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Objetivo: compreender a judicialização da saúde no Brasil e analisar, na perspectiva da desjudicialização da saúde, o Acordo de Cooperação Técnica, firmado em 02 de dezembro de 2021, entre a Secretaria de Estado de Saúde de Minas Gerais, a Advocacia Geral do Estado de Minas Gerais e a Defensoria Pública Estadual de Minas Gerais para a gestão dos medicamentos Ranibizumabe e Aflibercept. Método: realizou-se revisão narrativa da literatura sobre a judicialização da saúde e um estudo exploratório baseado em anaÌlise documental dos antecedentes do Acordo de Cooperação Técnica. Resultados e discussões: a autocomposição e solução consensual de conflitos por parte da Administração Pública possui amplo respaldo legal e, no atual cenário jurídico e administrativo, é o meio mais eficaz e eficiente para concretizar o interesse público subjacente, notadamente o direito à saúde, promovendo sua desjudicialização. Esse cenário aponta para o potencial de novas soluçoÌes, entre elas a implementação de diálogos interinstitucionais, como é exemplo o Acordo de Cooperação Técnica estudado, o qual projeta-se poder servir de embrião para uma tendência permanente na gestão da judicialização da saúde no âmbito da Secretaria de Estado da Saúde de Minas Gerais. Considerações finais: o acordo de cooperação estudado tem grande potencial para a desjudicialização das ações com pedidos dos medicamentos oftalmológicos, além de outros cujas incorporações forem propostas em seu bojo. Ele também promove a atuação sinérgica e convergente dos atores que atuam na judicialização. A perspectiva é que, a partir desse marco, estas ações judiciais diminuam e os pacientes passem a ser atendidos pela via de fornecimento administrativo do Sistema Único de Saúde.
Objective: to understand the judicialization of health in Brazil and analyze, from the perspective of health de-judicialization, the Technical Cooperation Agreement signed on December 2, 2021, between the State Health Departmentof Minas Gerais , the State Attorney General's Office of Minas Gerais, and the State Public Defender's Office of Minas Gerais for the management of the medications Ranibizumab and Aflibercept. Method: a narrative review of the literature on the judicialization of health and an exploratory study based on documentary analysis of the antecedents of the Technical Cooperation Agreement were carried out. Results and discussions: Self-composition and consensual resolution of conflicts by the Public Administration has broad legal support and, in the current legal and administrative scenario, is the most effective and efficient means of realizing the underlying public interest, notably the right to health, promoting its dejudicialization. This scenario points to the potential for new solutions, including the implementation of interinstitutional dialogues, such as the Technical Cooperation Agreement studied, which is expected to serve as the embryo for a permanent trend in the management of the judicialization of health within the scope of State Health Departmentof Minas Gerais. Final considerations: ahe cooperation agreement studied has great potential for the dejudicialization of actions with requests for ophthalmological medicines, in addition to others whose incorporations are proposed within it. It also promotes synergistic and convergent action by actors involved in judicialization. The perspective is that, from this milestone, these legal actions will decrease and patients will begin to be served through the United Health System administrative supply route.
