[show abstract][hide abstract] ABSTRACT: The established marker for tubular damage, urinary n-acetyl-beta-d-glucosaminidase is significantly increased in type 1 and 2 diabetes patients and is related to albuminuria and other diabetic complications. In this cross sectional study of type 2 diabetes patients with a history of albuminuria, we studied the relationship between excretion of n-acetyl-beta-d-glucosaminidase in urine and diabetic neuropathy.160 type 2 diabetes patients were screened for diabetic peripheral neuropathy and cardiovascular autonomic neuropathy. N-acetyl-beta-d-glucosaminidase excretion was detected in 24 h urine samples.Urinary excretion of n-acetyl-beta-d-glucosaminidase correlated significantly with -glucose control (fasting glucose r=0.18; p=0.04; HbA1c r=0.20; p=0.02) and urine albumin excretion (r=0.22; p=0.01). Binary regression analyses showed that increased urinary n-acetyl-beta-d-glucosaminidase concentration is an independent predictor for presence of clinical symptoms of peripheral neuropathy (OR 1.8 [95%CI 1.2-2.74] and vibration deficiency [OR 1.7; 95% CI 1.2-2.66]. There was also a significant negative association between urinary n-acetyl-beta-d-glucosaminidase and E/I-Ratio (r=-0.21, p<0.02) as well as the 30:15-Ratio (r=-0.24; p<0.01) of heart rate variability. Furthermore, increased n-acetyl-beta-d-glucosaminidase excretion independently predicted cardiovascular autonomic diabetic neuropathy with an OR for decreased E/I-Ratio of 1.7 [95%CI 1.1-2.75]; (p<0.02) and 30:15-Ratio:OR 2.4 [95% CI 1.26-4.45]; (p<0.01).Urinary n-acetyl-beta-d-glucosami-nidase excretion is an independent marker for diabetic peripheral and cardiovascular autonomic neuropathy in type 2 diabetic patients.
[show abstract][hide abstract] ABSTRACT: Glyoxalase 1 catalyses the detoxification of methylglyoxal, a major precursor of advanced glycation end products associated with aging, neurodegenerative diseases, and microvascular complications of diabetes. Here, we examine a possible association of a single nucleotide polymorphism of glyoxalase 1 gene (Glo1 A332C, rs4746 or rs2736654) with the prevalence of microvascular diabetic complications in patients with type 1 and type 2 diabetes.Genotyping was performed in 209 patients with type 1 and 524 patients with type 2 diabetes using polymerase chain reaction and subsequent cleavage by restriction endonuclease Bsa I.Frequencies of the glyoxalase 1 genotypes were different with respect to diabetes type with a significantly higher prevalence of A332A-genotype in type 1 diabetes (35.9% vs. 27.3%; p=0.03). In type 1 diabetes, there was no correlation of any genotype with diabetic retinopathy, nephropathy or neuropathy. In contrast, type 2 diabetic patients homozygous for the C332C allele showed a significantly increased prevalence of diabetic neuropathy (p=0.03; OR=1.49 [95%-CI: 1.04; 2.11]), while no association with diabetic nephropathy or retinopathy was found. However, the significance of this association was lost after correction for multiple testing.Our data suggest a possible association of C332C-genotype of the glyoxalase 1 gene with diabetic neuropathy in type 2 diabetes, supporting the hypothesis that methylglyoxal might be an important mediator of diabetic neuropathy in type 2 diabetes.
[show abstract][hide abstract] ABSTRACT: The receptor for advanced glycation endproduct (RAGE) is involved in diabetic complications and chronic inflammation, conditions known to affect the sensitivity towards apoptosis. Here, we studied the effect of genetically depleting RAGE on the susceptibility towards apoptosis. In murine osteoblastic cells, RAGE knockout increased both spontaneous and induced apoptosis. Decreased levels of B-cell lymphoma 2 protein and increased intrinsic apoptosis were observed in Rage(-/-) cells. Furthermore, loss of RAGE increased expression of the death receptor CD95 (Fas, Apo-1), CD95-dependent caspase activation and extrinsic apoptosis, whereas NF-kB-p65 nuclear translocation was diminished. Importantly, depletion of RAGE reduced the ubiquitination and degradation of p53 and p73 and increased their nuclear translocation. The increase of p53 and p73 transactivational activity was essential for the RAGE-dependent regulation of apoptosis, because knockdown of p53 and p73 significantly decreased apoptosis in RAGE-deficient but not in RAGE-expressing cells. Thus, the RAGE-mediated posttranslational regulation of p53 and p73 orchestrates a sequence of events culminating in control of intrinsic and extrinsic apoptosis signaling pathways.Oncogene advance online publication, 30 April 2012; doi:10.1038/onc.2012.150.
