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[PMID]:28743992
[Au] Autor:Cao J; Peng J; An H; He Q; Boronina T; Guo S; White MF; Cole PA; He L
[Ad] Endereço:Division of Metabolism, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
[Ti] Título:Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity.
[So] Source:Nat Commun;8(1):131, 2017 07 25.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Diabetes and obesity are characterized by insulin resistance and chronic low-grade inflammation. An elevated plasma concentration of lipopolysaccharide (LPS) caused by increased intestinal permeability during diet-induced obesity promotes insulin resistance in mice. Here, we show that LPS induces endoplasmic reticulum (ER) stress and protein levels of P300, an acetyltransferase involved in glucose production. In high-fat diet fed and genetically obese ob/ob mice, P300 translocates from the nucleus into the cytoplasm of hepatocytes. We also demonstrate that LPS activates the transcription factor XBP1 via the ER stress sensor IRE1, resulting in the induction of P300 which, in turn, acetylates IRS1/2, inhibits its association with the insulin receptor, and disrupts insulin signaling. Pharmacological inhibition of P300 acetyltransferase activity by a specific inhibitor improves insulin sensitivity and decreases hyperglycemia in obese mice. We suggest that P300 acetyltransferase activity may be a promising therapeutic target for the treatment of obese patients.Elevated plasma LPS levels have been associated with insulin resistance. Here Cao et al. show that LPS induces ER stress and P300 activity via the XBP1/IRE1 pathway. P300 acetylates IRS1/2 and inhibits its binding with the insulin receptor. The consequent impairment of insulin signaling can be rescued by pharmacological inhibition of P300.
[Mh] Termos MeSH primário: Proteína p300 Associada a E1A/metabolismo
Endotoxemia/metabolismo
Insulina/metabolismo
Obesidade/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Proteína p300 Associada a E1A/genética
Estresse do Retículo Endoplasmático/efeitos dos fármacos
Estresse do Retículo Endoplasmático/genética
Perfilação da Expressão Gênica/métodos
Immunoblotting
Resistência à Insulina
Lipopolissacarídeos/farmacologia
Fígado/efeitos dos fármacos
Fígado/metabolismo
Masculino
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Camundongos Endogâmicos C57BL
Camundongos Obesos
Obesidade/genética
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/metabolismo
Receptor de Insulina/genética
Receptor de Insulina/metabolismo
Proteína 1 de Ligação a X-Box/genética
Proteína 1 de Ligação a X-Box/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Insulin); 0 (Lipopolysaccharides); 0 (Membrane Proteins); 0 (X-Box Binding Protein 1); 0 (Xbp1 protein, mouse); EC 2.3.1.48 (E1A-Associated p300 Protein); EC 2.7.1.- (Ern2 protein, mouse); EC 2.7.10.1 (Receptor, Insulin); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:180217
[Lr] Data última revisão:
180217
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-00163-w


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[PMID]:29337057
[Au] Autor:Kamitani M; Miyatsuka T; Miura M; Azuma K; Suzuki L; Himuro M; Katahira T; Nishida Y; Fujitani Y; Watada H
[Ad] Endereço:Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
[Ti] Título:Heterogeneity of autophagic status in pancreatic ß cells under metabolic stress.
[So] Source:Biochem Biophys Res Commun;496(2):328-334, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Autophagy in ß cells has been demonstrated to play a pivotal role in cellular homeostasis and the progression of glucose intolerance. Although autophagic activity is affected by metabolic stress both in vivo and in vitro, it remains unclear as to what extent the autophagic status in each ß cell is different from its neighboring cells. To address this question, GFP-LC3 reporter mice, which can visualize the autophagic status of each ß cell as green-fluorescent puncta, were crossed with obese diabetic db/db mice. Imaging of green-fluorescent puncta in the islets of GFP-LC3 mice revealed that ß cells are a heterogeneous population, as the density of GFP-LC3 puncta in each cell was variable. Furthermore, the variability was greater in GFP-LC3; db/db mice than in non-diabetic GFP-LC3; db/+ mice. Furthermore, when GFP-LC3 mice were treated with a low dose of S961, which antagonizes insulin signaling without inducing overt hyperglycemia, the number of ß cells with a high density of GFP puncta was increased, suggesting that insulin resistance affects autophagic status independently of glucose profiles. These results suggest that pancreatic ß cells under metabolic stress are heterogeneous regarding their autophagic status, which provides insights into the cellular dynamics of each ß cell rather than the whole ß-cell population.
