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[PMID]:27778639
[Au] Autor:Arnold AC; Garland EM; Celedonio JE; Raj SR; Abumrad NN; Biaggioni I; Robertson D; Luther JM; Shibao CA
[Ad] Endereço:Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
[Ti] Título:Hyperinsulinemia and Insulin Resistance in Dopamine ß-Hydroxylase Deficiency.
[So] Source:J Clin Endocrinol Metab;102(1):10-14, 2017 Jan 01.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Context: Dopamine ß-hydroxylase (DBH) deficiency is a rare genetic disorder characterized by failure to convert dopamine to norepinephrine. DBH-deficient patients lack sympathetic adrenergic function and are therefore predisposed to orthostatic hypotension. DBH-deficient mice exhibit hyperinsulinemia, lower plasma glucose levels, and insulin resistance due to loss of tonic sympathetic inhibition of insulin secretion. The impact of DBH deficiency on glucose homeostasis in humans is unknown. Case Description: We describe the metabolic profile of an adolescent female DBH-deficient patient. The patient underwent genetic testing, cardiovascular autonomic function testing, and evaluation of insulin secretion and sensitivity with hyperglycemic clamp under treatment-naive conditions. All procedures were repeated after 1 year of treatment with the norepinephrine prodrug droxidopa (300 mg, 3 times a day). Genetic testing showed a homozygous mutation in the DBH gene (rs74853476). Under treatment-naive conditions, she had undetectable plasma epinephrine and norepinephrine levels, resulting in sympathetic noradrenergic failure and orthostatic hypotension (-32 mm Hg supine to seated). She had high adiposity (41%) and fasting plasma insulin levels (25 µU/mL), with normal glucose (91 mg/dL). Hyperglycemic clamp revealed increased glucose-stimulated insulin secretion and insulin resistance. Droxidopa restored plasma norepinephrine and improved orthostatic tolerance, with modest effects on glucose homeostasis. Conclusions: We provide evidence for impairment in cardiovascular autonomic regulation, hyperinsulinemia, enhanced glucose-stimulated insulin secretion, and insulin resistance in a DBH-deficient patient. These metabolic derangements were not corrected by chronic droxidopa treatment. These findings provide insight into the pathophysiology and treatment of DBH deficiency and into the importance of catecholaminergic mechanisms to resting metabolism.
[Mh] Termos MeSH primário: Doenças do Sistema Nervoso Autônomo/complicações
Dopamina beta-Hidroxilase/deficiência
Hiperinsulinismo/etiologia
Resistência à Insulina
Norepinefrina/deficiência
[Mh] Termos MeSH secundário: Adolescente
Animais
Droxidopa/uso terapêutico
Feminino
Seres Humanos
Hiperinsulinismo/diagnóstico
Hiperinsulinismo/tratamento farmacológico
Insulina/metabolismo
Camundongos
Prognóstico
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insulin); EC 1.14.17.1 (Dopamine beta-Hydroxylase); J7A92W69L7 (Droxidopa); X4W3ENH1CV (Norepinephrine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2016-3274


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[PMID]:29351550
[Au] Autor:Rachid TL; Silva-Veiga FM; Graus-Nunes F; Bringhenti I; Mandarim-de-Lacerda CA; Souza-Mello V
[Ad] Endereço:Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
[Ti] Título:Differential actions of PPAR-α and PPAR-ß/δ on beige adipocyte formation: A study in the subcutaneous white adipose tissue of obese male mice.
