A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Hypothalamic action of glutamate leads to body mass reduction through a mechanism partially dependent on JAK2

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Glutamate acts in the hypothalamus promoting region-, and cell-dependent effects on feeding. Part of these effects are mediated by NMDA receptors, which are up regulated in conditions known to promote increased food intake and thermogenesis, such as exposure to cold and consumption of highly caloric diets. Here, we hypothesized that at least part of the effect of glutamate on hypothalamic control of energy homeostasis would depend on the control of neurotransmitter expression and JAK2 signaling. The expression of NMDA receptors was co-localized to NPY/AgRP, POMC, CRH, and MCH but not to TRH and orexin neurons of the hypothalamus. The acute intracerebroventricular injection of glutamate promoted a dose-dependent increase in JAK2 tyrosine phosphorylation. In obese rats, 5 days intracerebroventricular treatment with glutamate resulted in the reduction of food intake, accompanied by a reduction of spontaneous motility and reduction of body mass, without affecting oxygen consumption. The reduction of food intake and body mass were partially restrained by the inhibition of JAK2. In addition, glutamate produced an increased hypothalamic expression of NPY, POMC, CART, MCH, orexin, CRH, and TRH, and the reduction of AgRP. All these effects on neurotransmitters were hindered by the inhibition of JAK2. Thus, the intracerebroventricular injection of glutamate results in the reduction of body mass through a mechanism, at least in part, dependent on JAK2, and on the broad regulation of neurotransmitter expression. These effects are not impaired by obesity, which suggest that glutamate actions in the hypothalamus may be pharmacologically explored to treat this disease. J. Cell. Biochem. 113: 11821189, 2012. (c) 2011 Wiley Periodicals, Inc.113411821189Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Enhanced insulin secretion and glucose tolerance in rats exhibiting low plasma free fatty acid levels and hypertriglyceridaemia due to congenital albumin deficiency

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Congenitally analbuminaemic individuals and rats (NARs) exhibit several metabolic abnormalities, including hypertriglyceridaemia and plasma free fatty acid deficiency. Our aim was to study glucose homeostasis and insulin secretion in NARs. Plasma concentrations of lipids, glucose and insulin and secretion of insulin from the pancreatic islets were measured in female NARs and control animals (SpragueDawley rats; SDRs). Glucose homeostasis tests were also performed. Plasma glucose levels were similar between NARs and SDRs, irrespective of feeding status. However, fed insulinaemia was similar to 37% higher (P= 0.05) in NARs than in SDRs. The NARs displayed a markedly increased glucose tolerance, i.e. the integrated glycaemic response was one-third that of the control animals. Enhanced glucose tolerance was associated with threefold higher insulinaemia at peak glycaemia after a glucose load than in the control animals. Similar peripheral insulin sensitivity was observed between groups. Isolated pancreatic islets from NARs secreted significantly more insulin than islets from SDRs in response to a wide range of glucose concentrations (2.833.3 mm). Despite having similar liver glycogen contents in the fully fed state, NARs had similar to 40% (P= 0.05) lower glycogen contents than SDRs after 6 h fasting. The injection of a gluconeogenic substrate, pyruvate, elicited a faster rise in glycaemia in NARs compared with SDRs. Overall, NARs displayed enhanced glucose tolerance, insulin secretion and gluconeogenic flux. The higher glucose tolerance in NARs compared with SDRs is attributed to enhanced islet responsiveness to secretagogues, while peripheral insulin sensitivity seems not to be involved in this alteration. We propose that the enhanced glucose metabolism is a chronic compensatory adaptation to decreased free fatty acid availability in NARs.974525533Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Instituto Nacional de Obesidade e Diabetes (INCT)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

A low-protein diet during pregnancy alters glucose metabolism and insulin secretion

