Peter P Nawroth

Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany

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Publications (487)2230.35 Total impact

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    ABSTRACT: Epidemiological studies have found that a diet high in fibre and coffee, but low in red meat, reduces the risk for type 2 diabetes. We tested the hypothesis that these nutritional modifications differentially improve whole-body insulin sensitivity (primary outcome) and secretion. Inclusion criteria were: age 18-69 years, BMI ≥30 kg/m(2), type 2 diabetes treated with diet, metformin or acarbose and known disease duration of ≤5 years. Exclusion criteria were: HbA1c >75 mmol/mol (9.0%), type 1 or secondary diabetes types and acute or chronic diseases including cancer. Patients taking any medication affecting the immune system or insulin sensitivity, other than metformin, were also excluded. Of 59 patients (randomised using randomisation blocks [four or six patients] with consecutive numbers), 37 (54% female) obese type 2 diabetic patients completed this controlled parallel-group 8-week low-energy dietary intervention. The participants consumed either a diet high in cereal fibre (whole grain wheat/rye: 30-50 g/day) and coffee (≥5 cups/day), and free of red meat (L-RISK, n = 17) or a diet low in fibre (≤10 g/day), coffee-free and high in red meat (≥150 g/day) diet (H-RISK, n = 20). Insulin sensitivity and secretion were assessed by hyperinsulinaemic-euglycaemic clamp and intravenous glucose tolerance tests with isotope dilution. Whole-body and organ fat contents were measured by magnetic resonance imaging and spectroscopy. Whole-body insulin sensitivity increased in both groups (mean [95% CI]) (H-RISK vs L-RISK: 0.8 [0.2, 1.4] vs 1.0 [0.4, 1.7] mg kg(-1) min(-1), p = 0.59), while body weight decreased (-4.8% [-6.1%, -3.5%] vs -4.6% [-6.0%, -3.3%], respectively). Hepatic insulin sensitivity remained unchanged, whereas hepatocellular lipid content fell in both groups (-7.0% [-9.6%, -4.5%] vs -6.7% [-9.5%, -3.9%]). Subcutaneous fat mass (-1,553 [-2,767, -340] cm(3) vs -751 [-2,047; 546] cm(3), respectively) visceral fat mass (-206 [-783, 371] cm(3) vs -241 [-856, 373] cm(3), respectively) and muscle fat content (-0.09% [-0.16%, -0.02%] vs -0.02% [-0.10%, 0.05%], respectively) decreased similarly. Insulin secretion remained unchanged, while the proinflammatory marker IL-18 decreased only after the L-RISK diet. No evidence of a difference between both low-energy diets was identified. Thus, energy restriction per se seems to be key for improving insulin action in phases of active weight loss in obese type 2 diabetic patients, with a potential improvement of subclinical inflammation with the L-RISK diet. Trial Registration: NCT01409330 Funding: This study was supported by the Ministry of Science and Research of the State of North Rhine-Westphalia (MIWF NRW), the German Federal Ministry of Health (BMG), the Federal Ministry for Research (BMBF) to the Center for Diabetes Research (DZD e.V.) and the Helmholtz Alliance Imaging and Curing Environmental Metabolic Diseases (ICEMED).