[show abstract][hide abstract] ABSTRACT: We hypothesised that diabetic patients would differ from those without diabetes in regard to the handling of glucose-derived reactive metabolites, evidenced by triosephosphate intermediates (TP(INT)) and methylglyoxal (MG), irrespective of the type of diabetes, plasma glucose level or HbA(1c) value.
To test this hypothesis, erythrocytes were isolated from patients with type 1 (n = 12) and type 2 (n = 12) diabetes with varying blood glucose and HbA(1c) levels. These were then compared with erythrocytes isolated from individuals without diabetes (n = 10), with respect to MG, as determined by HPLC, and TP(INT), as determined by endpoint enzymatic assays.
The concentrations of intracellular TP(INT) and MG were significantly elevated in erythrocytes from diabetic patients. Normalisation of either TP(INT) or MG to intracellular glucose concentration (nmol glucose/mgHb) confirmed that erythrocytes from diabetic patients accumulated more reactive metabolites than did those from healthy controls.
Diabetic patients can be characterised by an increased formation of TP(INT) and MG. The 25-fold increase of MG in type 1 and the 15-fold increase in type 2 diabetes, together with a several-fold increase in TP(INT) and decreased glyceraldehyde-3-phosphate dehydrogenase activity even under normal glucose conditions, imply that normalising glucose level cannot completely prevent late diabetic complications until this acquired error of metabolism has been restored.
[show abstract][hide abstract] ABSTRACT: A number of studies have addressed diabetic neuropathy (DN) in transgenic and knock out mouse models to unravel the molecular mechanisms underlying metabolic pain and loss of pain perception. However, it is difficult to compare these studies with each other or even with human DN due to experimental differences including the type of diabetes, the background strain of the respective mouse model, the methods of diabetes induction and the duration of diabetes, animal age and gender. To receive useful information for DN from genetically modified mice, it is therefore mandatory to first define the appropriate model and - if necessary - to backcross transgenic strains into the respective background to allow a reliable (and at least in part translatable to human DN) interpretation of the results.
[show abstract][hide abstract] ABSTRACT: The most common cause of Maturity-Onset Diabetes of the Young (MODY) are mutations in the Hepatic Nuclear Factor 1α (HNF-1α) gene, resulting in MODY3. In a family afflicted with diabetes, a novel nonsense mutation in HNF-1α, E41X, causing a termination codon behind the dimerization domain, was found. The penetrance in individuals older than 25 years was 81.8%. The age at manifestation of diabetes ranged from 18 to 63 years, only 2 out of 10 diabetic individuals developed the disease at ages younger than 25 years. Although diabetes duration lasted up to 35 years in this family, only one family member suffered from diabetic complications. Additional polymorphisms in HNF-1α, I27L and S487N, were found in this pedigree. Despite its biological inactivity, S487N polymorphism led in combination with E41X to a significant earlier manifestation of diabetes, whereas I27L polymorphism or increased Body Mass Index (BMI) did not. In spite of the severe gene defect, which truncates the protein behind the dimerization domain, the phenotype of E41X was relatively benign without frequent diabetic complications.
[show abstract][hide abstract] ABSTRACT: High-mobility group box 1 (HMGB1) protein is an innate danger signal for the initiation of host defence and tissue repair. The aim of this study was to analyse serum HMGB1 concentration and its correlation with infarct transmurality and functional recovery in patients with ST-elevation (STEMI) and non-ST-elevation myocardial infarction (NSTEMI).
We prospectively examined patients with first-time STEMI (n = 46) or NSTEMI (n = 49), treated according to current guidelines. Contrast-enhanced cardiac magnetic resonance imaging was performed 2-4 days after infarction for the estimation of infarct transmurality and was repeated after 6 months for the estimation of residual left ventricular function. HMGB1 was measured 2-4 days after infarction.
High-mobility group box 1 concentration was related to infarct size and to residual ejection fraction in patients with STEMI (r(2) = 0.81 and r(2) =0.40, respectively, P < 0.001 for both) and NSTEMI (r(2) = 0.74 and r(2) = 0.25, respectively, P < 0.001 for both). Receiver operating characteristic (ROC) curve-derived cut-off values of 6.2 and 5.9 ng mL(-1) for patients with STEMI and NSTEMI, respectively, were predictive of infarct transmurality greater than 75% (STEMI: area under the curve (AUC) = 0.93, standard error (SE) = 0.04, 95% confidence interval (CI) = 0.81-0.98; NSTEMI: AUC = 0.96, SE = 0.04, 95% CI = 0.86-0.99). HMGB1 cut-off values of 7.2 and 6.4 ng mL(-1) for patients with STEMI and NSTEMI, respectively, were predictive of residual ejection fraction 6 months after myocardial infarction (MI) (STEMI: AUC = 0.81, SE = 0.07, 95% CI = 0.66-0.91; NSTEMI: AUC = 0.81, SE = 0.09, 95% CI = 0.68-0.91).