[So] Source:PLoS One;13(1):e0191365, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND AIMS: Obesity compromises adipocyte physiology. PPARs are essential to adipocyte plasticity, but its isolated role in the browning phenomenon is not clear. This study aimed to examine whether activation of PPAR-α or PPAR-ß/δ could induce beige cell depots in the subcutaneous white adipose tissue of diet-induced obese mice. MATERIAL AND METHODS: Sixty animals were randomly assigned to receive a control diet (C, 10% lipids) or a high-fat diet (HF, 50% lipids) for ten weeks. Then each group was re-divided to begin the treatments that lasted 4 weeks, totalizing six groups: C, C-α (C plus PPAR-α agonist, 2.5 mg/kg BM), C-ß (C plus PPAR-ß/δ agonist, 1 mg/kg BM), HF, HF-α (HF plus PPAR-α agonist), HF-ß (HF plus PPAR-ß/δ agonist). RESULTS: HF animals presented with overweight, glucose intolerance and subcutaneous white adipocyte hypertrophy. Both treatments significantly attenuated these parameters. Browning, verified by UCP1 positive beige cells and enhanced body temperature, was just observed in PPAR-α treated groups. PPAR-α agonism also elicited an enhanced gene expression of the thermogenesis effector UCP1, the beige-selective gene TMEM26 and the PRDM16, an essential gene for brown-like phenotype maintenance in the beige adipocytes when compared to their counterparts. The enhanced CIDEA and the reduced UCP1 gene levels might justify the white phenotype predominance after the treatment with the PPAR-ß/δ agonist. CONCLUSIONS: This work provides evidence that the PPAR-ß/δ agonist ameliorated metabolic disorders through enhanced beta-oxidation and better tolerance to glucose, whereas the PPAR-α agonism was confirmed as a promising therapeutic target for treating metabolic diseases via beige cell induction and enhanced thermogenesis.
[Mh] Termos MeSH primário: Adipócitos Bege/efeitos dos fármacos
Obesidade/tratamento farmacológico
PPAR alfa/agonistas
PPAR delta/agonistas
PPAR beta/agonistas
[Mh] Termos MeSH secundário: Adipócitos Bege/metabolismo
Adipócitos Bege/patologia
Tecido Adiposo Branco/efeitos dos fármacos
Tecido Adiposo Branco/metabolismo
Tecido Adiposo Branco/patologia
Adiposidade/efeitos dos fármacos
Animais
Glicemia/metabolismo
Peso Corporal/efeitos dos fármacos
Tamanho Celular/efeitos dos fármacos
Dieta Hiperlipídica/efeitos adversos
Ingestão de Energia/efeitos dos fármacos
Expressão Gênica/efeitos dos fármacos
Intolerância à Glucose/tratamento farmacológico
Hiperinsulinismo/tratamento farmacológico
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Obesidade/metabolismo
Obesidade/patologia
Termogênese/efeitos dos fármacos
Proteína Desacopladora 1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Blood Glucose); 0 (PPAR alpha); 0 (PPAR delta); 0 (PPAR-beta); 0 (Ucp1 protein, mouse); 0 (Uncoupling Protein 1)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180120
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191365


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[PMID]:29351765
[Au] Autor:Warnken T; Delarocque J; Schumacher S; Huber K; Feige K
[Ad] Endereço:Clinic for Horses, University of Veterinary Medicine Hannover, Foundation, Bünteweg 9, 30559, Hannover, Germany. tobias.warnken@tiho-hannover.de.
[Ti] Título:Retrospective analysis of insulin responses to standard dosed oral glucose tests (OGTs) via naso-gastric tubing towards definition of an objective cut-off value.
[So] Source:Acta Vet Scand;60(1):4, 2018 Jan 19.
[Is] ISSN:1751-0147
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Insulin dysregulation (ID) with basal or postprandial hyperinsulinemia is one of the key findings in horses and ponies suffering from the equine metabolic syndrome (EMS). Assessment of ID can easily be performed in clinical settings by the use of oral glucose challenge tests. Oral glucose test (OGT) performed with 1 g/kg bodyweight (BW) glucose administered via naso-gastric tube allows the exact administration of a defined glucose dosage in a short time. However, reliable cut-off values have not been available so far. Therefore, the aim of the study was to describe variations in insulin response to OGT via naso-gastric tubing and to provide a clinical useful cut-off value for ID when using the insulin quantification performed with an equine-optimized insulin enzyme-linked immunosorbent assay. RESULTS: Data visualization revealed no clear separation in the serum insulin concentration of insulin sensitive and insulin dysregulated horses during OGT. Therefore, a model based clustering method was used to circumvent the use of an arbitrary limit for categorization. This method considered all data-points for the classification, taking into account the individual insulin trajectory during the OGT. With this method two clusters were differentiated, one with low and one with high insulin responses during OGT. The cluster of individuals with low insulin response was consistently detected, independently of the initialization parameters of the algorithm. In this cluster the 97.5% quantile of insulin is 110 µLU/mL at 120 min. We suggest using this insulin concentration of 110 µLU/mL as a cut-off value for samples obtained at 120 min in OGT. CONCLUSION: OGT performed with 1 g/kg BW glucose and administration via naso-gastric tubing can easily be performed under clinical settings. Application of the cut-off value of 110 µLU/mL at 120 min allows assessment of ID in horses.