    Diabetologia 11/2014; · 6.49 Impact Factor
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    ABSTRACT: To compare surgical versus medical treatment of type 2 diabetes mellitus (T2DM) remission and comorbidities in patients with a body mass index (BMI) less than 35 kg/m. Obesity surgery can achieve remission of T2DM and its comorbidities. Metabolic surgery has been proposed as a treatment option for diabetic patients with BMI less than 35 kg/m but the efficacy of metabolic surgery has not been conclusively determined. A systematic literature search identified randomized (RCT) and nonrandomized comparative observational clinical studies (OCS) evaluating surgical versus medical T2DM treatment in patients with BMI less than 35kg/m. The primary outcome was T2DM remission. Additional analyses comprised glycemic control, BMI, HbA1c level, remission of comorbidities, and safety. Random effects meta-analyses were calculated and presented as weighted odds ratio (OR) or mean difference (MD) with 95% confidence intervals (95% CI). Five RCTs and 6 OCSs (706 total T2DM patients) were included. Follow-up ranged from 12 to 36 months. Metabolic surgery was associated with a higher T2DM remission rate (OR: 14.1, 95% CI: 6.7-29.9, P < 0.001), higher rate of glycemic control (OR: 8.0, 95% CI: 4.2-15.2, P < 0.001) and lower HbA1c level (MD: -1.4%, 95% CI -1.9% to -0.9%, P < 0.001) than medical treatment. -5.5 kg/m, 95% CI: -6.7 to -4.3 kg/m, P < 0.001), rate of arterial hypertension (OR: 0.25, 95% CI: 0.12-0.50, P < 0.001) and dyslipidemia (OR: 0.21, 95% CI: 0.10-0.44, P < 0.001) were lower after surgery. Metabolic surgery is superior to medical treatment for short-term remission of T2DM and comorbidities. Further RCTs should address the long-term effects on T2DM complications and mortality.
    Annals of surgery. 11/2014;
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    ABSTRACT: Peritoneal dialysis (PD) is limited by peritoneal fibrosis and ultrafiltration failure. This is in part caused by the high concentration of glucose degradation products (GDPs) present in PD fluids (PDF) as a consequence of heat sterilization. Existing research in long-term PD has mainly dealt with the toxicity induced by GDPs and the development of therapeutic strategies to reduce the cellular burden of GDPs. Currently, there are few data regarding the potential role of detoxification systems of GDP in PD. In this study, the role of glyoxalase 1 (Glo1), the major detoxification pathway for dicarbonyl-derived GD such as methylglyoxal (MG) and glyoxal (Gx), was investigated in vivo using heterozygous knock-down mice for Glo1 (Glo1(-/+)).
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    ABSTRACT: The aim of this study was to determine the protective effects of human insulin and its analogues, B28Asp human insulin (insulin aspart) and B29Lys(ε-tetradecanoyl),desB30 human insulin (insulin detemir), against glucose-induced lifespan reduction and neuronal damage in the model organism Caenorhabditis elegans and to elucidate the underlying mechanisms.
    Diabetologia 10/2014; · 6.49 Impact Factor
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    ABSTRACT: Background Endothelial progenitor cells (EPC) are bone marrow-derived cells which can undergo differentiation into endothelial cells and participate in endothelial repair and angiogenesis. Insulin facilitates this in vitro mediated by the IGF-1 receptor. Clinical trials showed that the number of circulating EPCs is influenced by glucose control and EPC are a predictor of cardiovascular death. To study direct effects of insulin treatment on EPCs in type 2 diabetes patients, add-on basal insulin treatment was compared to an escalation of oral medication aiming at similar glucose control between the groups.Methods55 patients with type 2 diabetes (61.6±5.9 years) on oral diabetes medication were randomized in a 2:2:1 ratio in 3 groups. Patients were treated additionally with insulin glargine (n=20), NPH insulin (n=22) or escalated with oral medication (n=13). Number of circulating EPC, EPC-outgrowth, intima media thickness, skin microvascular function and HbA1c were documented at baseline and/or after 4 weeks and 4 months.ResultsHbA1c at baseline was, 7.3+/¿0.7% in the oral group, 7.3+/¿0.9% and 7.5+/¿0.7% in the glargine and NPH insulin respectively (p=0.713). HbA1c after 4 months decreased to 6.8+/¿0.8%, 6.6+/¿0.7% and 6.7+/¿0.6%, in the oral, glargine and NPH insulin group respectively (p=0.61). FACS analysis showed no difference in number of circulating EPC between the groups after 4 weeks and 4 months. However, the outgrowth of EPCs as detected by colony forming assay was increased in the NPH insulin and glargine groups (29.2+/¿6.4 and 29.4+/¿ 6.7 units respectively) compared to the group on oral medication (23.2+/¿6.3, p=0.013) after 4 months of treatment. A significant decrease of IMT from 0.80mm (+/¿0.14) at baseline to 0.76mm (+/¿0.12) after 4 months could be observed in all patients only (p=0.03) with a trend towards a reduction of IMT after 4 months when all patients on insulin treatment were compared to the oral treatment group (p=0.06). Skin microvascular function revealed no differences between the groups (p=0.74).Conclusion The study shows that a 4-month treatment with add-on insulin significantly increases the outgrowth of EPC in patients with type 2 diabetes mellitus.Trial registration(Clinical Trials Identifier: NCT00523393).