Objetivo: comprender la judicialización de la salud en Brasil y analizar, desde la perspectiva de la desjudicialización de la salud, el Acuerdo de Cooperación Técnica firmado el 2 de diciembre de 2021 entre la Secretaría de Estado de Saludde Minas Gerais, la Procuraduría General del Estado de Minas Gerais (AGE-MG) y la Defensoría Pública Estatal de Minas Gerais para la gestión de los medicamentos Ranibizumab y Aflibercept. Método: Se realizó una revisión narrativa de la literatura sobre la judicialización de la salud y un estudio exploratorio basado en un análisis documental de los antecedentes del Acuerdo de Cooperación Técnica. Resultados y discusiones: La autocomposición y resolución consensuada de conflictos por parte de la Administración Pública tiene un amplio respaldo legal y, en el actual escenario jurídico y administrativo, es el medio más eficaz y eficiente para realizar el interés público subyacente, en particular el derecho a la salud. promoviendo su desjudicialización. Este escenario apunta al potencial de nuevas soluciones, incluida la implementación de diálogos interinstitucionales, como el Acuerdo de Cooperación Técnica estudiado, que se espera sirva como embrión de una tendencia permanente en la gestión de la judicialización de la salud en el ámbito de la Secretaría de Estado de Salud de Minas Gerais. Consideraciones finales: el convenio de cooperación estudiado tiene un gran potencial para la desjudicialización de acciones con solicitudes de medicamentos oftalmológicos, además de otras cuyas incorporaciones se proponen dentro del mismo. También promueve acciones sinérgicas y convergentes por parte de los actores involucrados en la judicialización. La perspectiva es que, a partir de este hito, esas acciones legales disminuyan y los pacientes comiencen a ser atendidos a través de la vía administrativa de abastecimiento del Sistema de Salud Unido.
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Direito SanitárioRESUMO
The aim of this work was to evaluate possible mechanisms involved in the protective effect of N-acetyl-L-cysteine (NAC) on hepatic endocrine-metabolic, oxidative stress, and inflammatory changes in prediabetic rats. For that, normal male Wistar rats (60 days old) were fed for 21 days with 10% sucrose in their drinking water and 5 days of NAC administration (50 mg/kg, i.p.) and thereafter, we determined: serum glucose, insulin, transaminases, uric acid, and triglyceride levels; hepatic fructokinase and glucokinase activities, glycogen content, lipogenic gene expression; enzymatic and non-enzymatic oxidative stress, insulin signaling pathway, and inflammatory markers. Results showed that alterations evinced in sucrose-fed rats (hypertriglyceridemia, hyperinsulinemia, and high liver fructokinase activity together with increased liver lipogenic gene expression and oxidative stress and inflammatory markers) were prevented by NAC administration. P-endothelial nitric oxide synthase (P-eNOS)/eNOS and pAKT/AKT ratios, decreased by sucrose ingestion, were restored after NAC treatment. In conclusion, the results suggest that NAC administration improves glucose homeostasis, oxidative stress, and inflammation in prediabetic rats probably mediated by modulation of the AKT/NOS pathway. Administration of NAC may be an effective complementary strategy to alleviate or prevent oxidative stress and inflammatory responses observed in type 2 diabetes at early stages of its development (prediabetes).
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Estado Pré-Diabético , Ratos , Masculino , Animais , Acetilcisteína/farmacologia , Acetilcisteína/metabolismo , Estado Pré-Diabético/tratamento farmacológico , Ratos Wistar , Diabetes Mellitus Tipo 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sacarose/farmacologia , Estresse Oxidativo , Insulina/metabolismo , Transdução de Sinais , Glucose/farmacologia , Óxido Nítrico/metabolismoRESUMO
Maritime transport is considered a sustainable mean of transporting goods worldwide. In addition to cargo, ships unintentionally transport non-native species. While managing the transport of organisms through ballast water has been at the centre of international efforts, biofouling from ships has not been addressed in the same way and some potentially harmful practices, such as in-water cleaning, still occur worldwide. Another problem arising from ship operating standards is the equipment known as "open-loop scrubbers," which utilizes seawater to "wash" the sulfur content out of the heavy fuel oil (HFO) and, in turn, discharges an acidic wash water full of sulfur and other substances from fuel oils in the environment. Here, we compare the international regulations applied to both issues and how they have been implemented in Brazil so far, considering the perspective of ports and terminals. Results showed that six of sixteen states have already imposed restrictions/bans on scrubbers wash waters, indicating a clear movement in the direction of restricting the discharge as the best way to prevent air and marine pollution. Regarding biofouling, although there is hope with the adoption of the revised guidelines, there are still some doubts considering these are non-binding, depending on national policies to be implemented. In Brazil, there is no national policy yet, and all public ports prohibit vessels in-water cleaning.