[Mh] Termos MeSH primário: Teste de Tolerância a Glucose/veterinária
Glucose/administração & dosagem
Cavalos
Hiperinsulinismo/veterinária
Insulina/sangue
Síndrome Metabólica/veterinária
[Mh] Termos MeSH secundário: Animais
Glicemia/análise
Ensaio de Imunoadsorção Enzimática/veterinária
Hiperinsulinismo/diagnóstico
Intubação Gastrointestinal/veterinária
Síndrome Metabólica/sangue
Estudos Retrospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Insulin); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180121
[St] Status:MEDLINE
[do] DOI:10.1186/s13028-018-0358-8


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[PMID]:29365308
[Au] Autor:Chan YM; Balza R; High FA
[Ad] Endereço:From the Department of Medicine, Boston Children's Hospital (Y.-M.C.), the Departments of Radiology (R.B.) and Pediatrics (F.A.H.), Massachusetts General Hospital, and the Departments of Pediatrics (Y.-M.C., F.A.H.) and Radiology (R.B.), Harvard Medical School - all in Boston.
[Ti] Título:Case 3-2018: A 5-Month-Old Boy with Hypoglycemia.
[So] Source:N Engl J Med;378(4):381-389, 2018 Jan 25.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Doença de Depósito de Glicogênio Tipo I/diagnóstico
Hipoglicemia/etiologia
[Mh] Termos MeSH secundário: Diagnóstico Diferencial
Doença de Depósito de Glicogênio Tipo I/complicações
Seres Humanos
Hiperinsulinismo/diagnóstico
Lactente
Rim/diagnóstico por imagem
Rim/patologia
Fígado/diagnóstico por imagem
Fígado/patologia
Masculino
Tamanho do Órgão
Ultrassonografia
[Pt] Tipo de publicação:CASE REPORTS; CLINICAL CONFERENCE; JOURNAL ARTICLE
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180125
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMcpc1706107


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[PMID]:28911175
[Au] Autor:Skarra DV; Hernández-Carretero A; Rivera AJ; Anvar AR; Thackray VG
[Ad] Endereço:Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92093.
[Ti] Título:Hyperandrogenemia Induced by Letrozole Treatment of Pubertal Female Mice Results in Hyperinsulinemia Prior to Weight Gain and Insulin Resistance.
[So] Source:Endocrinology;158(9):2988-3003, 2017 Sep 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Women with polycystic ovary syndrome (PCOS) diagnosed with hyperandrogenism and ovulatory dysfunction have an increased risk of developing metabolic disorders, including type 2 diabetes and cardiovascular disease. We previously developed a model that uses letrozole to elevate endogenous testosterone levels in female mice. This model has hallmarks of PCOS, including hyperandrogenism, anovulation, and polycystic ovaries, as well as increased abdominal adiposity and glucose intolerance. In the current study, we further characterized the metabolic dysfunction that occurs after letrozole treatment to determine whether this model represents a PCOS-like metabolic phenotype. We focused on whether letrozole treatment results in altered pancreatic or liver function as well as insulin resistance. We also investigated whether hyperinsulinemia occurs secondary to weight gain and insulin resistance in this model or if it can occur independently. Our study demonstrated that letrozole-treated mice developed hyperinsulinemia after 1 week of treatment and without evidence of insulin resistance. After 2 weeks of letrozole treatment, mice became significantly heavier than placebo mice, demonstrating that weight gain was not required to develop hyperinsulinemia. After 5 weeks of letrozole treatment, mice exhibited blunted glucose-stimulated insulin secretion, insulin resistance, and impaired insulin-induced phosphorylation of AKT in skeletal muscle. Moreover, letrozole-treated mice exhibited dyslipidemia after 5 weeks of treatment but no evidence of hepatic disease. Our study demonstrated that the letrozole-induced PCOS mouse model exhibits multiple features of the metabolic dysregulation observed in obese, hyperandrogenic women with PCOS. This model will be useful for mechanistic studies investigating how hyperandrogenemia affects metabolism in females.