    Cardiovascular Diabetology 10/2014; 13(1):137. · 4.21 Impact Factor
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    ABSTRACT: Hyperglycemia causes micro- and macrovascular complications in diabetic patients. Elevated glucose (gluc) concentrations lead to increased formation of the highly reactive dicarbonyl methylglyoxal (MG); yet, the early consequences of MG for development of vascular complications in vivo is poorly understood. In this study zebrafish was used as a model organism to analyze early vascular effects and mechanisms of MG in vivo. High tissue glucose increased MG concentrations in tg(fli:EGFP) zebrafish embryos and rapidly induced several additional malformed and uncoordinated blood vessel structures that originated out of existing intersomitic blood vessels. However, larger blood vessels including the dorsal aorta and common cardinal vein were not affected. Expression silencing of MG degrading enzyme glyoxalase 1 (glo1) elevated MG concentrations and induced a similar vascular hyperbranching phenotype in zebrafish. MG enhanced phosphorylation of VEGF receptor 2 and its downstream target Akt/PKB. Pharmacological inhibitors for VEGF receptor 2 and Akt/PKB as well as MG scavenger aminoguanidine and glo1 activation prevented MG induced hyperbranching of intersomitic blood vessels. Taken together, MG acts on smaller blood vessels in zebrafish via the VEGF receptor signalling cascade, thereby describing a new mechanism that can explain vascular complications under hyperglycemia and elevated MG concentrations.
    Diabetes 08/2014; · 7.90 Impact Factor
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    ABSTRACT: Diabetic nephropathy is a growing health concern with characteristic sterile inflammation. As the underlying mechanisms of this inflammation remain poorly defined, specific therapies targeting sterile inflammation in diabetic nephropathy are lacking. Intriguingly, an association of diabetic nephropathy with inflammasome activation has recently been shown, but the pathophysiological relevance of this finding remains unknown. Within glomeruli, inflammasome activation was detected in endothelial cells and podocytes in diabetic humans and mice and in glucose-stressed glomerular endothelial cells and podocytes in vitro. Abolishing Nlrp3 or caspase-1 expression in bone marrow-derived cells fails to protect mice against diabetic nephropathy. Conversely, Nlrp3-deficient mice are protected against diabetic nephropathy despite transplantation of wild-type bone marrow. Pharmacological IL-1R antagonism prevented or even reversed diabetic nephropathy in mice. Mitochondrial reactive oxygen species (ROS) activate the Nlrp3 inflammasome in glucose or advanced glycation end product stressed podocytes. Inhibition of mitochondrial ROS prevents glomerular inflammasome activation and nephropathy in diabetic mice. Thus, mitochondrial ROS and Nlrp3-inflammasome activation in non-myeloid-derived cells aggravate diabetic nephropathy. Targeting the inflammasome may be a potential therapeutic approach to diabetic nephropathy.Kidney International advance online publication, 30 July 2014; doi:10.1038/ki.2014.271.
    Kidney International 07/2014; · 8.52 Impact Factor
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    ABSTRACT: The receptor for advanced glycation end-products (RAGE), a multiligand receptor of the immunoglobulin superfamily, takes part in various inflammatory processes. The role of this receptor in the context of intercellular communication, like nanotube (NT)-mediated interaction, is largely unknown. Here, we use cell cultures of human and murine peritoneal mesothelial cells as well as murine kidneys from wild-type and RAGE knockout mouse models to assess the role of RAGE in NT formation and function. We show that loss of RAGE function results in reduced NT numbers under physiological conditions and demonstrate the involvement of MAP kinase signaling in NT formation. Additionally, we show for the first time the existence of NTs in murine kidney tissue and confirm the correlation of RAGE expression and NT numbers. Under elevated oxidative stress conditions like renal ischemia or peritoneal dialysis, we demonstrate that RAGE absence does not prevent NT formation. Rather, increased NT numbers and attenuated kidney tissue damage could be observed, indicating that, depending on the predominant conditions, RAGE affects NT formation with implications for cellular communication.