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Incrustação Biológica , Incrustação Biológica/prevenção & controle , Água , Brasil , Monitoramento Ambiental , Navios , EnxofreRESUMO
"Yerba mate" (YM), an aqueous extract of Ilex paraguariensis, has antioxidant, diuretic, cardio-protective and hypoglycaemic properties. Since its effect on the pancreatic islets remains unclear, we evaluated insulin sensitivity and glucose-stimulated insulin secretion (GSIS) in rats consuming YM or tap water (C) for 21 days. Glucose tolerance, glycemia, triglyceridemia, insulinemia, TBARS and FRAP serum levels were evaluated. GSIS and mRNA levels of insulin signaling pathway and inflammatory markers were measured in isolated pancreatic islets from both groups. In C rats, islets were incubated with YM extract or its phenolic components to measure GSIS. YM improved glucose tolerance, enhanced GSIS, increased FRAP plasma levels and islet mRNA levels of IRS-1 and PI3K (p110), and decreased TBARS plasma levels and islet gene expression of TNF-α and PAI-1. Islets from C rats incubated with 100 µg/mL dry YM extract, 1 µM chlorogenic acid, 0.1 and 1 µM rutin, 1 µM caffeic acid or 1 µM quercetin showed an increase in GSIS. Our results suggest that YM enhances glucose tolerance because of its positive effects on GSIS, oxidative stress rate and insulin sensitivity in rat islets, suggesting that long-term dietary supplementation with YM may improve glucose homeostasis in pre-diabetes or type 2 diabetes.
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A high-fructose diet (HFD) induces murine alterations like those recorded in human prediabetes. Protective effects of isoespintanol (monoterpene isolated from Oxandra cf. xylopioides) on changes induced by HFD were evaluated. Animals were maintained for 21 days with a standard diet (C), 10% fructose (F), and F plus isoespintanol (FI, 10 mg/kg, i.p.). Glycemia, triglyceridemia, total and HDL-cholesterol, and insulin resistance index (IRX) were determined. Intraperitoneal glucose tolerance test (IGTT) was performed. In the liver, we measured glycogen, lipogenic gene expression (SREBP-1c, GPAT, FAS, and CPT1), oxidative stress (GSH and 3'-nitrotyrosine content), inflammation markers (iNOS, TNF-α, and PAI-1 gene expression; iNOS and COX-2 protein levels), p-eNOS, p-Akt, and p-GSK3ß protein levels. Isoespintanol corrected enhanced triglycerides, lipogenic genes, and IRX, and reduced HDL-cholesterol induced by HFD. Increased liver glycogen and inflammatory markers and decreased GSH, p-Akt, and p-GSK3ß measured in F rats were reversed by isoespintanol, and p-eNOS/e-NOS and iNOS/GADPH ratios were normalized. Isoespintanol restored glucose tolerance (IGTT) compared to F rats. These results demonstrate for the first time that isoespintanol prevents endocrine-metabolic alterations induced by HFD in prediabetic rats. These effects could be mediated by Akt/eNOS and Akt/GSK3ß pathways, suggesting its possible use as a therapeutic tool for the prevention of diabetes at early stages of its development (prediabetes).
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The oil spill of unknown origin that hit the Brazilian coast in 2019 led to the first activation of the National Contingency Plan, outside the scope of an exercise. The Brazilian Navy, the Environmental Agency and the Oil Agency worked together during the oil spill emergency at the Federal level, as the plan´s Monitoring and Evaluation Group. However, the distinctive characteristics and proportions of the incident demanded unanticipated actions. Therefore, this work aims to analyze the response actions, to evaluate policies and procedures in place and to propose improvements for the future. The paper discusses the anonymous and voluntary feedback from 150 professionals, obtained during the event, through a structured online form. The results of the survey are compared to findings in official documents, especially the Incident´s Final Report, prepared by the Brazilian Navy. The conclusion is that the Incident Command System, used to manage and coordinate clean-up operations, provided a swift and coordinated response as the oil reached the shore of 11 states. In contrast, there is a need to review the legal framework, including the Decree that established the National Contingency Plan, revisit response manuals, improve liaison and enhance communication channels among different authorities in the Brazilian Government.