[Mh] Termos MeSH primário: Hiperandrogenismo/induzido quimicamente
Hiperandrogenismo/complicações
Hiperinsulinismo/etiologia
Resistência à Insulina
Nitrilos/farmacologia
Maturidade Sexual/efeitos dos fármacos
Triazóis/farmacologia
Ganho de Peso/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Ingestão de Alimentos/efeitos dos fármacos
Metabolismo Energético/efeitos dos fármacos
Feminino
Glucose/metabolismo
Hiperinsulinismo/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Obesidade/induzido quimicamente
Obesidade/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nitriles); 0 (Triazoles); 7LKK855W8I (letrozole); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170916
[St] Status:MEDLINE
[do] DOI:10.1210/en.2016-1898


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[PMID]:28655717
[Au] Autor:Winn NC; Grunewald ZI; Gastecki ML; Woodford ML; Welly RJ; Clookey SL; Ball JR; Gaines TL; Karasseva NG; Kanaley JA; Sacks HS; Vieira-Potter VJ; Padilla J
[Ad] Endereço:Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri.
[Ti] Título:Deletion of UCP1 enhances ex vivo aortic vasomotor function in female but not male mice despite similar susceptibility to metabolic dysfunction.
[So] Source:Am J Physiol Endocrinol Metab;313(4):E402-E412, 2017 Oct 01.
[Is] ISSN:1522-1555
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Females are typically more insulin sensitive than males, which may be partly attributed to greater brown adipose tissue (BAT) activity and uncoupling protein 1 (UCP1) content. Accordingly, we tested the hypothesis that UCP1 deletion would abolish sex differences in insulin sensitivity and that whitening of thoracic periaortic BAT caused by UCP1 loss would be accompanied with impaired thoracic aortic function. Furthermore, because UCP1 exerts antioxidant effects, we examined whether UCP1 deficiency-induced metabolic dysfunction was mediated by oxidative stress. Compared with males, female mice had lower HOMA- and AT-insulin resistance (IR) despite no significant differences in BAT UCP1 content. UCP1 ablation increased HOMA-IR, AT-IR, and whitening of BAT in both sexes. Expression of UCP1 in thoracic aorta was greater in wild-type females compared with males. Importantly, deletion of UCP1 enhanced aortic vasomotor function in females only. UCP1 ablation did not promote oxidative stress in interscapular BAT. Furthermore, daily administration of the free radical scavenger tempol for 8 wk did not abrogate UCP1 deficiency-induced increases in adiposity, hyperinsulinemia, or liver steatosis. Collectively, we report that ) in normal chow-fed mice housed at 25°C, aortic UCP1 content was greater in females than males and its deletion improved ex vivo aortic vasomotor function in females only; ) constitutive UCP1 content in BAT was similar between females and males and loss of UCP1 did not abolish sex differences in insulin sensitivity; and ) the metabolic disruptions caused by UCP1 ablation did not appear to be contingent upon increased oxidative stress in mice under normal dietary conditions.
[Mh] Termos MeSH primário: Tecido Adiposo Marrom/metabolismo
Tecido Adiposo Branco/metabolismo
Aorta/metabolismo
Resistência à Insulina/genética
Estresse Oxidativo/genética
Proteína Desacopladora 1/genética
Sistema Vasomotor/metabolismo
[Mh] Termos MeSH secundário: Adiposidade/genética
Animais
Aorta/fisiopatologia
Fígado Gorduroso/genética
Fígado Gorduroso/metabolismo
Feminino
Hiperinsulinismo/genética
Hiperinsulinismo/metabolismo
Técnicas In Vitro
Masculino
Camundongos
Camundongos Knockout
Fatores Sexuais
Sistema Vasomotor/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ucp1 protein, mouse); 0 (Uncoupling Protein 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170629
[St] Status:MEDLINE
[do] DOI:10.1152/ajpendo.00096.2017


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[PMID]:28605468
[Au] Autor:Johnson KW; Neale A; Gordon A; Roessig J; Bezwada P; Vukelich S; Goldfine I; Rubin P
[Ad] Endereço:Research and Development, XOMA Corporation, Berkeley, California 94710.