[Mh] Termos MeSH primário: Autofagia/efeitos dos fármacos
Glucose/metabolismo
Células Secretoras de Insulina/metabolismo
Proteínas Associadas aos Microtúbulos/genética
Peptídeos/efeitos dos fármacos
Receptor de Insulina/genética
[Mh] Termos MeSH secundário: Animais
Autofagia/genética
Contagem de Células
Células Cultivadas
Cruzamentos Genéticos
Regulação da Expressão Gênica
Genes Reporter
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Células Secretoras de Insulina/efeitos dos fármacos
Células Secretoras de Insulina/patologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Obesos
Camundongos Transgênicos
Proteínas Associadas aos Microtúbulos/metabolismo
Peptídeos/farmacologia
Receptor de Insulina/antagonistas & inibidores
Receptor de Insulina/metabolismo
Transdução de Sinais
Análise de Célula Única
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MAP1LC3 protein, mouse); 0 (Microtubule-Associated Proteins); 0 (Peptides); 0 (S961 peptide); 147336-22-9 (Green Fluorescent Proteins); EC 2.7.10.1 (Receptor, Insulin); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE


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[PMID]:28972997
[Au] Autor:Jahandideh F; Chakrabarti S; Davidge ST; Wu J
[Ad] Endereço:Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
[Ti] Título:Egg white hydrolysate shows insulin mimetic and sensitizing effects in 3T3-F442A pre-adipocytes.
[So] Source:PLoS One;12(10):e0185653, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Insulin resistance and inflammation in adipose tissue is a key mechanism underlying metabolic syndrome, a growing health problem characterized by diabetes, obesity and hypertension. Previous work from our research group has demonstrated the potential of egg white ovotransferrin derived bioactive peptides against hypertension, oxidative stress and inflammation in vitro and in vivo. Egg white hydrolysate (EWH) has also shown anti-hypertensive effects in spontaneously hypertensive rats. Given the interplay among hypertension, inflammation, oxidative stress and metabolic syndrome, the objective of the study was to test the EWH on differentiation, insulin signaling and inflammatory responses in 3T3-F442A pre-adipocytes. Our study suggested that EWH could promote adipocyte differentiation as shown by increased lipid accumulation, increased release of adiponectin and upregulation of peroxisome proliferator associated receptor gamma (PPARγ) and CCAAT/ enhancer binding protein alpha (C/EBP-α). In addition to enhanced insulin effects on the upregulation of protein kinase B/Akt phosphorylation, EWH treatment increased extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation to a level similar to that of insulin, indicating insulin sensitizing and mimetic properties of the EWH. EWH further attenuated cytokine induced inflammatory marker; cyclooxygenase -2 (COX-2) by 48.78%, possibly through the AP-1 pathway by down regulating c-Jun phosphorylation in adipocytes. Given the critical role of adipose in the pathogenesis of insulin resistance and metabolic syndrome, EWH may have potential applications in the prevention and management of metabolic syndrome and its complications.
[Mh] Termos MeSH primário: Adipócitos/metabolismo
Clara de Ovo
Insulina/metabolismo
Mimetismo Molecular
[Mh] Termos MeSH secundário: Células 3T3
Adipócitos/citologia
Adiponectina/metabolismo
Animais
Western Blotting
Diferenciação Celular
Relação Dose-Resposta a Droga
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Camundongos
PPAR gama/metabolismo
Fosforilação
Receptor de Insulina/metabolismo
Transdução de Sinais
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adiponectin); 0 (Insulin); 0 (PPAR gamma); EC 2.7.10.1 (Receptor, Insulin); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185653


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[PMID]:28957663
[Au] Autor:Zhao N; Liu CC; Van Ingelgom AJ; Martens YA; Linares C; Knight JA; Painter MM; Sullivan PM; Bu G
[Ad] Endereço:Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
[Ti] Título:Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes.