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Poluição por Petróleo , BrasilRESUMO
Background and Objectives: The work was aimed to determine the chronological sequence of events triggered by a fructose-rich diet (FRD) (10% w/v in the drinking water) in normal rats. Material and Methods: Serum parameters, liver and islet markers of metabolism, inflammation and oxidative stress were determined weekly for 21 days. Results: At the end of the first week, rats fed with a FRD showed an early increase in circulating triglycerides, fat liver deposit, and enzymatic activity of liver glucokinase and glucose-6-phosphate dehydrogenase (G6P-DH). After two weeks of such a diet, liver glucose-6-phosphatase (G6Pase) activity and liver oxidative stress markers were significantly increased. Liver sterol regulatory element-binding protein 1c (SREBP1c) mRNA also increased in the second week while their target genes fatty acid synthase (FAS) and glycerol-3-phosphate dehydrogenase (GPAT) enhanced their expression at the third week. Liver and pancreatic inflammation markers also enhanced their gene expression in the last week of treatment. Whereas both control and FRD rats remained normoglycemic throughout the entire period of treatment, blood insulin levels were significantly higher in FRD animals at the third week, thereby evidencing an insulin-resistant state (higher HOMA-IR, HOMA-B and HIS indexes). Pancreatic islets isolated from rats fed with a FRD for 3 weeks also increased glucose-induced insulin secretion (8.3 and 16.7 mM). Conclusions: FRD induces asynchronous changes involving early hypertriglyceridemia together with intrahepatic lipid deposit and metabolic disturbances from week one, followed by enhanced liver oxidative stress, liver and pancreas inflammation, pancreatic ß-cell dysfunction, and peripheral insulin-resistance registered at the third week. Knowledge of time-course adaptation mechanisms involved in our rat model could be helpful in developing appropriate strategies to prevent the progression from prediabetes to Type 2 diabetes (T2D) triggered by unhealthy diets.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Animais , Dieta , Frutose/efeitos adversos , Ratos , Ratos WistarRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Cocoa extracts rich in polyphenols are used as potential agent for treating diabetes. Cocoa polyphenols have been proved to ameliorate important hallmarks of type-2 diabetes (T2D). They can regulate glucose levels by increasing insulin secretion, promoting ß-cell proliferation and a reduction of insulin resistance. In addition, epidemiological evidence indicates that consumption of flavonoid decreases the incidence of T2D. AIM OF THE STUDY: T2D is preceded by a prediabetic state in which the endocrine-metabolic changes described in T2D are already present. Since epidemiological evidence indicates that consumption of flavonoid decreases its incidence, we evaluated possible preventive effects of polyphenol-enriched cocoa extract on a model of prediabetes induced by sucrose. MATERIALS AND METHODS: We determined circulating parameters and insulin sensitivity indexes, liver protein carbonyl groups and reduced glutathione, liver mRNA expression levels of lipogenic enzymes, expression of different pro-inflammatory mediators, fructokinase activity and liver glycogen content. For that, radioimmunoassay, real-time polymerase chain reaction, Western blot, spectrophotometry, and immunohistochemistry were used. RESULTS: We demonstrated that sucrose administration triggered hypertriglyceridemia, insulin-resistance, and liver increased oxidative stress and inflammation markers compared to control rats. Additionally, we found an increase in glycogen deposit, fructokinase activity, and lipogenic genes expression (SREBP-1c, FAS and GPAT) together with a decrease in P-Akt and P-eNOS protein content (Pâ¯<â¯0.05). Sucrose-induced insulin resistance, hepatic carbohydrate and lipid dysmetabolism, oxidative stress, and inflammation were effectively disrupted by polyphenol-enriched cocoa extract (PECE) co-administration (Pâ¯<â¯0.05). CONCLUSION: Dietary administration of cocoa flavanols may be an effective and complementary tool for preventing or reverting T2D at an early stage of its development (prediabetes).