[Ti] Título:Attenuation of Insulin Action by an Allosteric Insulin Receptor Antibody in Healthy Volunteers.
[So] Source:J Clin Endocrinol Metab;102(8):3021-3028, 2017 Aug 01.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: XOMA 358 (X358) is a fully human monoclonal antibody to the insulin receptor that acts as a negative allosteric modulator of insulin signaling. It is being developed as a novel treatment of hyperinsulinemic hypoglycemia. This report describes pharmacokinetic (PK) and pharmacodynamic (PD) data from a first-in-human clinical trial. Methods: A double-blind, placebo-controlled, single-ascending-dose study was performed with 29 healthy adult males randomized to intravenous infusion of placebo or X358 at 0.1-, 0.3-, 1-, 3-, 6-, or 9-mg/kg dose levels. The primary objective was to assess safety and tolerability, and secondary objectives included PK and PD analyses. A short insulin tolerance test (ITT) was implemented in the 3- to 9-mg/kg dose cohorts at baseline and postinfusion. Results: There were no deaths, serious adverse events (AEs), or subject discontinuations due to AEs. There were no clinically meaningful safety findings. X358 exhibited dose-proportional PK with a half-life of 21 days. Dose-dependent elevations of circulating insulin levels, likely related to reduced insulin clearance via monoclonal antibody action at receptors, represented a sensitive biomarker of X358 exposure. X358-dependent increases in postprandial glucose levels and fasting homeostatic model assessment of insulin resistance values were observed and persisted for at least 1 week at the higher dose levels. In all the ITT cohorts, the slope for glucose lowering was substantially attenuated after X358 infusion of a similar magnitude, but with increasing duration with rising dose level. Conclusion: Single X358 infusions were well tolerated and resulted in a dose-dependent reduction in insulin sensitivity. Clinical development of X358 in hyperinsulinemic, hypoglycemic conditions is proceeding.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/farmacologia
Glicemia/efeitos dos fármacos
Hiperinsulinismo/tratamento farmacológico
Hipoglicemia/tratamento farmacológico
Período Pós-Prandial/efeitos dos fármacos
Receptor de Insulina/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adolescente
Adulto
Regulação Alostérica
Anticorpos Monoclonais/administração & dosagem
Método Duplo-Cego
Jejum/metabolismo
Meia-Vida
Voluntários Saudáveis
Seres Humanos
Hiperinsulinismo/complicações
Hipoglicemia/etiologia
Resistência à Insulina
Masculino
Receptor de Insulina/imunologia
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Blood Glucose); 0 (XOMA 358); EC 2.7.10.1 (Receptor, Insulin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2017-00822


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[PMID]:28575111
[Au] Autor:Järgen P; Dietrich A; Herling AW; Hammes HP; Wohlfart P
[Ad] Endereço:5th Medical Department, Universitätsmedizin Mannheim (UMM), University of Heidelberg, Mannheim, Germany.
[Ti] Título:The role of insulin resistance in experimental diabetic retinopathy-Genetic and molecular aspects.