[So] Source:Neuron;96(1):115-129.e5, 2017 Sep 27.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Diabetes and impaired brain insulin signaling are linked to the pathogenesis of Alzheimer's disease (AD). The association between diabetes and AD-associated amyloid pathology is stronger among carriers of the apolipoprotein E (APOE) ε4 gene allele, the strongest genetic risk factor for late-onset AD. Here we report that apoE4 impairs neuronal insulin signaling in human apoE-targeted replacement (TR) mice in an age-dependent manner. High-fat diet (HFD) accelerates these effects in apoE4-TR mice at middle age. In primary neurons, apoE4 interacts with insulin receptor and impairs its trafficking by trapping it in the endosomes, leading to impaired insulin signaling and insulin-stimulated mitochondrial respiration and glycolysis. In aging brains, the increased apoE4 aggregation and compromised endosomal function further exacerbate the inhibitory effects of apoE4 on insulin signaling and related functions. Together, our study provides novel mechanistic insights into the pathogenic mechanisms of apoE4 and insulin resistance in AD.
[Mh] Termos MeSH primário: Apolipoproteína E4/metabolismo
Endossomos/metabolismo
Resistência à Insulina/fisiologia
Insulina/fisiologia
Neurônios/citologia
Neurônios/metabolismo
Receptor de Insulina/metabolismo
[Mh] Termos MeSH secundário: Envelhecimento/metabolismo
Envelhecimento/fisiologia
Animais
Apolipoproteína E3/genética
Apolipoproteína E4/genética
Respiração Celular/fisiologia
Dieta Hiperlipídica
Feminino
Glicólise/fisiologia
Masculino
Camundongos
Camundongos Knockout
Camundongos Transgênicos
Mitocôndrias/fisiologia
Neurônios/fisiologia
Cultura Primária de Células
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoprotein E3); 0 (Apolipoprotein E4); 0 (Insulin); EC 2.7.10.1 (Receptor, Insulin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170929
[St] Status:MEDLINE


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[PMID]:28915272
[Au] Autor:Renna LV; Bosè F; Iachettini S; Fossati B; Saraceno L; Milani V; Colombo R; Meola G; Cardani R
[Ad] Endereço:Laboratory of Muscle Histopathology and Molecular Biology, IRCCS-Policlinico San Donato, San Donato Milanese, Milan, Italy.
[Ti] Título:Receptor and post-receptor abnormalities contribute to insulin resistance in myotonic dystrophy type 1 and type 2 skeletal muscle.
[So] Source:PLoS One;12(9):e0184987, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant multisystemic disorders caused by expansion of microsatellite repeats. In both forms, the mutant transcripts accumulate in nuclear foci altering the function of alternative splicing regulators which are necessary for the physiological mRNA processing. Missplicing of insulin receptor (IR) gene (INSR) has been associated with insulin resistance, however, it cannot be excluded that post-receptor signalling abnormalities could also contribute to this feature in DM. We have analysed the insulin pathway in skeletal muscle biopsies and in myotube cultures from DM patients to assess whether downstream metabolism might be dysregulated and to better characterize the mechanism inducing insulin resistance. DM skeletal muscle exhibits alterations of basal phosphorylation levels of Akt/PKB, p70S6K, GSK3ß and ERK1/2, suggesting that these changes might be accompanied by a lack of further insulin stimulation. Alterations of insulin pathway have been confirmed on control and DM myotubes expressing fetal INSR isoform (INSR-A). The results indicate that insulin action appears to be lower in DM than in control myotubes in terms of protein activation and glucose uptake. Our data indicate that post-receptor signalling abnormalities might contribute to DM insulin resistance regardless the alteration of INSR splicing.
[Mh] Termos MeSH primário: Processamento Alternativo
Antígenos CD
Regulação da Expressão Gênica
Resistência à Insulina/genética
Distrofia Miotônica
Receptor de Insulina
Transdução de Sinais
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Antígenos CD/biossíntese
Antígenos CD/genética
Feminino
Seres Humanos
Masculino
Meia-Idade
Proteínas Musculares/genética
Proteínas Musculares/metabolismo
Distrofia Miotônica/genética
Distrofia Miotônica/metabolismo
Receptor de Insulina/biossíntese
Receptor de Insulina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD); 0 (Muscle Proteins); EC 2.7.10.1 (INSR protein, human); EC 2.7.10.1 (Receptor, Insulin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170916
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184987


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[PMID]:28901894
[Au] Autor:Xie C; Li Y; Li J; Zhang L; Zhou G; Gao F
[Ad] Endereço:Key Laboratory of Animal Origin Food Production and Safety Guarantee of Jiangsu Province,Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control,College of Animal Science and Technology,Nanjing Agricultural University,Nanjing 210095,People's Republic of
[Ti] Título:Dietary starch types affect liver nutrient metabolism of finishing pigs.