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)In pancreatic islets, glucose metabolism is a key process for insulin secretion, and pregnancy requires an increase in insulin secretion to compensate for the typical insulin resistance at the end of this period. Because a low-protein diet decreases insulin secretion, this type of diet could impair glucose homeostasis, leading to gestational diabetes. In pancreatic islets, we investigated GLUT2, glucokinase and hexokinase expression patterns as well as glucose uptake, utilization and oxidation rates. Adult control non-pregnant (CNP) and control pregnant (CP) rats were fed a normal protein diet (17%), whereas low-protein non-pregnant (LPNP) and low-protein pregnant (LPP) rats were fed a low-protein diet (6%) from days 1 to 15 of pregnancy. The insulin secretion in 2.8?mmol l-1 of glucose was higher in islets from LPP rats than that in islets from CP, CNP and LPNP rats. Maximal insulin release was obtained at 8.3 and 16.7?mmol l-1 of glucose in LPP and CP groups, respectively. The glucose doseresponse curve from LPNP group was shifted to the right in relation to the CNP group. In the CP group, the concentrationresponse curve to glucose was shifted to the left compared with the CNP group. The LPP groups exhibited an inverted U-shape doseresponse curve. The alterations in the GLUT2, glucokinase and hexokinase expression patterns neither impaired glucose metabolism nor correlated with glucose islet sensitivity, suggesting that beta-cell sensitivity to glucose requires secondary events other than the observed metabolic/molecular events. Copyright (c) 2011 John Wiley & Sons, Ltd.302114121Fundacao de Amparo a Pesquisa do Estado de Mato Grosso [0786/2006]Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundacao de Amparo a Pesquisa do Estado de Mato Grosso [0786/2006]CNPq [305155/2004-0

Chaperone Insufficiency Links TLR4 Protein Signaling to Endoplasmic Reticulum Stress

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Inflammation plays an important pathogenic role in a number of metabolic diseases such as obesity, type 2 diabetes, and atherosclerosis. The activation of inflammation in these diseases depends at least in part on the combined actions of TLR4 signaling and endoplasmic reticulum stress, which by acting in concert can boost the inflammatory response. Defining the mechanisms involved in this phenomenon may unveil potential targets for the treatment of metabolic/inflammatory diseases. Here we used LPS to induce endoplasmic reticulum stress in the human monocyte cell-line, THP-1. The unfolded protein response, produced after LPS, was dependent on CD14 activity but not on RNA-dependent protein kinase and could be inhibited by an exogenous chemical chaperone. The induction of the endoplasmic reticulum resident chaperones, GRP94 and GRP78, by LPS was of a much lower magnitude than the effect of LPS on TLR4 and MD-2 expression. In face of this apparent insufficiency of chaperone expression, we induced the expression of GRP94 and GRP78 by glucose deprivation. This approach completely reverted endoplasmic reticulum stress. The inhibition of either GRP94 or GRP78 with siRNA was sufficient to rescue the protective effect of glucose deprivation on LPS-induced endoplasmic reticulum stress. Thus, insufficient LPS-induced chaperone expression links TLR4 signaling to endoplasmic reticulum stress.287191558015589Fundacao de Amparo a Pesquisa de Sao PauloConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Protein restriction in early life is associated with changes in insulin sensitivity and pancreatic beta-cell function during pregnancy