High-mobility group box 1 serum levels represent a highly valuable surrogate marker for infarct transmurality and for the prediction of residual left ventricular function after MI.
Journal of Internal Medicine 03/2011; 270(3):245-53. · 6.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: Urinary liver-type fatty acid binding protein (L-FABP) and kidney injury molecule (KIM)-1, novel urinary biomarkers of renal tubulointerstitial function, have previously been associated with acute ischaemic kidney injury. We studied the clinical significance of urinary L-FABP, KIM-1 and N-acetyl-beta-glucosaminidase (NAG) as potential markers of renal function and chronic ischaemic injury in patients with diabetic nephropathy.
A total of 130 type 2 diabetes patients with early diabetic nephropathy and 40 healthy controls were studied. Urinary L-FABP, KIM-1, NAG, albumin excretion rate (AER) and creatinine clearance were obtained from 24-h urine samples, and correlated with measures of red blood cell count, renal function and metabolic control.
Urinary L-FABP was significantly increased in diabetes patients compared with healthy controls [8.1 (interquartile 0.6-11.6) vs. 2.4 (0.5-3.6) microg/g creatinine, P < 0.001] and correlated with AER (r = 0.276, P = 0.002), creatinine clearance (r = -0.189, P = 0.033) and haemoglobin levels (r = -0.190, P = 0.030). In multivariable linear regression analysis, haemoglobin (beta = -0.247, P = 0.015) and AER (beta = 0.198, P = 0.046) were significant predictors of urinary L-FABP. Prevalent anaemia was independently associated with a 6-fold risk for increased tubulointerstitial kidney damage (upper vs. lower two L-FABP tertiles: OR, 6.06; 95% CI: 1.65-22.23; P = 0.007). Urinary KIM-1 was not significantly associated with kidney function, AER, or measures of red blood cell count while urinary NAG was associated with parameters of glucose control and renal function.
Different urinary biomarkers may reflect distinct pathophysiological mechanisms of tubulointerstitial damage in early diabetic nephropathy: Urinary L-FABP could be a novel biomarker for chronic intrarenal ischaemia.
European Journal of Clinical Investigation 11/2009; 40(2):95-102. · 3.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: The pattern recognition receptor or receptor for AGE (RAGE) is constitutionally expressed in a few cell types only. However in almost all cells studied so far it is induced by reactions known to initiate inflammation. Its biological activity seems to be mainly dependent on the presence of its various ligands, including AGE, S100-calcium binding protein/calgranulins, high-mobility group protein 1, amyloid-beta-peptides and the family of beta-sheet fibrils, all known to be elevated in chronic metabolic, malignant and inflammatory diseases. The RAGE pathway interacts with cytokine-, lipopolysaccharide-, oxidised LDL- and glucose-triggered cellular reactions by turning a short-lasting inflammatory response into a sustained change of cellular function driven by perpetuated activation of the proinflammatory transcription factor, nuclear factor kappa-B. RAGE-mediated persistent cell activation is of pivotal importance in various experimental and clinical settings, including diabetes and its complications, neurodegeneration, ageing, tumour growth, and autoimmune and infectious inflammatory disease. Due to RAGE's central role in maintaining perpetuated cell activation, various therapeutic attempts to block RAGE or its ligands are currently under investigation. Despite broad experimental evidence for the role of RAGE in chronic disease, knowledge of its physiological function is still missing, limiting predictions about safety of long-term inhibition of RAGE x ligand interaction in chronic diseases.
[show abstract][hide abstract] ABSTRACT: Type 2 diabetes and impaired glucose tolerance are an increasing burden not only for affected patients, but also for the whole health care system. The pathophysiology of diabetes and its late complications are far from being understood with hyperglycaemia being only the last sign of a long lasting and complex metabolic dysfunction. One major problem in finding therapeutic targets is the fact that the cellular disorders responsible for the development of diabetes involve phylogenetically ancient repair mechanisms. This is one of the reasons why therapeutic targeting of these mechanisms is difficult with the exception of life-style interventions which are, however, limited by individual compliance. In addition, the impact of many therapeutic agents on the entire organism is not well understood. Blood glucose control cannot be considered "high tech" medicine and requires non-medical personnel to reach defined blood glucose targets. Non-adherence to treatment and life-style changes, however, facilitate the interaction of patients and medical personnel and individuals with diabetes are therefore often considered themselves to "blame" for being affected by diabetes. Finally, generating treatment guidelines is extremely difficult as clinical studies targeting vascular endpoints need more than 10 years to become informative, partly due to the so-called glycaemic memory.