[So] Source:Br J Nutr;118(5):353-359, 2017 Sep.
[Is] ISSN:1475-2662
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:This study aimed to evaluate the effect of different starch types on liver nutrient metabolism of finishing pigs. In all ninety barrows were randomly allocated to three diets with five replicates of six pigs, containing purified waxy maize starch (WMS), non-waxy maize starch (NMS) and pea starch (PS) (the amylose to amylopectin ratios were 0·07, 0·19 and 0·28, respectively). After 28 d of treatments, two per pen (close to the average body weight of the pen) were weighed individually, slaughtered and liver samples were collected. Compared with the WMS diet, the PS diet decreased the activities of glycogen phosphorylase, phosphoenolpyruvate carboxykinase and the expression of phosphoenolpyruvate carboxykinase 1 in liver (P0·05). Compared with the WMS diet, the PS diet reduced the expressions of glutamate dehydrogenase and carbamoyl phosphate synthetase 1 in liver (P<0·05). PS diet decreased the expression of the insulin receptor, and increased the expressions of mammalian target of rapamycin complex 1 and ribosomal protein S6 kinase ß-1 in liver compared with the WMS diet (P<0·05). These findings indicated that the diet with higher amylose content could down-regulate gluconeogenesis, and cause less fat deposition and more protein deposition by affecting the insulin/PI3K/protein kinase B signalling pathway in liver of finishing pigs.
[Mh] Termos MeSH primário: Ração Animal/análise
Dieta/veterinária
Fígado/metabolismo
Amido/administração & dosagem
[Mh] Termos MeSH secundário: Alanina Transaminase/sangue
Alanina Transaminase/genética
Amilopectina/administração & dosagem
Amilopectina/análise
Amilose/administração & dosagem
Amilose/análise
Animais
Aspartato Aminotransferases/sangue
Aspartato Aminotransferases/genética
Glicemia/metabolismo
Carbamoil-Fosfato Sintase (Amônia)/genética
Carbamoil-Fosfato Sintase (Amônia)/metabolismo
Ácido Graxo Sintases/sangue
Ácido Graxo Sintases/genética
Gluconeogênese
Glutamato Desidrogenase/genética
Glutamato Desidrogenase/metabolismo
Insulina/metabolismo
Metabolismo dos Lipídeos/genética
Alvo Mecanístico do Complexo 1 de Rapamicina
Complexos Multiproteicos/genética
Complexos Multiproteicos/metabolismo
Ervilhas/química
Fosfatidilinositol 3-Quinases/genética
Fosfatidilinositol 3-Quinases/metabolismo
Proteínas Proto-Oncogênicas c-akt/genética
Proteínas Proto-Oncogênicas c-akt/metabolismo
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Receptor de Insulina/genética
Receptor de Insulina/metabolismo
Proteínas Quinases S6 Ribossômicas 70-kDa/genética
Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
Transdução de Sinais
Suínos
Serina-Treonina Quinases TOR/genética
Serina-Treonina Quinases TOR/metabolismo
Zea mays/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Insulin); 0 (Multiprotein Complexes); 0 (RNA, Messenger); 9005-25-8 (Starch); 9005-82-7 (Amylose); 9037-22-3 (Amylopectin); EC 1.4.1.2 (Glutamate Dehydrogenase); EC 2.3.1.85 (Fatty Acid Synthases); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.6.1.2 (Alanine Transaminase); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.10.1 (Receptor, Insulin); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa); EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 2); EC 6.3.4.16 (Carbamoyl-Phosphate Synthase (Ammonia))
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170914
[St] Status:MEDLINE
[do] DOI:10.1017/S0007114517002252


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[PMID]:28867578
[Au] Autor:Rostami F; Javan M; Moghimi A; Haddad-Mashadrizeh A; Fereidoni M
[Ad] Endereço:Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.