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Malnutrition in early life impairs glucose-stimulated insulin secretion in adulthood. Conversely, pregnancy is associated with a significant increase in glucose-stimulated insulin secretion under conditions of normoglycaemia. A failure in beta-cell adaptive changes may contribute to the onset of diabetes. Thus, glucose homeostasis and beta-cell function were evaluated in control-fed pregnant (CP) and non-pregnant (CNP) or protein-restricted pregnant (LPP) and non-pregnant (LPNP) rats, from fetal to adult life, and in protein-restricted rats that were recovered after weaning (RP and RNP). The typical insulin resistance of pregnancy was not observed in the RP rats, nor did pregnancy increase the insulin content/islet in the LPP group. The glucose dose-response curves from pregnant rats were shifted to the left in relation to the nonpregnant rats, except in the recovered group. Glucose utilisation but not oxidation in islets from the RP and LPP groups was reduced at a concentration of 8.3mM-glucose compared with islets from the CP group. Cyclic AMP content and the potentiation of glucose-stimulated insulin secretion by isobutylmethylxanthine at a concentration of 2.8mM-glucose indicated increased adenylyl cyclase 3 activity but reduced protein kinase A-alpha activity in islets from the RP and LPP rats. Protein kinase C (PKC)-alpha but not phospholipase C (PLC)-beta 1 expression was reduced in islets from the RP group. Phorbol-12-myristate 13-acetate produced a less potent stimulation of glucose-stimulated insulin secretion in the RP group. Thus, the alterations exhibited by islets from the LPP group appeared to be due to reduced islet mass and/or insulin biosynthesis. In the RP group the loss of the adaptive capacity apparently resulted from uncoupling between glucose metabolism and the amplifying signals of the secretory process, as well as a severe attenuation of the PLC/PKC pathway.o TEXTO COMPLETO DESTE ARTIGO, ESTARÁ DISPONÍVEL À PARTIR DE AGOSTO DE 2015.1092236247Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPEMAT (Fundacao de Amparo a Pesquisa do Estado de Mato Grosso) [0786/2006]Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)CNPq [305155/2004-0]FAPEMAT (Fundacao de Amparo a Pesquisa do Estado de Mato Grosso) [0786/2006]CAPES [PROCAD 022/2007

Taurine enhances the anorexigenic effects of insulin in the hypothalamus of rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Taurine is known to modulate a number of metabolic parameters such as insulin secretion and action and blood cholesterol levels. Recent data have suggested that taurine can also reduce body adiposity in and in rodents. Since body adiposity is mostly regulated by insulin-responsive hypothalamic neurons involved in the control of feeding and thermogenesis, we hypothesized that some of the activity of taurine in the control of body fat would be exerted through a direct action in the hypothalamus. Here, we show that the intracerebroventricular injection of an acute dose of taurine reduces food intake and locomotor activity, and activates signal transduction through the Akt/FOXO1, JAK2/STAT3 and mTOR/AMPK/ACC signaling pathways. These effects are accompanied by the modulation of expression of NPY. In addition, taurine can enhance the anorexigenic action of insulin. Thus, the aminoacid, taurine, exerts a potent anorexigenic action in the hypothalamus and enhances the effect of insulin on the control of food intake.42624032410Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Inhibition of Hypothalamic Inflammation Reverses Diet-Induced Insulin Resistance in the Liver

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Defective liver gluconeogenesis is the main mechanism leading to fasting hyperglycemia in type 2 diabetes, and, in concert with steatosis, it is the hallmark of hepatic insulin resistance. Experimental obesity results, at least in part, from hypothalamic inflammation, which leads to leptin resistance and defective regulation of energy homeostasis. Pharmacological or genetic disruption of hypothalamic inflammation restores leptin sensitivity and reduces adiposity. Here, we evaluate the effect of a hypothalamic anti-inflammatory approach to regulating hepatic responsiveness to insulin. Obese rodents were treated by intracerebroventricular injections, with immunoneutralizing antibodies against Toll-like receptor (TLR) 4 or tumor necrosis factor (TNF)alpha, and insulin signal transduction, hepatic steatosis, and gluconeogenesis were evaluated. The inhibition of either TLR4 or TNF alpha reduced hypothalamic inflammation, which was accompanied by the reduction of hypothalamic resistance to leptin and improved insulin signal transduction in the liver. This was accompanied by reduced liver steatosis and reduced hepatic expression of markers of steatosis. Furthermore, the inhibition of hypothalamic inflammation restored defective liver glucose production. All these beneficial effects were abrogated by vagotomy. Thus, the inhibition of hypothalamic inflammation in obesity results in improved hepatic insulin signal transduction, leading to reduced steatosis and reduced gluconeogenesis. All these effects are mediated by parasympathetic signals delivered by the vagus nerve. Diabetes 61:1455-1462, 201261614551462Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP