Catechol estrogens stimulate insulin secretion in pancreatic β-cells via activation of the transient receptor potential A1 (TRPA1) channel

Estrogen hormones play an important role in controlling glucose homeostasis and pancreatic β-cell function. Despite the significance of estrogen hormones for regulation of glucose metabolism, little is known about the roles of endogenous estrogen metabolites in modulating pancreatic β-cell function. In this study, we evaluated the effects of major natural estrogen metabolites, catechol estrogens, on insulin secretion in pancreatic β-cells. We show that catechol estrogens, hydroxylated at positions C2 and C4 of the steroid A ring, rapidly potentiated glucose-induced insulin secretion via a nongenomic mechanism. 2-Hydroxyestrone, the most abundant endogenous estrogen metabolite, was more efficacious in stimulating insulin secretion than any other tested catechol estrogens. In insulin-secreting cells, catechol estrogens produced rapid activation of calcium influx and elevation in cytosolic free calcium. Catechol estrogens also generated sustained elevations in cytosolic free calcium and evoked inward ion current in HEK293 cells expressing the transient receptor potential A1 (TRPA1) cation channel. Calcium influx and insulin secretion stimulated by estrogen metabolites were dependent on the TRPA1 activity and inhibited with the channel-specific pharmacological antagonists or the siRNA. Our results suggest the role of estrogen metabolism in a direct regulation of TRPA1 activity with potential implications for metabolic diseases

Polyomic profiling reveals significant hepatic metabolic alterations in glucagon-receptor (GCGR) knockout mice: implications on anti-glucagon therapies for diabetes

<p>Abstract</p> <p>Background</p> <p>Glucagon is an important hormone in the regulation of glucose homeostasis, particularly in the maintenance of euglycemia and prevention of hypoglycemia. In type 2 Diabetes Mellitus (T2DM), glucagon levels are elevated in both the fasted and postprandial states, which contributes to inappropriate hyperglycemia through excessive hepatic glucose production. Efforts to discover and evaluate glucagon receptor antagonists for the treatment of T2DM have been ongoing for approximately two decades, with the challenge being to identify an agent with appropriate pharmaceutical properties and efficacy relative to potential side effects. We sought to determine the hepatic & systemic consequence of full glucagon receptor antagonism through the study of the glucagon receptor knock-out mouse (Gcgr^-/-) compared to wild-type littermates.</p> <p>Results</p> <p>Liver transcriptomics was performed using Affymetric expression array profiling, and liver proteomics was performed by iTRAQ global protein analysis. To complement the transcriptomic and proteomic analyses, we also conducted metabolite profiling (~200 analytes) using mass spectrometry in plasma. Overall, there was excellent concordance (R = 0.88) for changes associated with receptor knock-out between the transcript and protein analysis. Pathway analysis tools were used to map the metabolic processes in liver altered by glucagon receptor ablation, the most notable being significant down-regulation of gluconeogenesis, amino acid catabolism, and fatty acid oxidation processes, with significant up-regulation of glycolysis, fatty acid synthesis, and cholesterol biosynthetic processes. These changes at the level of the liver were manifested through an altered plasma metabolite profile in the receptor knock-out mice, e.g. decreased glucose and glucose-derived metabolites, and increased amino acids, cholesterol, and bile acid levels.</p> <p>Conclusions</p> <p>In sum, the results of this study suggest that the complete ablation of hepatic glucagon receptor function results in major metabolic alterations in the liver, which, while promoting improved glycemic control, may be associated with adverse lipid changes.</p

Search for supersymmetry in events with at least three electrons or muons, jets, and missing transverse momentum in proton-proton collisions at root s=13 TeV

A search for new physics is carried out in events with at least three electrons or muons in any combination, jets, and missing transverse momentum. Results are based on the sample of proton-proton collision data produced by the LHC at a center-of-mass energy of 13TeV and collected by the CMS experiment in 2016. The data sample analyzed corresponds to an integrated luminosity of 35.9 fb(-1). Events are classified according to the number of b jets, missing transverse momentum, hadronic transverse momentum, and the invariant mass of same-flavor dilepton pairs with opposite charge. No significant excess above the expected standard model background is observed. Exclusion limits at 95% confidence level are computed for four different supersymmetric simplified models with pair production of gluinos or third-generation squarks. In the model with gluino pair production, with subsequent decays into a top quark-antiquark pair and a neutralino, gluinos with masses smaller than 1610 GeV are excluded for a massless lightest supersymmetric particle. In the case of bottom squark pair production, the bottom squark masses are excluded up to 840 GeV for charginos lighter than 200 GeV. For a simplified model of heavy top squark pair production, the (t) over tilde (2) mass is excluded up to 720, 780, or 710 GeV for models with an exclusive (t) over tilde (2) -> (t) over tilde H-1 decay, an exclusive (t) over tilde (2) -> (t) over tilde (1)Z decay, or an equally probable mix of those two decays. In order to provide a simplified version of the analysis for easier interpretation, a small set of aggregate signal regions also has been de fined, providing a compromise between simplicity and analysis sensitivity.Peer reviewe

Autocrine/paracrine interactions moendocrine pancreasdulating hormone release in the endocrine pancreas