    Cell and Tissue Research 05/2014; · 3.68 Impact Factor
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    ABSTRACT: Current guidelines for the treatment of type 2 diabetes focus on pharmacological treatment of glucose and cardio-vascular risk factors. The aim of this prospective randomized controlled intervention study was to examine the effects of a psychosocial intervention on clinical endpoints and risk factors in patients with type 2 diabetes and early diabetic kidney disease.110 patients were randomized to receive an 8-week mindfulness-based stress reduction (MBSR) training (n=53) compared to standard care (n=57). The study was carried out open-labelled and randomization was performed computer-generated in a 1:1 ratio. Primary outcome of the study was the change in urinary albumin excretion (albumin-creatinine-ratio, ACR); secondary outcomes were metabolic parameters, intima media thickness (IMT), psychosocial parameters and cardiovascular events.89 patients (42 in control group and 47 in intervention group) were analysed after 3 years of follow-up. After 1 year, the intervention group showed a reduction of ACR from 44 [16/80] to 39 [20/71] mg/g, while controls increased from 47 [16/120] to 59 [19/128] mg/g (p=0.05). Parallel to the reduction of stress levels after 1 year, the intervention-group additionally showed reduced catecholamine levels (p<0.05), improved 24 h-mean arterial (p<0.05) and maximum systolic blood pressure (p<0.01), as well as a reduction in IMT (p<0.01). However, these effects were lost after 2 and 3 years of follow-up.This is the first study to show that a psychosocial intervention improves cardiovascular risk factors in high risk type 2 diabetes patients. Trial-Registration: NCT00263419 Trial registration: NCT00263419.
    Experimental and Clinical Endocrinology & Diabetes 05/2014; · 1.56 Impact Factor
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    05/2014; 29 Suppl 3:iii419-iii433.
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    ABSTRACT: Insulin exerts a direct action on vascular cells, thereby affecting the outcome and progression of diabetic vascular complications. However, the mechanism through which insulin signalling is impaired in the endothelium of diabetic individuals remains unclear. In this work, we have evaluated the role of the AGE precursor methylglyoxal (MGO) in generating endothelial insulin resistance both in cells and in animal models. Time course experiments were performed on mouse aortic endothelial cells (MAECs) incubated with 500 μmol/l MGO. The glyoxalase-1 inhibitor S-p-bromobenzylglutathione-cyclopentyl-diester (SpBrBzGSHCp2) was used to increase the endogenous levels of MGO. For the in vivo study, an MGO solution was administrated i.p. to C57BL/6 mice for 7 weeks. MGO prevented the insulin-dependent activation of the IRS1/protein kinase Akt/endothelial nitric oxide synthase (eNOS) pathway, thereby blunting nitric oxide (NO) production, while extracellular signal-regulated kinase (ERK1/2) activation and endothelin-1 (ET-1) release were increased by MGO in MAECs. Similar results were obtained in MAECs treated with SpBrBzGSHCp2. In MGO- and SpBrBzGSHCp2-exposed cells, inhibition of ERK1/2 decreased IRS1 phosphorylation on S616 and rescued insulin-dependent Akt activation and NO generation, indicating that MGO inhibition of the IRS1/Akt/eNOS pathway is mediated, at least in part, by ERK1/2. Chronic administration of MGO to C57BL/6 mice impaired whole-body insulin sensitivity and induced endothelial insulin resistance. MGO impairs the action of insulin on the endothelium both in vitro and in vivo, at least in part through an ERK1/2-mediated mechanism. These findings may be instrumental in developing novel strategies for preserving endothelial function in diabetes.