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Cacau/química , Diabetes Mellitus Tipo 2/prevenção & controle , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Estado Pré-Diabético/tratamento farmacológico , Animais , Diabetes Mellitus Tipo 2/metabolismo , Sacarose Alimentar/efeitos adversos , Modelos Animais de Doenças , Humanos , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Polifenóis/isolamento & purificação , Polifenóis/uso terapêutico , Estado Pré-Diabético/sangue , Estado Pré-Diabético/etiologia , Estado Pré-Diabético/metabolismo , Ratos , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
In recent decades a worldwide increase has been reported in the consumption of unhealthy high calorie diets associated with marked changes in meal nutrient composition, such as a higher intake of refined carbohydrates, which leads to the speculatation that changes in food habits have contributed to the current epidemic of obesity and type 2 diabetes. Among these refined carbohydrates, fructose has been deeply investigated and murine models of high fructose diet have emerged as useful tools to study dietary-induced insulin resistance, impaired glucose tolerance, dyslipidemia and alterations in glucose metabolism. Since oxidative stress has been demonstrated to play a key pathogenic role in the alterations described above, several lines of research have focused on the possible preventive effects of antioxidant/redox state regulation therapy, among which alpha-lipoic acid has been extensively investigated. The following references discussed support the fact that co-administration of alpha-lipoic acid normalized the changes generated by fructose rich diets, thereby making this compound a good therapeutic tool, also administered as a food supplement, to prevent endocrine-metabolic disturbances triggered by high fructose associated with obesity and type 2 diabetes at an early stage of development (prediabetes).
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Diabetes Mellitus Tipo 2/prevenção & controle , Sistema Endócrino/metabolismo , Frutose/efeitos adversos , Obesidade/prevenção & controle , Ácido Tióctico/administração & dosagem , Animais , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Sistema Endócrino/efeitos dos fármacos , Humanos , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacosRESUMO
[This corrects the article DOI: 10.1155/2016/7838290.].
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AIM: Hypothalamic obese rats are characterized by pre-diabetes, dyslipidemia, hyperadiposity, inflammation and, liver dysmetabolism with oxidative stress (OS), among others. We studied endocrine-metabolic dysfunctions and, liver OS and inflammation in both monosodium l-glutamate (MSG)-neonatally damaged and control litter-mate (C) adult male rats, either chronically treated with N-Acetyl-l-Cysteine since weaned (C-NAC and MSG-NAC) or not. METHODOLOGY: We evaluated circulating TBARS, glucose, insulin, triglycerides, uric acid (UA) and, aspartate and alanine amino-transferase; insulin sensitivity markers (HOMA indexes, Liver Index of Insulin Sensitivity -LISI-) were calculated and liver steps of the insulin-signaling pathway were investigated. Additionally, we monitored liver OS (protein carbonyl groups, GSH and iNOS level) and inflammation-related markers (COX-2 and TNFα protein content; gene expression level of Il1b, Tnfα and Pai-1); and carbohydrate and lipid metabolic functions (glucokinase/fructokinase activities and, mRNA levels of Srebp1c, Fas and Gpat). KEY FINDINGS: Chronic NAC treatment in MSG rats efficiently decreased the high circulating levels of triglycerides, UA, transaminases and TBARS, as well as peripheral (high insulinemia and HOMA indexes) and liver (LISI and the P-AKT:AKT and P-eNOS:eNOS protein ratio values) insulin-resistance. Moreover, NAC therapy in MSG rats prevented liver dysmetabolism by decreasing local levels of OS and inflammation markers. Finally, NAC-treated MSG rats retained normal liver glucokinase and fructokinase activities, and Srebp1c, Fas and Gpat (lipogenic genes) expression levels. SIGNIFICANCE: Our study strongly supports that chronic oral antioxidant therapy (NAC administration) prevented the development of pre-diabetes, dyslipidemia, and inflamed-dysmetabolic liver in hypothalamic obese rats by efficiently decreasing high endogenous OS.
