Loss of Autophagy Diminishes Pancreatic β Cell Mass and Function with Resultant Hyperglycemia

SummaryAutophagy is a cellular degradation-recycling system for aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in various diseases including neurodegeneration, its role in pancreatic β cells and glucose homeostasis has not been described. We produced mice with β cell-specific deletion of Atg7 (autophagy-related 7). Atg7 mutant mice showed impaired glucose tolerance and decreased serum insulin level. β cell mass and pancreatic insulin content were reduced because of increased apoptosis and decreased proliferation of β cells. Physiological studies showed reduced basal and glucose-stimulated insulin secretion and impaired glucose-induced cytosolic Ca2+ transients in autophagy-deficient β cells. Morphologic analysis revealed accumulation of ubiquitinated protein aggregates colocalized with p62, which was accompanied by mitochondrial swelling, endoplasmic reticulum distension, and vacuolar changes in β cells. These results suggest that autophagy is necessary to maintain structure, mass and function of pancreatic β cells, and its impairment causes insulin deficiency and hyperglycemia because of abnormal turnover and function of cellular organelles

Renal Toxicity Evaluation and Comparison Between Visipaque (Iodixanol) and Hexabrix (Ioxaglate) in Patients With Renal Insufficiency Undergoing Coronary Angiography The RECOVER Study: A Randomized Controlled Trial

ObjectivesThis study sought to compare the nephrotoxicity of iodixanol and ioxaglate in patients with renal impairment undergoing coronary angiography.BackgroundIodixanol, a nonionic, dimeric, iso-osmolar contrast medium (IOCM), may be less nephrotoxic than low-osmolar contrast media (LOCM) in high-risk patients.MethodsIn a prospective, randomized trial in 300 adults with creatinine clearance (CrCl) ≤60 ml/min, patients received either iodixanol or ioxaglate and underwent coronary angiography with or without percutaneous coronary intervention. The primary end point was the incidence of contrast-induced nephropathy (CIN) (an increase in serum creatinine [SCr] ≥25% or ≥0.5 mg/dl [≥44.2 μmol/l]). The incidence of CIN in patients with severe renal impairment at baseline (CrCl <30 ml/min) or diabetes and in those receiving large doses (≥140 ml) of contrast medium was also determined.ResultsThe incidence of CIN was significantly lower with iodixanol (7.9%) than with ioxaglate (17.0%; p = 0.021), corresponding to an odds ratio (OR) of CIN of 0.415 (95% confidence interval [CI] 0.194 to 0.889) for iodixanol. The incidence of CIN was also significantly lower with iodixanol in patients with severe renal impairment (p = 0.023) or concomitant diabetes (p = 0.041), or in patients given ≥140 ml of contrast media (p = 0.038). Multivariate analysis identified use of ioxaglate (OR 2.65, 95% CI 1.11 to 6.33, p = 0.028), baseline SCr, mg/dl (OR 2.0, 95% CI 1.04 to 3.85, p = 0.038), and left ventricular ejection fraction, % (OR 0.97, 95% CI 0.94 to 0.99, p = 0.019) as independent risk factors for CIN.ConclusionsThe IOCM iodixanol was significantly less nephrotoxic than ioxaglate, an ionic, dimeric LOCM. (The RECOVER Trial; http://clinicaltrials.gov; NCT00247325

Regulation of endothelial cell and endothelial progenitor cell survival and vasculogenesis by integrin-linked kinase

OBJECTIVE: New vessel formation is a dynamic process of attachment, detachment, and reattachment of endothelial cells (ECs) and endothelial progenitor cells (EPCs) with each other and with the extracellular matrix (ECM). Integrin-linked kinase (ILK) plays a pivotal role in ECM-mediated signaling. Therefore, we investigated the role of ILK in ECs and EPCs during neovascularization. METHODS AND RESULTS: In human umbilical cord vein ECs and EPCs, endogenous ILK expression, along with subsequent cell survival signals phospho-Akt and phospho-glycogen synthase kinase 3beta, was reduced after anchorage or nutrient deprivation. Even brief anchorage deprivation resulted in retarded capillary tube formation by ECs. Adenoviral ILK gene transfer in ECs and EPCs reversed the decrease in cell survival signals after anchorage or nutrient deprivation, leading to enhanced survival, reduced apoptosis, and significantly accelerated the functional recovery after reattachment. And ILK overexpressing EPCs significantly improved blood flow recovery and prevented limb loss in nude mice hindlimb ischemia model. Furthermore, the efficacy of systemic delivery was equivalent to local injection of ILK-EPCs. CONCLUSIONS: ILK overexpression protects ECs and EPCs from anchorage- or nutrient-deprived stress and enhances neovascularization, suggesting that ILK is an optimal target gene for genetically modified cell-based therapy. Neovascularization is a dynamic process of detachment and reattachment of ECs and EPCs. Endogenous ILK expression was decreased in various stress conditions, and the gene transfer of ILK protected ECs and EPCs from temporary anchorage or nutrient deprivation. Furthermore, ILK gene transfer in EPCs significantly enhanced neovascularization in vivo