    Diabetologia 04/2014; · 6.49 Impact Factor
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    ABSTRACT: Age and gender are two factors that determine the risk of atherosclerosis. The latter effect is only partly understood. Dicarbonyls, in particular methylglyoxal, participate in the development of atherosclerosis, and their major detoxification route is the enzyme glyoxalase 1 (GLO1), which is known to decrease during aging. GLO1 expression and activity were studied in atherosclerotic carotid artery lesions of 71 patients with respect to demographic and clinical characteristics. GLO1 activity was nonsignificantly reduced by >50% in individuals with carotid artery disease compared with control individuals. There was no significant difference in GLO1 expression between the groups; however, the GLO1 activity-to-protein ratio showed a significant reduction for the carotid artery disease patients compared with the controls. The reduction in the GLO1 activity-to-protein ratio was more pronounced in men and was associated with increased inflammation shown by a significant elevation in the expression-level of interleukin-1β. These data suggest that GLO1 is regulated on the post-translational level by factors such as gender as well as factors that affect the overall burden of atherosclerosis.
    Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 04/2014; · 3.52 Impact Factor
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    ABSTRACT: Increased risk of osteoporosis and its clinical significance in patients with diabetes is controversial. We analyze osteoporosis prevalence and determinants of bone mineral density (BMD) in patients with type 1 and 2 diabetes. Three hundred and ninety-eight consecutive diabetic patients from a single outpatient clinic received a standardized questionnaire on osteoporosis risk factors, and were evaluated for diabetes-related complications, HbA1c levels, and lumbar spine (LS) and femoral neck (FN) BMD. Of these, 139 (71 men, 68 women) type 1 and 243 (115 men, 128 women) type 2 diabetes patients were included in the study. BMD (T-scores and values adjusted for age, BMI and duration of disease) was compared between patient groups and between patients with type 2 diabetes and population-based controls (255 men, 249 women). For both genders, adjusted BMD was not different between the type 1 and type 2 diabetes groups but was higher in the type 2 group compared with controls (p < 0.0001). Osteoporosis prevalence (BMD T-score < -2.5 SD) at FN and LS was equivalent in the type 1 and type 2 diabetes groups, but lower in type 2 patients compared with controls (FN:13.0% vs 21.2%, LS:6.1% vs 14.9% men; FN:21.9% vs 32.1%, LS:9.4% vs 26.9% women). Osteoporosis prevalence was higher at FN-BMD than at LS-BMD. BMD was positively correlated with BMI and negatively correlated with age, but not correlated with diabetes-specific parameters (therapy, HbBA1c, micro- and macrovascular complications) in all subgroups. Fragility fracture prevalence was low (5.2%) and not different between diabetes groups. Fracture patients had lower BMDs compared with those without fractures; however, BMD T-score was above -2.5 SD in most patients. Diabetes-specific parameters did not predict BMD. Fracture occurrence was similar in both diabetes groups and related to lower BMD, but seems unrelated to the threshold T-score, <-2.5 SD. These results suggest that osteoporosis, and related fractures, is a clinically significant and commonly underestimated problem in diabetes patients.
    BMC Endocrine Disorders 04/2014; 14(1):33. · 2.65 Impact Factor
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    ABSTRACT: The effect of metformin on methylglyoxal (MG) metabolism was studied in a prospective non-randomized 24 weeks trial in patients with type 2 diabetes.Metformin treatment, in addition to life style intervention, significantly reduced morning glucose and HbA1c whilst body weight and BMI were only marginally reduced during the 24 week trial. Treatment significantly reduced both plasma MG and carboxymethyl-lysine (CML), a marker of oxidative stress. The reduction in MG was paralleled by a significant increase in the activity of Glyoxalase 1 (Glo1), the major route of MG detoxification, in peripheral blood mononuclear cells and red blood cells. Multivariate analysis showed that the changes in MG were dependent upon the metformin treatment.This study supports previous findings that metformin can reduce plasma MG in type 2 diabetic patients. However, given the observed increase in Glo1 activity, this reduction is due not only to the scavenging properties of metformin, but the restoration of Glo1 activity.
    Experimental and Clinical Endocrinology & Diabetes 04/2014; · 1.56 Impact Factor
  • Thomas Fleming, Peter P Nawroth
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    ABSTRACT: Patients suffering from DN (diabetic neuropathy) suffer from the coexistence of positive (i.e. pain, hypersensitivity, tingling, cramps, cold feet, etc.) and negative (i.e. loss of sensory perception, delayed wound healing, etc.) symptoms. Elevated blood glucose alone cannot explain the development and progression of DN. Recently it has been shown that the endogenous reactive metabolite MG (methylglyoxal), elevated as a consequence of reduced Glo1 (glyoxalase I), can contribute to the gain of function via post-translational modification of neuronal ion channels involved in chemosensing and action potential generation in nociceptive nerve endings. The effects of dicarbonyls on the neuronal compartment provides a unifying mechanism for the development of DN. Targeting the accumulation and effects of MG may therefore provide new, more effective, therapeutic approaches for the treatment of DN.
    Biochemical Society Transactions 04/2014; 42(2):439-42. · 2.59 Impact Factor
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    ABSTRACT: The clinical symptoms of diabetic neuropathy (DN) manifest in a time dependent manner as a positive symptoms (i. e. pain, hypersensitivity, tingling, cramps, cold feet etc.) during its early stages and by a loss of function (i. e. loss of sensory perception, delayed wound healing etc.) predominating in the later stages. Elevated blood glucose alone cannot explain the development and progression of DN and the lowering of blood glucose is insufficient in preventing and/or reversing neuropathy in patients with type 2 diabetes. Recently it has been shown that the endogenous reactive metabolite methylglyoxal (MG) can contribute to the gain of function via post-translational modification in DN of neuronal ion channels involved in chemosensing and action potential generation in nociceptive nerve endings. Dicarbonyls, such as MG, that are elevated in diabetic patients, modify DNA as well as extra- and intracellular proteins, leading to the formation of advanced glycation endproducts (AGEs). Increased formation of AGEs leads to increased cellular stress, dysfunction and ultimately cell death. The interaction of AGE-modified proteins through cell surface receptors, such as RAGE, can lead to increased cellular activation and sustained inflammatory responses, which are the molecular hallmarks of the later, degenerative, stages of DN. The direct and indirect effects of dicarbonyls on nerves or neuronal microvascular network provides a unifying mechanism for the development and progression of DN. Targeting the accumulation of MG and/or prevention of RAGE interactions may therefore provide new, more effective, therapeutic approaches for the treatment of DN.
    Experimental and Clinical Endocrinology & Diabetes 03/2014; · 1.56 Impact Factor
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    ABSTRACT: The factor V Leiden (FVL) mutation is the most frequent genetic cause of venous thrombosis in Caucasians. However, protective effects have been suggested to balance the disadvantages. We have recently observed protective effects of FVL mutation on experimental diabetic nephropathy in mice as well as an association with reduced albuminuria in two human cohorts of diabetic patients. In the present study we aimed to reevaluate these findings in an independent, larger cohort of 1905 Caucasians at risk of developing type 2 diabetes and extend possible associations to earlier disease stages of nephropathy. Carriers of FVL mutation had a significantly lower urine albumin excretion (P = 0.03) and tended to have lower plasma creatinine concentrations (P = 0.07). The difference in plasma creatinine concentrations was significant after adjustment for the influencing factors: age, gender, and lean body mass (P = 0.048). These observations at a very early "disease" stage are an important extension of previous findings and suggest that modification of glomerular dysfunction by FVL mutation is relevant during very early stages of diabetic nephropathy. This makes the underlying mechanism an interesting therapeutic target and raises the question whether FVL mutation may also exert protective effects in other glomerulopathies.
    ISRN endocrinology. 01/2014; 2014:530830.
