Stefan Kopf

Soluble RAGE but not endogenous secretory RAGE is associated with albuminuria in patients with type 2 diabetes

BackgroundTotal circulating soluble receptor for advanced glycation endproducts (sRAGE) and a more defined endogenous secretory splice variant of the receptor (esRAGE) were shown to be associated with different markers of cardiovascular risk in patients with diabetes. Since previous data were partly divergent, the aim of this study was to compare sRAGE and esRAGE in a head-to-head analysis in patients with type 2 diabetes (T2DM) with albuminuria.MethodssRAGE and esRAGE were studied in plasma of 110 T2DM patients using enzyme-linked immunosorbant assays (ELISA) detecting either sRAGE or esRAGE only. Both sRAGE and esRAGE were compared with regard to applicability as markers for vascular disease and glucose control in T2DM.ResultsIn bivariate analysis, sRAGE correlated with age (R = 0.22, p = 0.02) and the 24 hour albumin excretion rate (R = 0.18, p = 0.05), while esRAGE correlated positively with age only (R = 0.23, p = 0.02). In contrast to previous reports, neither sRAGE nor esRAGE correlated with glucose control or intima-media-thickness (IMT) as a predictor of macrovascular disease. In multivariate regression models, the associations between sRAGE and albuminuria as well as esRAGE and age were shown to be independent of glucose control, diabetes duration, body-mass index, glomerular filtration rate, blood pressure and gender.ConclusionThis is the first study comparing sRAGE and esRAGE as markers of vascular complications in patients with T2DM. sRAGE but not esRAGE is independently associated with albuminuria in these patients while neither sRAGE nor esRAGE are associated with markers of glucose control or macrovascular disease.

Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy

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.

Sustained Effects of a Mindfulness-Based Stress-Reduction Intervention in Type 2 Diabetic Patients Design and first results of a randomized controlled trial (The Heidelberger Diabetes and Stress-Study)

OBJECTIVE To determine whether a mindfulness-based stress reduction (MBSR) intervention is effective for reducing psychosocial distress (i.e., depression, psychosocial stress) and the progression of nephropathy (i.e., albuminuria) and for improving the subjective health status of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes and microalbuminuria were randomized to a mindfulness-based intervention (n = 53) or a treatment-as-usual control (n = 57) group. The study is designed to investigate long-term outcomes over a period of 5 years. We present data up to the first year of follow-up (FU). RESULTS At FU, the MBSR group showed lower levels of depression (d = 0.71) and improved health status (d = 0.54) compared with the control group. No significant differences in albuminuria were found. Per-protocol analysis also showed higher stress reduction in the intervention group (d = 0.64). CONCLUSIONS MBSR intervention achieved a prolonged reduction in psychosocial distress. The effects on albuminuria will be followed up further.

Effect of Metformin on Methylglyoxal Metabolism in Patients with Type 2 Diabetes

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.

Effects of stress reduction on cardiovascular risk factors in type 2 diabetes patients with early kidney disease - results of a randomized controlled trial (HEIDIS).

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 http://clinicaltrials.gov/ct2/show/NCT00263419 TRIAL REGISTRATION: clinicaltrials.gov-Identifier: NCT00263419.

Influence of insulin and glargine on outgrowth and number of circulating endothelial progenitor cells in type 2 diabetes patients: a partially double-blind, randomized, three-arm unicenter study

BackgroundEndothelial 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).ConclusionThe 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).

A scavenger peptide prevents methylglyoxal induced pain in mice

The reactive metabolite methylglyoxal (MG) has been identified as mediator of pain. Scavenging of free MG and the prevention of MG-derived post-translational modifications may provide a useful therapeutic treatment. An arginine-rich, fatty acid coupled, cyclic peptide (CycK(Myr)R4E) with high proteolytic stability and prolonged circulation was developed for the scavenging of MG. It was shown to reduce the formation of albumin-MG adducts in vitro and prevented MG-induced pain by reducing plasma MG levels through the formation of peptide-MG adducts in vivo. CycK(Myr)R4E therefore presents a promising option for the treatment of pain and other diabetic complications associated with high MG levels.

Transient hyperthyroidism after surgery for secondary hyperparathyroidism: a common problem

BackgroundPostoperative hyperthyroidism occurs in approximately one third of patients following parathyroidectomy due to primary hyperparathyroidism (PHP), but has only rarely been described in secondary hyperparathyroidism (SHP). The frequency, course, and laboratory markers of postoperative hyperthyroidism in SHP remain unknown. Our purpose was to evaluate the frequency and the clinical course of postoperative hypcrthyroidism following surgery of SHP and to determine the diagnostic value of thyroglobulin in this setting.Material and MethodsA total of 40 patients undergoing parathyroidectomy because of SHP were included in this study. Thyroid stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fl4), and thyroglobulin (Tg) were determined one day before and on day 1, 3, 5, 10, and 40 after surgery. At each of these visits patients were clinically evaluated for signs or symptoms of hyperthyroidism.ResultsBiochemical evidence of hyperthyroidism was evident in 77% of patients postoperatively despite of preoperatively normal serum levels. TSH dropped from 1.18 ± 0.06mU/L to 0.15 ± 0.07mU/L (p = 0.0015). Free triiodothyronine (fT3) and fT4 levels increased from 2.86 ± 0.02ng/L and 10.32 ± 0.13ng/L, respectively, to their maximum of 4.83 ± 0.17ng/L and 19.35 ± 0.58ng/L, respectively. Thyroglobulin levels rose from 3.8 ± 0.8ng/mL to 111.8 ± 45.3ng/mL (p < 0.001). At day 40 all thyroid related laboratory values were within normal range. Correlation analysis of postoperative values revealed significant correlations for lowest TSH (r = -0.32; p = 0.038), and highest fT3 (r = 0.55; p < 0.001) and fT4 levels (r = 0.67; p < 0.001) with Tg.ConclusionTransient hyperthyroidism is frequent after parathyroidectomy for SHP with Tg being a suitable marker. Awareness of this self-limiting disorder is important to avoid inappropriate and potentially harmful treatment.

Renal Function in Type 2 Diabetes Following Gastric Bypass.

BACKGROUND Metabolic surgery for obese patients with type 2 diabetes (T2D) yields short- and long-term remission rates of 60-90%. Its effects on diabetesassociated complications such as neuropathy and nephropathy have not been well studied to date. Hardly any data are available on this subject with respect to moderately obese patients (body mass index [BMI] 25-35 kg/m2) with insulin-dependent T2D. Our previous studies suggest that, in such patients, treatment with a Roux-en-Y gastric bypass (RYGB) improves diabetic neuropathy. In this pilot study, we investigate the course of diabetic nephropathy after RYGB surgery. METHODS 20 insulin-dependent patients whose T2D was inadequately controlled with medication, and whose BMI was in the range 25-35 kg/m2, were prospectively included in a pilot study. All patients underwent a standardized RYGB operation. Blood and urine tests for renal function were performed before surgery and 12 and 24 months afterward. RESULTS The serum creatinine level fell from 0.82 ± 0.23 to 0.69 ± 0.13 mg/dL (p = 0.0025) in the first 12 months after surgery and was unchanged a further 12 months later. The glomerular filtration rate (eGFR) rose in the first 24 months after surgery from 96.4 ± 28.7 to 111.7 ± 23.3 mL/min/1.73 m2 (p = 0.0093). The urinary albumin/creatinine and high-molecular-weight adiponectin/creatinine ratios fell markedly in the first 24 months after surgery (2.89 ± 3.14 versus 1.00 ± 0.24 mg/mmol [p = 0.0491] and 0.18 ± 0.06 versus 0.04 ± 0.01 μg/g [p = 0.0392]). CONCLUSION RYGB has positive effects on renal function and may therefore be a good treatment option for moderately obese, insulin-dependent patients whose T2D cannot be adequately controlled with medication. These results still need to be confirmed in randomized, controlled trials with longer periods of followup.

Uncoupled iron homeostasis in type 2 diabetes mellitus

Diabetes mellitus is frequently associated with iron overload conditions, such as primary and secondary hemochromatosis. Conversely, patients affected by type 2 diabetes mellitus (T2DM) show elevated ferritin levels, a biomarker for increased body iron stores. Despite these documented associations between dysregulated iron metabolism and T2DM, the underlying mechanisms are poorly understood. Here, we show that T2DM patients have reduced serum levels of hepcidin, the iron-regulated hormone that maintains systemic iron homeostasis. Consistent with this finding, we also observed an increase in circulating iron and ferritin levels. Our analysis of db/db mice demonstrates that this model recapitulates the systemic alterations observed in patients. Interestingly, db/db mice show an overall hepatic iron deficiency despite unaltered expression of ferritin and the iron importer TfR1. In addition, the liver correctly senses increased circulating iron levels by activating the BMP/SMAD signaling pathway even though hepcidin expression is decreased. We show that increased AKT phosphorylation may override active BMP/SMAD signaling and decrease hepcidin expression in 10-week old db/db mice. We conclude that the metabolic alterations occurring in T2DM impact on the regulation of iron homeostasis on multiple levels. As a result, metabolic perturbations induce an “iron resistance” phenotype, whereby signals that translate increased circulating iron levels into hepcidin production, are dysregulated.Key messagesT2DM patients show increased circulating iron levels.T2DM is associated with inappropriately low hepcidin levels.Metabolic alterations in T2DM induce an “iron resistance” phenotype.