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Acetilcisteína/uso terapêutico , Hipotálamo/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Obesidade/tratamento farmacológico , Estado Pré-Diabético/prevenção & controle , Acetilcisteína/farmacologia , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Hipotálamo/metabolismo , Resistência à Insulina/fisiologia , Masculino , Obesidade/sangue , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Estado Pré-Diabético/sangue , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
Islet-Neogenesis Associated Protein-Pentadecapeptide (INGAP-PP) increases ß-cell mass and enhances glucose and amino acids-induced insulin secretion. Our aim was to demonstrate its effect on liver metabolism. For that purpose, adult male Wistar rats were injected twice-daily (10â¯days) with saline solution or INGAP-PP (250⯵g). Thereafter, serum glucose, triglyceride and insulin levels were measured and homeostasis model assessment (HOMA-IR) and hepatic insulin sensitivity (HIS) were determined. Liver glucokinase and glucose-6-phosphatase (G-6-Pase) expression and activity, phosphoenolpyruvate carboxykinase (PEPCK) expression, phosphofructokinase-2 (PFK-2) protein content, P-Akt/Akt and glycogen synthase kinase-3ß (P-GSK3/GSK3) protein ratios and glycogen deposit were also determined. Additionally, glucokinase activity and G-6-Pase and PEPCK gene expression were also determined in isolated hepatocytes from normal rats incubated with INGAP-PP (5⯵g/ml). INGAP-PP administration did not modify any of the serum parameters tested but significantly increased activity of liver glucokinase and the protein level of its cytosolic activator, PFK-2. Conversely, INGAP-PP treated rats decreased gene expression and enzyme activity of gluconeogenic enzymes, G-6-Pase and PEPCK. They also showed a higher glycogen deposit and P-GSK3/GSK3 and P-Akt/Akt ratio. In isolated hepatocytes, INGAP-PP increased GK activity and decreased G-6-Pase and PEPCK expression. These results demonstrate a direct effect of INGAP-PP on the liver acting through P-Akt signaling pathway. INGAP-PP enhances liver glucose metabolism and deposit and reduces its production/output, thereby contributing to maintain normal glucose homeostasis. These results reinforce the concept that INGAP-PP might become a useful tool to treat people with impaired islet/liver glucose metabolism as it occurs in T2D.
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Metabolismo dos Carboidratos/efeitos dos fármacos , Fígado/metabolismo , Oligopeptídeos/farmacologia , Proteínas Associadas a Pancreatite/química , Transdução de Sinais/efeitos dos fármacos , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Oligopeptídeos/química , Ratos , Ratos WistarRESUMO
We investigated the impact of chronic hypercorticosteronemia (due to neonatal monosodium L-glutamate, MSG, and treatment) on liver oxidative stress (OS), inflammation, and carbohydrate/lipid metabolism in adult male rats. We evaluated the peripheral concentrations of several metabolic and OS markers and insulin resistance indexes. In liver we assessed (a) OS (GSH and protein carbonyl groups) and inflammatory (IL-1b, TNFa, and PAI-1) biomarkers and (b) carbohydrate and lipid metabolisms. MSG rats displayed degenerated optic nerves, hypophagia, low body and liver weights, and enlarged adipose tissue mass; higher peripheral levels of glucose, triglycerides, insulin, uric acid, leptin, corticosterone, transaminases and TBARS, and peripheral and liver insulin resistance; elevated liver OS, inflammation markers, and glucokinase (mRNA/activity) and fructokinase (mRNA). Additionally, MSG liver phosphofructokinase-2, glucose-6-phosphatase (mRNA and activity) and glucose-6-phosphate dehydrogenase, Chrebp, Srebp1c, fatty acid synthase, and glycerol-3-phosphate (mRNAs) were increased. In conclusion adult MSG rats developed an insulin-resistant state and increased OS and serious hepatic dysfunction characterized by inflammation and metabolic signs suggesting increased lipogenesis. These features, shared by both metabolic and Cushing's syndrome human phenotypes, support that a chronic glucocorticoid-rich endogenous environment mainly impacts on hepatic glucose cycle, displacing local metabolism to lipogenesis. Whether correcting the glucocorticoid-rich environment ameliorates such dysfunctions requires further investigation.