[So] Source:PLoS One;12(6):e0178658, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Diabetic retinopathy is characterized by defects in the retinal neurovascular unit. The underlying mechanisms of impairment-including reactive intermediates and growth-factor dependent signalling pathways and their possible interplay are incompletely understood. This study aims to assess the relative role of hyperglycemia and hyperinsulinemia alone or in combination on the gene expression patterning in the retina of animal models of diabetes. MATERIAL AND METHODS: As insulinopenic, hyperglycemic model reflecting type 1 diabetes, male STZ-Wistar rats (60mg/kg BW; i.p. injection at life age week 7) were used. Male obese ZDF rats (fa/fa) were used as type-2 diabetes model characterized by persisting hyperglycemia and transient hyperinsulinemia. Male obese ZF rats (fa/fa) were used reflecting euglycemia and severe insulin resistance. All groups were kept till an age of 20 weeks on respective conditions together with appropriate age-matched controls. Unbiased gene expression analysis was performed per group using Affymetrix gene arrays. Bioinformatics analysis included analysis for clustering and differential gene expression, and pathway and upstream activator analysis. Gene expression differences were confirmed by microfluidic card PCR technology. RESULTS: The most complex genetic regulation in the retina was observed in ZDF rats with a strong overlap to STZ-Wistar rats. Surprisingly, systemic insulin resistance alone in ZF rats without concomitant hyperglycemia did not induce any significant change in retinal gene expression pattern. Pathway analysis indicate an overlap between ZDF rats and STZ-treated rats in pathways like complement system activation, acute phase response signalling, and oncostatin-M signalling. Major array gene expression changes could be confirmed by subsequent PCR. An analysis of upstream transcriptional regulators revealed interferon-γ, interleukin-6 and oncostatin-M in STZ and ZDF rats. CONCLUSIONS: Systemic hyperinsulinaemia without hyperglycemia does not result in significant gene expression changes in retina. In contrast, persistent systemic hyperglycemia boosts much stronger expression changes with a limited number of known and new key regulators.
[Mh] Termos MeSH primário: Diabetes Mellitus Experimental/metabolismo
Diabetes Mellitus Tipo 2/fisiopatologia
Retinopatia Diabética/metabolismo
Regulação da Expressão Gênica
Resistência à Insulina
[Mh] Termos MeSH secundário: Proteínas da Fase Aguda
Animais
Ativação do Complemento
Diabetes Mellitus Experimental/genética
Diabetes Mellitus Tipo 2/genética
Diabetes Mellitus Tipo 2/metabolismo
Retinopatia Diabética/genética
Proteínas do Olho/biossíntese
Proteínas do Olho/genética
Perfilação da Expressão Gênica
Hiperglicemia/complicações
Hiperglicemia/genética
Hiperglicemia/metabolismo
Hiperinsulinismo/complicações
Hiperinsulinismo/genética
Hiperinsulinismo/metabolismo
Masculino
Oncostatina M/biossíntese
Oncostatina M/genética
Ratos Mutantes
Ratos Wistar
Retina/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acute-Phase Proteins); 0 (Eye Proteins); 106956-32-5 (Oncostatin M)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170603
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0178658


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[PMID]:28549478
[Au] Autor:Silberberg Y; Kupiec M; Sharan R
[Ad] Endereço:Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel.
[Ti] Título:GLADIATOR: a global approach for elucidating disease modules.
[So] Source:Genome Med;9(1):48, 2017 May 26.
[Is] ISSN:1756-994X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Understanding the genetic basis of disease is an important challenge in biology and medicine. The observation that disease-related proteins often interact with one another has motivated numerous network-based approaches for deciphering disease mechanisms. In particular, protein-protein interaction networks were successfully used to illuminate disease modules, i.e., interacting proteins working in concert to drive a disease. The identification of these modules can further our understanding of disease mechanisms. METHODS: We devised a global method for the prediction of multiple disease modules simultaneously named GLADIATOR (GLobal Approach for DIsease AssociaTed mOdule Reconstruction). GLADIATOR relies on a gold-standard disease phenotypic similarity to obtain a pan-disease view of the underlying modules. To traverse the search space of potential disease modules, we applied a simulated annealing algorithm aimed at maximizing the correlation between module similarity and the gold-standard phenotypic similarity. Importantly, this optimization is employed over hundreds of diseases simultaneously. RESULTS: GLADIATOR's predicted modules highly agree with current knowledge about disease-related proteins. Furthermore, the modules exhibit high coherence with respect to functional annotations and are highly enriched with known curated pathways, outperforming previous methods. Examination of the predicted proteins shared by similar diseases demonstrates the diverse role of these proteins in mediating related processes across similar diseases. Last, we provide a detailed analysis of the suggested molecular mechanism predicted by GLADIATOR for hyperinsulinism, suggesting novel proteins involved in its pathology. CONCLUSIONS: GLADIATOR predicts disease modules by integrating knowledge of disease-related proteins and phenotypes across multiple diseases. The predicted modules are functionally coherent and are more in line with current biological knowledge compared to modules obtained using previous disease-centric methods. The source code for GLADIATOR can be downloaded from http://www.cs.tau.ac.il/~roded/GLADIATOR.zip .