Re-expression of fetal troponin isoforms in the postinfarction failing heart of the rat

Molecular switches between the troponin T and I isoforms are known to occur in various conditions, but the results from studies of failing human hearts with various etiologies are contradictory and it is not certain whether troponin isoform changes occur. Therefore, the molecular switching of troponin isoforms during normal development and heart failure (HF) after myocardial infarction were investigated in Sprague-Dawley rats at the fetal, neonate, and normal adult stages, and in a postinfarction adult HF group. During normal development, switching from the fetal to the adult pattern of the troponin T and I isoforms was observed. Immunoblotting of postinfarction failing hearts revealed a marked increase in the fetal isoform of cardiac TnT (cTnT) (fetal/adult cTnT isoforms: normal adult = 0.61 +/- 0.09 vs postinfarction HF = 1.59 +/- 0.13, p < 0.001). Also, the amount of the adult troponin I (TnI) isoform decreased significantly in the postinfarction failing heart. In the semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) with glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) as an internal standard, the mRNA of fetal cTnT increased in the postinfarction failing heart (fetal cTnT/GAPDH: control = 0.22 vs HF rat = 0.84, p < 0.05). Therefore, molecular switching of the troponin T and I isoforms occurred during the normal development of the rat, and there was re-expression of the fetal pattern of the isoforms in the postinfarction failing heart of the adult rat

Effects of angiotensin converting enzyme inhibitor and calcium antagonist on endothelial function in patients with essential hypertension

The endothelium plays an important role in maintaining vascular tone and function. Essential hypertension is associated with alterations in endothelial function. The effects of antihypertensive agents on endothelial function have not been fully evaluated in human hypertension and data on the forearm circulation of humans are controversial. The aim of this study was to determine whether treatment with an angiotensin converting enzyme (ACE) inhibitor or a calcium antagonist improves endothelial dysfunction in hypertensive patients and whether the mechanism involved could be related to antioxidant activity. Endothelial function was estimated using venous occlusion plethysmography in 18 hypertensive patients and 11 healthy volunteers. The patients in the hypertension group were treated with enalapril or amlodipine. The change of forearm blood flow (FBF) was measured during acetylcholine infusion through the brachial artery and also during intra-arterial vitamin C infusion to explore the effects of vitamin C on responses to acetylcholine. FBF response to acetylcholine was significantly enhanced by intra-arterial infusion of vitamin C in the hypertensive group before antihypertensive treatment. Co-infusion of L-NMMA(N(G)-monomethyl-L-arginine), an inhibitor of nitric oxide synthase, blunted forearm blood flow response to acetylcholine. After antihypertensive treatment with enalapril or amlodipine for 2 months in the hypertensive group, endothelium-dependent vasorelaxation (vasodilatory response to acetylcholine) was significantly improved. Even though the mechanisms leading to depressed endothelial function in essential hypertension remain to be elucidated, our study shows that treatment with an ACE inhibitor or a calcium antagonist resulted in demonstrable improvement by a mechanism that is probably related to antioxidant activity

Fabrication and Characteristics of mc-Si Solar Cells with RIE-Textured Surface

Reactive ion etching (RIE) texturing is well-known as an effective method to form the surface structure on a multi-crystalline (mc-Si) wafer that has grains with randomly oriented crystallites. The saw damage removal (SDR) process using HF/HNO 3/D.I (HND) solution was employed in this work, since the etching rate of RIE dry etching was lower than that of wet etching. The surface morphology on mc-Si surface was formed by RIE using a gas flow ratio of SF 6:O 2 = 1:1.22. The control of RF power and working pressure could etch the mc-Si surface of the 15.6 × 15.6 cm 2 area uniformly during RIE texturing process. The surface morphologies textured for 5 and 10 min were needle-like structures and sharp grass-like structures, respectively. Solar cells with the needle-like structure had higher values for open circuit voltage (V oc), short circuit current (I sc), fill factor (FF), and efficiency, despite higher reflectance compared to those with the sharp grass-like structure. The cell textured for 10 min was expected to have non-homogeneous emitter layer as the dark I-V curves of the cells textured for 5 and 10 min were compared. © 2012 Kyungil University.