Michaelblackburn8641

Mechanistically, we determine that nitrate induces these phenotypic changes in primary adipocytes through the xanthine oxidoreductase catalysed reduction of nitrate to nitric oxide and independently of Peroxisome Proliferator-Activated Receptor α. The nitrate-mediated enhancement of glucose uptake and catabolism in white adipose tissue may be a key contributor to the anti-diabetic effects of this anion. © 2020 by the American Diabetes Association.Identifying gene variants causing monogenic diabetes increases understanding of disease etiology and allows for implementation of precision therapy to improve metabolic control and quality of life. Here, we aimed to assess the prevalence of monogenic diabetes in diabetic youth in Lithuania, uncover potential diabetes-related gene variants, and prospectively introduce precision treatment. First, we assessed all pediatric and most young adult diabetic patients in Lithuania (n = 1209) for diabetes-related autoimmune antibodies. We then screened all antibody-negative patients using targeted high-throughput sequencing of more than 300 potential candidate genes. In this group, 40.7% had monogenic diabetes, with the highest percentage (100%) in infants (diagnosis at ages 0-12 months), followed by those diagnosed at ages >1-18 years (40.3%) and at >18-25 years (22.2%). The overall prevalence of monogenic diabetes in diabetic youth in Lithuania was 3.5% (1.9% for GCK diabetes, 0.7% for HNF1A, 0.2% for HNF4A and ABCC8, 0.3% for KCNJ11, and 0.1% for INS). Furthermore, we identified likely pathogenic variants in 11 additional genes. Microvascular complications were present in 26% of those with monogenic diabetes. Prospective treatment change was successful in over 50% of eligible candidates, with C-peptide over 252 pmol/L emerging as the best prognostic factor. © 2020 by the American Diabetes Association.Spike conduction velocity characteristically differs between myelinated and unmyelinated axons. Here we test whether spikes of myelinated and unmyelinated paths differ in other respects by measuring rat retinal ganglion cell (RGC) spike duration in the intraretinal, unmyelinated nerve fiber layer and the extraretinal, myelinated optic nerve and optic chiasm. We find that rapid spike firing and illumination broaden spikes in intraretinal axons but not in extraretinal axons. RGC axons thus initiate spikes intraretinally and normalize spike duration extraretinally. Additionally, we analyze spikes that were recorded in a previous study of rhesus macaque retinogeniculate transmission and find that rapid spike firing does not broaden spikes in optic tract. The spike normalization we find reduces the number of spike properties that can change during RGC light responses. However, this is not because identical spikes fire in all axons. Instead, our recordings show that different subtypes of RGC generate axonal spikes ikes to facilitate signal transfer by different mechanisms at RGC synapses onto subcortical target neurons. Copyright © 2020 Fogli Iseppe et al.BACKGROUND The genetic architecture of non-acquired focal epilepsies (NAFEs) becomes increasingly unravelled using genome-wide sequencing datasets. However, it remains to be determined how this emerging knowledge can be translated into a diagnostic setting. To bridge this gap, we assessed the diagnostic outcomes of exome sequencing (ES) in NAFE. METHODS 112 deeply phenotyped patients with NAFE were included in the study. Diagnostic ES was performed, followed by a screen to detect variants of uncertain significance (VUSs) in 15 well-established focal epilepsy genes. Explorative gene prioritisation was used to identify possible novel candidate aetiologies with so far limited evidence for NAFE. RESULTS ES identified pathogenic or likely pathogenic (ie, diagnostic) variants in 13/112 patients (12%) in the genes DEPDC5, NPRL3, GABRG2, SCN1A, PCDH19 and STX1B. this website Two pathogenic variants were microdeletions involving NPRL3 and PCDH19. Nine of the 13 diagnostic variants (69%) were found in genes of the GATOR1 complex, a potentially druggable target involved in the mammalian target of rapamycin (mTOR) signalling pathway. In addition, 17 VUSs in focal epilepsy genes and 6 rare variants in candidate genes (MTOR, KCNA2, RBFOX1 and SCN3A) were detected. Five patients with reported variants had double hits in different genes, suggesting a possible (oligogenic) role of multiple rare variants. CONCLUSION This study underscores the molecular heterogeneity of NAFE with GATOR1 complex genes representing the by far most relevant genetic aetiology known to date. Although the diagnostic yield is lower compared with severe early-onset epilepsies, the high rate of VUSs and candidate variants suggests a further increase in future years. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Autosomal dominant polycystic kidney disease is characterized by progressive development and enlargement of kidney cysts, leading to ESKD. Because the kidneys are under high metabolic demand, it is not surprising that mounting evidence suggests that a metabolic defect exists in in vitro and animal models of autosomal dominant polycystic kidney disease, which likely contributes to cystic epithelial proliferation and subsequent cyst growth. Alterations include defective glucose metabolism (reprogramming to favor aerobic glycolysis), dysregulated lipid and amino acid metabolism, impaired autophagy, and mitochondrial dysfunction. Limited evidence supports that cellular kidney metabolism is also dysregulated in humans with autosomal dominant polycystic kidney disease. There are notable overlapping features and pathways among metabolism, obesity, and/or autosomal dominant polycystic kidney disease. Both dietary and pharmacologic-based strategies targeting metabolic abnormalities are being considered as therapies toing metabolic-focused therapeutic approaches with compounds targeting other signaling cascades altered in autosomal dominant polycystic kidney disease, such as tolvaptan. Copyright © 2020 by the American Society of Nephrology.OBJECTIVE Higher neighborhood walkability has been associated with a lower risk of type 2 diabetes mellitus (T2DM) by promoting greater physical activity (thereby reducing weight and lowering insulin resistance). However, it is not known if walkability may similarly reduce maternal risk of gestational diabetes mellitus (GDM), which arises in the setting of the severe physiologic insulin resistance of pregnancy. Indeed, the insulin resistance of pregnancy is primarily driven by placental hormones and not maternal weight gain. Thus, we sought to evaluate the impact of neighborhood walkability on maternal risk of GDM and the pathophysiologic determinants thereof (insulin sensitivity and pancreatic beta-cell function). METHODS In this study, 1318 women reported their pregravid physical activity (Baecke questionnaire) while undergoing an oral glucose tolerance test (OGTT) at mean 29.3 weeks' gestation. The OGTT identified 290 women with GDM and enabled assessment of insulin sensitivity and beta-cell function. Based on their residential Walk Score, the women were stratified into the following four established categories of neighborhood walkability car dependent (n=328), somewhat walkable (n=315), very walkable (n=406), and walker's paradise (n=269).