[Mh] Termos MeSH primário: Algoritmos
Biologia Computacional/métodos
Predisposição Genética para Doença
Mapas de Interação de Proteínas
[Mh] Termos MeSH secundário: Seres Humanos
Hiperinsulinismo/diagnóstico
Hiperinsulinismo/genética
Redes e Vias Metabólicas
Anotação de Sequência Molecular
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170528
[St] Status:MEDLINE
[do] DOI:10.1186/s13073-017-0435-z


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[PMID]:28528338
[Au] Autor:da Silva Franco CC; Previate C; de Barros Machado KG; Piovan S; Miranda RA; Prates KV; Moreira VM; de Oliveira JC; Barella LF; Gomes RM; Francisco FA; Martins IP; Pavanello A; Ribeiro TA; Tófolo LP; Malta A; de Souza AA; Alves VS; da Silva Silveira S; Marçal Natali MR; Fernando Besson JC; de Morais H; de Souza HM; de Sant Anna JR; Alves de Castro Prado MA; de Freitas Mathias PC
[Ad] Endereço:Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringá, Maringá, Brazil.
[Ti] Título:Chronic Glibenclamide Treatment Attenuates Walker-256 Tumour Growth in Prediabetic Obese Rats.
[So] Source:Cell Physiol Biochem;42(1):81-90, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: The sulphonylurea glibenclamide (Gli) is widely used in the treatment of type 2 diabetes. In addition to its antidiabetic effects, low incidences of certain types of cancer have been observed in Gli-treated diabetic patients. However, the mechanisms underlying this observation remain unclear. The aim of the present work was to evaluate whether obese adult rats that were chronically treated with an antidiabetic drug, glibenclamide, exhibit resistance to rodent breast carcinoma growth. METHODS: Neonatal rats were treated with monosodium L-glutamate (MSG) to induce prediabetes. Control and MSG groups were treated with Gli (2 mg/kg body weight/day) from weaning to 100 days old. After Gli treatment, the control and MSG rats were grafted with Walker-256 tumour cells. After 14 days, grafted rats were euthanized, and tumour weight as well as glucose homeostasis were evaluated. RESULTS: Treatment with Gli normalized tissue insulin sensitivity and glucose tolerance, suppressed fasting hyperinsulinaemia, reduced fat tissue accretion in MSG rats, and attenuated tumour growth by 27% in control and MSG rats. CONCLUSIONS: Gli treatment also resulted in a large reduction in the number of PCNA-positive tumour cells. Although treatment did improve the metabolism of pre-diabetic MSG-rats, tumour growth inhibition may be a more direct effect of glibenclamide.
[Mh] Termos MeSH primário: Proliferação Celular/efeitos dos fármacos
Glibureto/farmacologia
Estado Pré-Diabético/prevenção & controle
[Mh] Termos MeSH secundário: Animais
Caquexia/etiologia
Linhagem Celular Tumoral
Glucose/metabolismo
Glibureto/uso terapêutico
Hiperinsulinismo/prevenção & controle
Hipoglicemiantes/farmacologia
Hipoglicemiantes/uso terapêutico
Imuno-Histoquímica
Masculino
Obesidade/complicações
Obesidade/metabolismo
Obesidade/patologia
Estado Pré-Diabético/etiologia
Antígeno Nuclear de Célula em Proliferação/metabolismo
Ratos
Ratos Wistar
Glutamato de Sódio/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hypoglycemic Agents); 0 (Proliferating Cell Nuclear Antigen); IY9XDZ35W2 (Glucose); SX6K58TVWC (Glyburide); W81N5U6R6U (Sodium Glutamate)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170522
[St] Status:MEDLINE
[do] DOI:10.1159/000477117



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