclear proteome analysis of frozen heart tissue collected in biobanks. Keywords Nuclear extract. Frozen tissue. Transcription factors. Heart tissue Abbreviations DPBS Dulbecco's phosphate-buffered saline ECL Enhanced chemiluminescence GAPDH Glyceraldehyde-3-phosphate dehydrogenase LV Left ventricle LV dP/dt max Maximum rate of rise of left ventricular pressure PY-STAT3 Tyrosine-phosphorylated signal transducer and activator of transcription 3 SERCA2 Sarcoplasmic/endoplasmic reticulum Ca 2+-ATPase 2 SR Sarcoplasmic reticulum TF Transcription factor
XIth International Congress on Thrombosis and Haemostasis
Signal processing in platelets seems to involve polyphosphoinositide (PPI) metabolism, although d... more Signal processing in platelets seems to involve polyphosphoinositide (PPI) metabolism, although direct coupling between PPI metabolism and responses has not been proved. Neomycin binds tightly to PPIs and has been used to probe the involvement of PPI metabolism and responses in platelets. Neomycin(SO4)3 powerfully inhibited ADP- and adrenaline-induced aggregation of platelets in PRP. This was partly due to the sulphate anion; the chloride form was therefore prepared. Platelets were prelabelled in PRP with 32P-Pi. and transferred by gel filtration to a calcium-free Tyrode’s solution (GFP). Increasing concentrations (2-5 mM) of neomycinCl6 caused progressive inhibition of thrombin-induced aggregation, dense granule secretion, acid hydrolase secretion and formation of 32P-phosphatidic acid (PA); the inhibition was immediate, not affected by aspirin and counteracted by increasing thrombin concentrations. Incubation of neomycin (up to 5 mM) with this GFP or with P-Pi. On GFP prepared fro...
Atherosclerosis
High levels of Lp(a) may contribute to the residual cardiovascular risk in statin-treated dyslipi... more High levels of Lp(a) may contribute to the residual cardiovascular risk in statin-treated dyslipidemic patients. • Reported data on modulatory effects of statins on plasma Lp(a) levels are inconsistent. • Statin treatment increases Lp(a) levels in patients with dyslipidemia, exclusively in those with the LMW apo(a) phenotype. • The increase in Lp(a) levels upon statin treatment was not associated with common LPA SNPs or change in LDL cholesterol.
Trials, Jan 16, 2018
Patients with type 2 diabetes mellitus (T2D) are prone to micro- and macro-vascular complications... more Patients with type 2 diabetes mellitus (T2D) are prone to micro- and macro-vascular complications. Monomeric and oligomeric flavanols (MOF) isolated from grape seeds (Vitis vinifera) have been linked to improved endothelial function and vascular health. The aim of this study is to determine the effect of a daily supplementation of 200 mg MOF on renal endothelial function of patients with T2D and microalbuminuria. For this double-blind, placebo-controlled, randomized, multicenter trial 96 individuals (ages 40-85 years) with T2D and microalbuminuria will be recruited. Participants will be randomly assigned to the intervention group, receiving 200 mg of MOF daily for 3 months, or to the control group, receiving a placebo. The primary endpoint is the evolution over time in albumin excretion rate (AER) until 3 months of intervention as compared with placebo. Secondary endpoints are the evolution over time in established plasma markers of renal endothelial function-asymmetric dimethylargi...
Diabetologia, 2018
Weight-loss programmes for adults with type 2 diabetes are less effective in the long term owing ... more Weight-loss programmes for adults with type 2 diabetes are less effective in the long term owing to regain of weight. Our aim was to determine the 2 year effectiveness of a cognitive behavioural group therapy (group-CBT) programme in weight maintenance after diet-induced weight loss in overweight and obese adults with type 2 diabetes, using a randomised, parallel, non-blinded, pragmatic study design. We included 158 obese adults (median BMI 36.3 [IQR 32.5-40.0] kg/m) with type 2 diabetes from the outpatient diabetes clinic of Erasmus MC, the Netherlands, who achieved ≥5% weight loss on an 8 week very low calorie diet. Participants were randomised (stratified by weight loss) to usual care or usual care plus group-CBT (17 group sessions). The primary outcomes were the between-group differences after 2 years in: (1) body weight; and (2) weight regain. Secondary outcomes were HbA levels, insulin dose, plasma lipid levels, depression, anxiety, self-esteem, quality of life, fatigue, physi...
Diet-induced weight loss and markers of endothelial dysfunction and inflammation in treated patients with type 2 diabetes
Clinical Nutrition ESPEN
s u m m a r y Background & aims: Overweight and obesity increase cardiovascular mortality... more s u m m a r y Background & aims: Overweight and obesity increase cardiovascular mortality in patients with type 2 diabetes (T2D). In a recent trial, however, diet-induced weight loss did not reduce the cardiovascular risk of patients with T2D, possibly due to the parallel intensive medical treatment. We investigated the effect of diet-induced weight loss on cardiovascular risk factors in overweight and obese patients with T2D, and whether this effect was influenced by the use of statins, ACE inhibitors, metformin and duration of T2D. Methods: Patients with T2D and BMI >27 were subjected to an energy-restricted diet during 4 months. Before and after intervention, plasma levels of sICAM-1, sVCAM-1, hsCRP, vWF and classical biomarkers were measured. The association of the change in biomarker levels with medication use and T2D history, corrected for age, sex and change in insulin dose, was tested by matched linear regression analyses.
The anti-inflammatory function of high-density lipoprotein in type II diabetes: A systematic review
Journal of Clinical Lipidology
Soluble LR11 associates with aortic root calcification in asymptomatic treated male patients with familial hypercholesterolemia
Atherosclerosis
Despite statin treatment, a high prevalence of severe vascular calcification is found in patients... more Despite statin treatment, a high prevalence of severe vascular calcification is found in patients with familial hypercholesterolemia (FH). We assessed the relation between the circulating soluble form of low-density lipoprotein receptor relative with 11 ligand-binding repeats (sLR11), a risk factor for cardiovascular disease, and vascular calcification in asymptomatic statin-treated heterozygous FH patients. In 123 asymptomatic heterozygous FH patients (age 40-69 years), aortic root (ARC), aortic valve (AVC) and coronary artery calcification (CAC) were determined with CT-based calcium scoring expressed in Agatston units. Plasma sLR11 levels were measured by sandwich ELISA. Seventy-three patients displayed ARC, 48 had AVC and 96 CAC. Plasma sLR11 levels were positively correlated with the presence of ARC (r = 0.2, p = 0.03), but not with AVC or CAC. The correlation between sLR11 levels and ARC was restricted to male FH patients (r = 0.31, p = 0.006). Multivariate logistic analyses showed that the association of plasma sLR11 with the presence of ARC was independent of other determinants (Adjusted Odds Ratio, 2.01 (95% CI = 1.28-3.16) p = 0.002). Plasma sLR11 is associated with ARC in male FH patients and may be mechanistically involved in the differential distribution of atherosclerotic lesions in the vasculature.