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BACKGROUND: Heart failure and arrhythmias occur more frequently in patients with type 2 diabetes (T2DM) than in the general population. T2DM is preceded by a prediabetic condition marked by elevated reactive oxygen species (ROS) and subclinical cardiovascular defects. Although multifunctional Ca2+ calmodulin-dependent protein kinase II (CaMKII) is ROS-activated and CaMKII hyperactivity promotes cardiac diseases, a link between prediabetes and CaMKII in the heart is unprecedented. OBJECTIVES: To prove the hypothesis that increased ROS and CaMKII activity contribute to heart failure and arrhythmogenic mechanisms in early stage diabetes. METHODS-RESULTS: Echocardiography, electrocardiography, biochemical and intracellular Ca2+ (Ca2+i) determinations were performed in fructose-rich diet-induced impaired glucose tolerance, a prediabetes model, in rodents. Fructose-rich diet rats showed decreased contractility and hypertrophy associated with increased CaMKII activity, ROS production, oxidized CaMKII and enhanced CaMKII-dependent ryanodine receptor (RyR2) phosphorylation compared to rats fed with control diet. Isolated cardiomyocytes from fructose-rich diet showed increased spontaneous Ca2+i release events associated with spontaneous contractions, which were prevented by KN-93, a CaMKII inhibitor, or addition of Tempol, a ROS scavenger, to the diet. Moreover, fructose-rich diet myocytes showed increased diastolic Ca2+ during the burst of spontaneous Ca2+i release events. Mice treated with Tempol or with sarcoplasmic reticulum-targeted CaMKII-inhibition by transgenic expression of the CaMKII inhibitory peptide AIP, were protected from fructose-rich diet-induced spontaneous Ca2+i release events, spontaneous contractions and arrhythmogenesis in vivo, despite ROS increases. CONCLUSIONS: RyR2 phosphorylation by ROS-activated CaMKII, contributes to impaired glucose tolerance-induced arrhythmogenic mechanisms, suggesting that CaMKII inhibition could prevent prediabetic cardiovascular complications and/or evolution.