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    ABSTRACT: Background Coagulation and prothrombotic potential have genuinely been associated with increased cardiovascular risk. However, not all studies in this regard are conclusive. Some clinical trials have shown an increased frequency of cardiovascular complications in patients receiving direct thrombin inhibitors. Previous data from human subjects after acute cardiovascular events showed an inverse association between the thrombin generation marker F1 + 2 and cardiovascular endpoints indicating that not the lowest, but a slightly elevated propensity for thrombin generation is associated with a lower risk of cardiovascular events. This observation has been supported by findings in animal models of atherosclerosis. Hence, we evaluated the association between the endogenous thrombin potential (ETP) and cardiovascular death (CVD) and markers of vascular dysfunction in a large prospective study with long-term follow up. Method After excluding patients receiving anticoagulants we tested ETP in 2196 participants (median follow up ten years) for its ability to predict vascular death (CVD). In addition, the association between ETP and sVCAM-1, sICAM-1, LpPLA2, hsCRP and SAA was determined. Results We observed an inverse association between ETP and CVD with the lowest hazard ratio in the 4th ETP quartile. The nadirs of sICAM-1 or sVCAM-1 were observed in the 3rd, for LpPLA2 in the 4th ETP quartile. Conversely, hsCRP and SAA were highest in the 4th quartile. Conclusions These results demonstrate that not the lowest ETP possible, but slightly higher levels are associated with a reduced risk of CVD and lower markers of endothelial dysfunction, suggesting a more complex role of thrombin in cardiovascular disease.
    International Journal of Cardiology. 01/2014;
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    ABSTRACT: The receptor for advanced glycation endproducts, RAGE, is a multiligand receptor and NF-κB activator leading to perpetuation of inflammation. We investigated whether and how RAGE is involved in mediation of anti-inflammatory properties of protein C. We analyzed the effect of protein C on leukocyte adhesion and transmigration in WT- and RAGE-deficient mice using intravital microscopy of cremaster muscle venules during trauma- and TNFα-induced inflammation. Both, protein C (PC, Ceprotin, 100 U/kg) and activated protein C (aPC, 24 µg/kg/h) treatment significantly inhibited leukocyte adhesion in WT mice in these inflammation models. The impaired leukocyte adhesion after trauma-induced inflammation in RAGE knockout mice could not be further reduced by PC and aPC. After TNFα-stimulation, however, aPC but not PC treatment effectively blocked leukocyte adhesion in these mice. Consequently, we asked whether RAGE is involved in PC activation. Since RAGE-deficient mice and endothelial cells showed insufficient PC activation, and since thrombomodulin (TM) and endothelial protein C receptor (EPCR) are reduced on the mRNA and protein level in RAGE deficient endothelial cells, an involvement of RAGE in TM-EPCR-dependent PC activation is likely. Moreover, TNFα-induced activation of MAPK and upregulation of ICAM-1 and VCAM-1 are reduced both in response to aPC treatment and in the absence of RAGE. Thus, there seems to be interplay of the RAGE and the PC pathway in inflammation. RAGE controls anti-inflammatory properties and activation of PC, which might involve EPCR and TM.