Der Chirurg 06/2009; 80(5):398, 400-4, 406-9. · 0.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: This study examined a possible association of the G>C polymorphism at nucleotide -174 in the promoter region of the interleukin-6 (IL-6) gene (rs1800795) with the prevalence of diabetic complications in 235 patients with type 1 and 498 patients with type 2 diabetes. Genotyping was performed using polymerase chain reaction (PCR) and subsequent cleavage by Nla III restriction endonuclease. Analyzing all diabetic patients together demonstrated that 301 patients (41.1%) carried the GG genotype, 114 (15.6%) the CC genotype, and 318 (43.3%) were heterozygous for the GC genotype. However, there was no correlation of any of the genotypes with the prevalence of diabetic nephropathy or diabetic neuropathy, but subjects with the CC genotype had a significantly higher prevalence of diabetic retinopathy compared to patients with the GC and GG genotype (p=0.016). This association was mainly lost when a logistic regression model was adjusted for diabetes duration (p=0.07). Consistently, a weak but not significant association of the polymorphism with diabetic retinopathy was observed when type 1 and type 2 diabetic patients were analyzed separately (patients with type 1 diabetes: p=0.12; patients with type 2 diabetes: p=0.09). Analogically, no association of the polymorphism was found for diabetic nephropathy or diabetic neuropathy in these groups. In conclusion these data suggest no major influence of the -174G>C variant in the promoter region of the IL-6 gene on the development of microvascular complications in patients with diabetes.
Hormone and Metabolic Research 01/2009; 41(4):308-13. · 2.15 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tubular damage is a major feature in the development of diabetic nephropathy. This study investigates the effects of the thiazolidindione rosiglitazone on angiotensin II and advanced glycation end product-induced tubular activation in human proximal tubular epithelial cells IN VITRO. Angiotensin II and advanced glycation end products, both induced a dose-dependent sustained activation of the redox-sensitive transcription factor, Nuclear Factor KAPPA B (NF-kappaB). Nuclear translocation of NF-kappaB was evident already after one hour and persistent for more than four days. Co-incubation of proximal tubular epithelial cells with rosiglitazone significantly reduced angiotensin II and advanced glycation end product-mediated generation of reactive oxygen species, angiotensin II-dependent advanced glycation end product formation, NF-kappaB activation, and NF-kappaB-dependent pro inflammatory gene expression. Most importantly, rosiglitazone effects on NFkappaB activation were maximal at later time points, indicating that rosiglitazone treatment confers long lasting renoprotective effects.
Hormone and Metabolic Research 09/2008; 40(11):752-9. · 2.15 Impact Factor
[show abstract][hide abstract] ABSTRACT: Multimeric high molecular weight (HMW) forms of adiponectin were previously shown to be inversely associated with the extent of atherosclerosis in males and are down-regulated in patients with the metabolic syndrome and type 2 diabetes. In this study, potential influences of atorvastatin therapy on adiponectin multimer distribution were studied in patients with type 2 diabetes.
The effect of 40 mg atorvastatin on HMW, medium molecular weight (MMW), and low molecular weight (LMW) isoforms of adiponectin were investigated in 75 patients (23 females; 52 males) with type 2 diabetes in an 8-week-long, placebo-controlled and randomized study. Adiponectin multimeric isoforms were detected by Western blot analysis.
After atorvastatin therapy the median serum concentration of HMW adiponectin increased significantly by 42.3% (1.68 vs. 2.39 microg/ml; P < 0.001), while concentrations of MMW adiponectin and LMW adiponectin significantly decreased by 20.8% and 23.2%, respectively (MMW: 3.31 vs. 2.62 microg/ml, P = 0.047; LMW: 0.56 vs. 0.43 microg/ml, P = 0.033). Median total adiponectin levels were not significantly altered by atorvastatin treatment (6.0 vs. 6.2 microg/ml, P = 0.898). Consequently, the HMW: total-adiponectin ratio significantly increased by 25.0% (0.40 vs. 0.50; P = 0.013).
Atorvastatin therapy is associated with significant changes in adiponectin multimer distribution in patients with type 2 diabetes. Since total adiponectin levels were not affected by intervention, atorvastatin may shift adiponectin size towards the HMW form.