[Ti] Título:Streptozotocin-induced hippocampal astrogliosis and insulin signaling malfunction as experimental scales for subclinical sporadic Alzheimer model.
[So] Source:Life Sci;188:172-185, 2017 Nov 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Insulin signaling malfunction has recently been suggested as a preliminary event involved in the etiology of Sporadic Alzheimer's disease (SAD). In order to develop insulin resistance-related SAD model, rats were treated with streptozotocin, intracerebroventricularly (icv-STZ). Nevertheless, given the lack of knowledge regarding sub-clinical stages of SAD, the current challenging issue is establishing a practical pre-clinical SAD model. Despite some proposed mechanisms, such as insulin malfunction, neuroinflammation, and gliosis, icv-STZ mechanism of action is not fully understood yet and Streptozotocin-induced rat model of Alzheimer has still major shortcomings. MAIN METHODS: Using three STZ doses (0.5, 1, and 3mg/kg) and three testing time (short-term, medium-term and long-term), we sought the best dose of STZ in order to mimic the characteristic feature of sAD in rats. So, we conducted a series of fifteen-week follow-up cognitive and non-cognitive studies. Besides, IR, tau and ChAT mRNA levels were measured, along with histological analysis of astrocyte, dark neuron numbers, and pyramidal layer thickness, in order to compare the effects of different doses of icv-STZ. KEY FINDINGS: STZ 3mg/kg caused cognitive and insulin signaling disturbance from the very first testing-time. STZ1-injected animals, however, showed an augmented hippocampal astrocyte numbers in a short time; they, also, were diagnosed with disturbed insulin signaling in medium-term post icv-STZ-injection. Moreover, behavioral, molecular and histological impairments induced by 0.5mg/kg icv-STZ were slowly progressing in comparison to high doses of STZ. SIGNIFICANCE: STZ1 and 0.5mg/kg-treated animals are, respectively, suggested as a suitable experimental model of MCI, and sub-clinical stage.
[Mh] Termos MeSH primário: Doença de Alzheimer/diagnóstico
Gliose/patologia
Hipocampo/patologia
Resistência à Insulina
Insulina/metabolismo
Sintomas Prodrômicos
Estreptozocina/efeitos adversos
[Mh] Termos MeSH secundário: Animais
Astrócitos/patologia
Colina O-Acetiltransferase/biossíntese
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Comportamento Exploratório/efeitos dos fármacos
Gliose/induzido quimicamente
Infusões Intraventriculares
Masculino
Aprendizagem em Labirinto/efeitos dos fármacos
Neurônios/patologia
Ratos
Receptor de Insulina/biossíntese
Recognição (Psicologia)/efeitos dos fármacos
Teste de Desempenho do Rota-Rod
Estreptozocina/administração & dosagem
Fatores de Tempo
Proteínas tau/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insulin); 0 (tau Proteins); 5W494URQ81 (Streptozocin); EC 2.3.1.6 (Choline O-Acetyltransferase); EC 2.7.10.1 (Receptor, Insulin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170905
[St] Status:MEDLINE


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[PMID]:28820880
[Au] Autor:Sangaletti R; D'Amico M; Grant J; Della-Morte D; Bianchi L
[Ad] Endereço:Department of Physiology and Biophysics, University of Miami, Miller School of Medicine, Miami, Florida, United States of America.
[Ti] Título:Knock-out of a mitochondrial sirtuin protects neurons from degeneration in Caenorhabditis elegans.
[So] Source:PLoS Genet;13(8):e1006965, 2017 Aug.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sirtuins are NAD⁺-dependent deacetylases, lipoamidases, and ADP-ribosyltransferases that link cellular metabolism to multiple intracellular pathways that influence processes as diverse as cell survival, longevity, and cancer growth. Sirtuins influence the extent of neuronal death in stroke. However, different sirtuins appear to have opposite roles in neuronal protection. In Caenorhabditis elegans, we found that knock-out of mitochondrial sirtuin sir-2.3, homologous to mammalian SIRT4, is protective in both chemical ischemia and hyperactive channel induced necrosis. