Untersuchung des Oxidationsverhaltens von orientierten Messing-Einkristallen zur Aufklärung der Bildung von Zinkoxid auf kupferähnlichen Oberflächen

Im Rahmen dieser Arbeit wurde die Bildung von Zinkoxid auf Messing-Einkristalloberflächen untersucht. Mit dem Rastertunnelmikroskop konnte erstmals die Struktur von Zinkoxid, das sich auf einer kupferähnlichen Messing(111)-Oberfläche gebildet hat, atomar aufgelöst werden. Nach Sauerstoffexposition bei Raumtemperatur bildet sich Zinkoxid in Terrassendefekten und an Stufenkanten in einer hexagonalen Struktur, die Aufgrund der Gitterfehlanpassung axial verzerrt wird. Nach Oxidation bei höheren Kristalltemperaturen kommt es zur Bildung von amorphen Zinkoxid-Clustern an Stufenkanten. Eine Kupferoxidation ist nur beim Messingkristall mit geringem Zinkgehalt beobachtbar. Dabei bilden sich nach der Oxidation bei Raumtemperatur Kupfer-Sauerstoff-Reihen auf den Terrassen. Diese Reihen folgen der Kristallsymmetrie des Substrates. Nach Sauerstoffexposition bei höherer Kristalltemperatur kommt es zur Bildung verschiedener Kupferoxidspezies auf den Terrassen

Bradykinin Decreases Podocyte Permeability through ADAM17-Dependent Epidermal Growth Factor Receptor Activation and Zonula Occludens-1 Rearrangement

Recent data show that increases in bradykinin (BK) concentration contribute to the beneficial effects of angiotensin-converting enzyme inhibitor (ACEI) treatment in chronic kidney disease. However, the possible role of BK in attenuated proteinuria, often seen in ACEI-treated patients, is not well studied. Here, we report that BK decreases mouse podocyte permeability through rearrangement of the tight junction protein zonula occludens-1 (ZO-1) and identify some of the major signaling events leading to permeability change. We show that BK2 receptor (BK2R) stimulation transactivates the epidermal growth factor receptor (EGFR). EGFR transactivation is mediated by a disintegrin and metalloenzyme (ADAM) family members, which are required for both extracellular signal-regulated kinase (ERK) and EGFR activation by BK. Using a gene-silencing approach we observed that both BK-induced ERK activation and BK-induced permeability decrease in podocytes is attenuated by ADAM17 down-regulation, and we identified epiregulin (ER) as the EGFR ligand participating in ADAM-dependent BK2R-EGFR cross-talk. EGFR inhibition attenuated both ZO-1 rearrangement and BK-induced permeability decreases in podocyte. We propose that ZO-1 redistribution is an important element of BK-induced permeability change and the signaling events involved in ZO-1 rearrangement include transactivation of the EGFR via ADAM17 activation and ER shedding. Our data indicate that ADAM17 and the EGFR may be potential novel therapeutic targets in diabetic nephropathy and other chronic kidney diseases

Sequential Intensification of Metformin Treatment in Type 2 Diabetes With Liraglutide Followed by Randomized Addition of Basal Insulin Prompted by A1C Targets

OBJECTIVE-We evaluated the addition of liraglutide to metformin in type 2 diabetes followed by intensification with basal insulin (detemir) if glycated hemoglobin (A1C) >= 7%. RESEARCH DESIGN AND METHODS-In 988 participants from North America and Europe uncontrolled on metformin +/- sulfonylurea, sulfonylurea was discontinued and liraglutide 1.8 mg/day added for 12 weeks (run-in). Subsequently, those with A1C >= 7% were randomized 1:1 to 26 weeks' open-label addition of insulin detemir to metformin + liraglunde (n = 162) or continuation without insulin detemir (n = 161). Patients achieving A1C <7% continued unchanged treatment (observational arm). The primary end point was A1C change between randomized groups. RESULTS-Of 821 participants completing the run-in, 61% (n = 498) achieved A1C <7% (mean change -1.3% from 7.7% at start), whereas 39% (n = 323) did not (-0.6% from 8.3% at start). During run-in, 167 of 988 (17%) withdrew; 46% of these due to gastrointestinal adverse events. At week 26, A1C decreased further, by 0.5% (from 7.6% at randomization) with insulin detemir (n = 162) versus 0.02% increase without insulin detemir (n = 157) to 7.1 and 7.5%, respectively (estimated treatment difference -0.52 [95% CI -0.68 to -0.36]; P <0.0001). Forty-three percent of participants with insulin detemir versus 17% without reached A1C <7%. Mean weight decreased by 3.5 kg during run-in, then by 0.16 kg with insulin detemir or 0.95 kg without insulin detemir. In the randomized phase, no major hypoglycemia occurred and minor hypoglycemia rates were 0.286 and 0.029 events per participant-year with and without insulin detemir (9.2 vs. 1.3%). CONCLUSIONS-Supplementation of metformin with liraglutide and then insulin detemir was well tolerated in the majority of patients, with good glycemic control, sustained weight loss, and very low hypoglycemia rate

Liraglutide and renal outcomes in type 2 diabetes

BACKGROUND In a randomized, controlled trial that compared liraglutide, a glucagon-like peptide 1 analogue, with placebo in patients with type 2 diabetes and high cardiovascular risk who were receiving usual care, we found that liraglutide resulted in lower risks of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) and death. However, the long-term effects of liraglutide on renal outcomes in patients with type 2 diabetes are unknown. METHODS We report the prespecified secondary renal outcomes of that randomized, controlled trial in which patients were assigned to receive liraglutide or placebo. The secondary renal outcome was a composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease. The risk of renal outcomes was determined with the use of time-to-event analyses with an intention-to-treat approach. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. RESULTS A total of 9340 patients underwent randomization, and the median follow-up of the patients was 3.84 years. The renal outcome occurred in fewer participants in the liraglutide group than in the placebo group (268 of 4668 patients vs. 337 of 4672; hazard ratio, 0.78; 95% confidence interval [CI], 0.67 to 0.92; P=0.003). This result was driven primarily by the new onset of persistent macroalbuminuria, which occurred in fewer participants in the liraglutide group than in the placebo group (161 vs. 215 patients; hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P=0.004). The rates of renal adverse events were similar in the liraglutide group and the placebo group (15.1 events and 16.5 events per 1000 patient-years), including the rate of acute kidney injury (7.1 and 6.2 events per 1000 patient-years, respectively). CONCLUSIONS This prespecified secondary analysis shows that, when added to usual care, liraglutide resulted in lower rates of the development and progression of diabetic kidney disease than placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.