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Arritmias Cardíacas/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cálcio/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Aminoácidos/metabolismo , Animais , Arritmias Cardíacas/patologia , Arritmias Cardíacas/prevenção & controle , Benzilaminas/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/química , Cromo/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Frutose/administração & dosagem , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/prevenção & controle , Masculino , Camundongos , Miócitos Cardíacos/metabolismo , Ácidos Nicotínicos/metabolismo , Fosforilação , Estado Pré-Diabético/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Retículo Sarcoplasmático/metabolismo , Sulfonamidas/farmacologiaRESUMO
AIMS: Fructose administration induces hepatic oxidative stress, insulin resistance, inflammatory and metabolic changes. We tested their potential pathogenic relationship and whether these alterations can be prevented by R/S-α-lipoic acid. MAIN METHODS: Wistar rats received during 21days a commercial diet or the same diet supplemented with 10% fructose in drinking water without/with R/S-α-lipoic acid injection. After this period, we measured a) serum glucose, triglyceride, insulin, homeostasis model assessment-insulin resistance (HOMA-IR), insulin glucose ratio (IGR) and Matsuda indexes and b) liver oxidative stress, inflammatory markers and insulin signaling pathway components. KEY FINDINGS: Fructose fed rats had hyperinsulinemia, hypertriglyceridemia, higher HOMA-IR, IGR and lower Matsuda indices compared to control animals, together with increased oxidative stress markers, TNFα, IL1ß and PAI-1 gene expression, and TNFα and COX-2 protein content. Whereas insulin receptor level was higher in fructose fed rats, their tyrosine-residue phosphorylation was lower. IRS1/IRS2 protein levels and IRS1 tyrosine-phosphorylation rate were lower in fructose fed rats. All changes were prevented by R/S-α-lipoic acid co-administration. SIGNIFICANCE: Fructose-induced hepatic oxidative stress, insulin resistance and inflammation form a triad that constitutes a vicious pathogenic circle. This circle can be effectively disrupted by R/S-α-lipoic acid co-administration, thus suggesting mutual positive interaction among the triad components.
Assuntos
Frutose/efeitos adversos , Inflamação/dietoterapia , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/patologia , Estresse Oxidativo/efeitos dos fármacos , Ácido Tióctico/farmacologia , Ácido Tióctico/uso terapêutico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Glicemia/metabolismo , Ciclo-Oxigenase 2/biossíntese , Suplementos Nutricionais , Expressão Gênica/efeitos dos fármacos , Inflamação/sangue , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Insulina/sangue , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina/genética , Interleucina-1beta/biossíntese , Fígado/metabolismo , Masculino , Fosforilação/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/biossíntese , Ratos , Ratos Wistar , Receptor de Insulina/biossíntese , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/biossínteseRESUMO
In the present study, we investigated the role of NADPH oxidase in F (fructose)-rich-diet-induced hepatic OS (oxidative stress) and metabolic changes, and their prevention by apocynin co-administration. Wistar rats were fed for 21 days on (i) a control diet, (ii) a control diet plus 10% F in the drinking water, (iii) a control diet with apocynin in the drinking water (CA) and (iv) F plus apocynin in the drinking water (FA). Glycaemia, triglyceridaemia, NEFAs (non-esterified fatty acids) and insulinaemia were determined. In the liver, we measured (i) NADPH oxidase activity, and gene and protein expression; (ii) protein carbonyl groups, GSH and TBARSs (thiobarbituric acid-reactive substances); (iii) catalase, CuZn-SOD (superoxide dismutase) and Mn-SOD expression; (iv) liver glycogen and lipid content; (v) GK (glucokinase), G6Pase (glucose-6-phosphatase) and G6PDH (glucose-6-phosphate dehydrogenase) activities; (vi) FAS (fatty acid synthase), GPAT (glycerol-3-phosphate acyltransferase), G6Pase and G6PDH, IL-1ß (interleukin-1ß), PAI-1 (plasminogen-activator inhibitor-1) and TNFα (tumour necrosis factor α) gene expression; and (vii) IκBα (inhibitor of nuclear factor κB α) protein expression. F-fed animals had high serum TAG (triacylglycerol), NEFA and insulin levels, high liver NADPH oxidase activity/expression, increased OS markers, reduced antioxidant enzyme expression, and increased glycogen, TAG storage and GK, G6Pase and G6PDH activities. They also had high G6Pase, G6PDH, FAS, GPAT, TNFα and IL-1ß gene expression and decreased IκBα expression. Co-administration of apocynin to F-fed rats prevented the development of most of these abnormalities. In conclusion, NADPH oxidase plays a key role in F-induced hepatic OS production and probably also in the mechanism of liver steatosis, suggesting its potential usefulness for the prevention/treatment of T2DM (Type 2 diabetes mellitus).