    PLoS ONE 01/2014; 9(2):e89422. · 3.53 Impact Factor
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    ABSTRACT: Adiponectin and urinary adiponectin excretions have been ascribed a function in glomerular physiology and seem to indicate vascular disease in diabetes. The aim of this study was to compare the urinary excretion of albumin and adiponectin as predictors for decline of renal function in patients with type 2 diabetes and early kidney disease. Over 141 patients were screened for renal function (estimated GFR, ml/min*1.73 m(2)), albumin excretion rate (AER, mg/24 h), total as well as high molecular weight (HMW) urinary adiponectin excretion (ng/mol u-creatinine). AER and adiponectin excretion were studied as predictors of renal function after 1 year. After 1 year, 36 patients were in the upper quartile of eGFR decline and defined as progressors (delta eGFR = - 12.3 ± 6.3) while the remaining 105 patients were defined as non-progressors (delta eGFR = 1.4 ± 6.0). At baseline, HMW-adiponectin excretion was positively correlated with HbA1c (p < 0.001) and negatively with eGFR (p < 0.001), but not with AER (p = 0.14). Progressors showed increased urinary HMW-adiponectin at baseline (158[IQR41/479] vs. 65[24/168] ng/mol; p < 0.01), while total adiponectin (182[101/1534] vs. 345[118/1361] ng/mol) and AER (48[23/109] vs. 46[25/108] mg/24 h) excretion showed no differences between the groups. Multivariate logistic regression showed that HMW-adiponectin excretion was an independent predictor of renal progression in all patients (OR 1.86 [95 % CI 1.34-2.59]; p < 0.01), especially in those (n = 45) with normal AER at baseline (OR 2.16 [95 % CI 1.1-4.56]; p < 0.05). Urinary HMW-adiponectin but not AER improved the prediction of progressors in ROC analysis (AUC 0.72 [95 % CI 0.63-0.81] vs. 0.80 [95 % CI 0.71-0.90], p < 0.05). In conclusion, urinary HMW-adiponectin excretion may identify diabetes patients at increased risk for progression of kidney disease.
    Acta Diabetologica 12/2013; · 4.63 Impact Factor

Publication Stats

18k Citations
2,230.35 Total Impact Points


  • 1989–2014
    • Universität Heidelberg
      • • Institute of Clinical Chemistry
      • • Institute of Medical Psychology
      • • Institute of Pathology (Mannheim)
      • • I. Medical Clinic
      • • Department of Internal Medicine I, Endocrinology and Metabolism
      • • University Hospital of Internal Medicine
      • • University Hospital of Anaesthesiology
      • • Medical Psychology
      Heidelburg, Baden-Württemberg, Germany
  • 2011–2012
    • Otto-von-Guericke-Universität Magdeburg
      • Institute for Clinical Chemistry and Pathobiochemistry
      Magdeburg, Saxony-Anhalt, Germany
    • National Institutes of Health
      • Branch of Experimental Immunology
      Bethesda, MD, United States
  • 2009–2012
    • University of Amsterdam
      • Faculty of Medicine AMC
      Amsterdam, North Holland, Netherlands
    • University of Leipzig
      Leipzig, Saxony, Germany
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Center for Infection and Immunity Amsterdam
      Amsterdam, North Holland, Netherlands
  • 2007–2009
    • Technische Universität München
      München, Bavaria, Germany
  • 1988–2009
    • Columbia University
      • • College of Physicians and Surgeons
      • • Department of Surgery
      • • Department of Physiology and Cellular Biophysics
      New York City, NY, United States
  • 2008
    • BASF Corporation
      • Occupational Medical and Health Protection Department
      Florham Park, New Jersey, United States
  • 2006–2007
    • NCI-Frederick
      Maryland, United States
  • 2005
    • German Cancer Research Center
      Heidelburg, Baden-Württemberg, Germany
    • Georgia Health Sciences University
      • Medical College of Georgia
      Augusta, GA, United States
  • 2003
    • Justus-Liebig-Universität Gießen
      • Faculty of Medicine
      Gießen, Hesse, Germany
    • Friedrich-Schiller-University Jena
      Jena, Thuringia, Germany
  • 1999–2002
    • University of Tuebingen
      • Department of Internal Medicine
      Tübingen, Baden-Württemberg, Germany
  • 2000
    • Universitätsklinikum Tübingen
      Tübingen, Baden-Württemberg, Germany
    • University of Vienna
      Wien, Vienna, Austria
  • 1990–1997
    • Bernhard Nocht Institute for Tropical Medicine
      Hamburg, Hamburg, Germany
  • 1995
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
  • 1986–1988
    • Oklahoma Medical Research Foundation
      Oklahoma City, Oklahoma, United States
    • Mount Sinai School of Medicine
      • Department of Medicine
      Manhattan, NY, United States
  • 1987
    • University of New Mexico
      Albuquerque, New Mexico, United States
    • CUNY Graduate Center
      New York City, New York, United States
  • 1985
    • New York Medical College
      • Department of Medicine
      New York City, New York, United States