Human islet transplantation is emerging as an alternative to pancreas transplantation or insulin therapy in the treatment of type I diabetes. It has been possible to achieve euglycemia by transplanting isolated human islets in patients who suffer from the long term side effects of diabetes and insulin therapy. However, the islet transplantation procedure is still experimental. To obtain FDA approval, each batch of islets will have to be labeled with its potency to meet the transplantation criteria. Consequently, finding an in vitro test that predicts the quality of the islets prior to transplantation will require a better understanding of the human islet physiology. In this thesis we report on the generation of an in vitro perifusion machine with high throughput capabilities which integrates with other commercial high content screening systems. These technologies were successfully applied to measure [Ca2+]i and hormone release from batches of damaged islets with decreased viability, and it was possible to differentiate those islets from their undamaged counterparts. Pharmacological profiling of individual batches of islet cells proved feasible, measuring both [Ca2+]i and hormone release. Moreover, we showed that the hormone release assay can be used to distinguish batches of human islets from healthy donors and donors with type II diabetes. Our data on human islets revealed a cytoarchitecture that differs from that of other animal models used to study islet physiology and diabetes. In the human islet, all endocrine cells are intermingled throughout the islets without the mantle-core segregation observed in the rodent islet. The endocrine cells are facing blood vessels and they appear without a specific pattern. Additionally, [Ca2+]i handling in human islets is different from that in mouse islets. While the entire human islet does not show oscillations in [Ca2+]i as described for the mouse islet, single human beta cells show oscillations in [Ca2+]i that resemble those found in mouse. Our data showed that glutamate is a potent stimulus for glucagon secretion but not for insulin secretion. While glutamate induced increases in [Ca2+]i in alpha cells through activation of the voltage gated Ca2+ channels, it does not cause any change in [Ca2+]i in beta cells. We provided evidences that alpha cells express the machinery needed for glutematergic signaling. We propose that glutamate released from the alpha cell activates the glutamate receptors in the alpha cell plasma membrane to allow more Ca2+ into the alpha cells and further increase glucagon release. Finally, we demonstrated that ATP exerts different effects in human and in rodent islets. In human islets, ATP potentiated insulin release, at basal and at high glucose concentration, but it did not do so in mouse, rat, or pig islets. This potentiation most likely occurs by activation of purinergic receptors of the P2X3 type located in the beta cell plasma membrane. Upon activation, these receptors become permeable to Ca2+, allowing an influx of this ion into the beta cell cytoplasm, which stimulates further insulin release. Hence, ATP serves as an autocrine signal that forms a positive feedback loop stimulating insulin release in a glucose independent manner. The suggestion that both alpha and beta cells utilize positive feedback loops to potentiate the secretion of their respective hormones might indicate that glucose alone is insufficient to achieve adequate glucagon and insulin release from the alpha and beta cells and that other additional autocrine/paracrine signals are required to achieve fine-tuned exocytosis

Field distribution and genetic variability of Panicum mosaic virus satellite RNAs in St. Augustine decline

Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Includes bibliographical references (leaves 48-61).Issued also on microfiche from Lange Micrographics.'St. Augustine decline' is a viral disease associated with St. Augustinegrass, Stenotaphrum secundatum (Walt.) Kuntze, a turfgrass common to the Gulf Coast region of the United States. A survey of 204 plants from two locations in southeast Texas indicates that this disease is a result of an infection with Panicum mosaic virus (genus Panicovirus; family Tombusviridae) (PMV), or in any combination with satellite panicum mosaic virus (SPMV), and/or with its satellite RNAs (satRNAs). In the field, leaf symptoms representative of PMV infections with or without cc-infections by SPMV or satRNAs ranged from a severe bleaching to a mild chlorotic mottle. However, after five months growth in the greenhouse, these symptoms shifted towards a relatively homogeneous chlorotic mottle phenotype, suggesting the influence of environmental conditions. Ribonuclease protection assays (RPAS) indicated a high degree of genetic variability in PMV satRNAs infecting St. Augustinegrass at the College Station (CS) and Corpus Christi (CC) locations. The RPAS grouped satRNAs according to the place of origin, either CS or CC with only 6 exceptions out of 100 satRNAs. Two satRNAs collected in CC were placed in the CS cluster and four collected in CS were placed in CC cluster. Hence, these data shown that different but overlapping population of PMV satRNA can be found in CS and CC

El emprendedorismo y su relación con la informalidad en las microempresas de reciclaje del “sector santa rosa”-San Martín de Porres, 2017

TesisLima NorteEscuela Académico Profesional de AdministraciónAdministración de OperacionesLa investigación “El emprendedorismo y su relación con la informalidad en las microempresas de reciclaje del “sector santa rosa” –San Martín De Porres, 2017”; tuvo como objetivo general determinar la relación del emprendedorismo con la informalidad en las microempresas de reciclaje del “sector santa rosa” – san Martin de Porres, 2017. La población de estudio fue, 30 microempresas de reciclaje ubicadas en el sector “santa rosa”, San Martin de Porres y la muestra fue de 30 microempresas. La técnica de investigación fue la encuesta y un cuestionario de 20 preguntasen la escala de tipo Likert, dirigido hacia los dueños de estas microempresas. La validación del instrumento se realizó mediante juicio de expertos y la Fiabilidad del mismo se calculó a través del coeficiente Alfa de Crombach. Recolectados los datos se procesaron mediante el SPSS V. 20. Teniendo como resultado que la relación del emprendedorismo con la informalidad es significativa, y se concluye que para que la empresa aumente su rentabilidad es importante realizar un emprendimiento de acorde a los parámetros establecidos por el marco legal y normativo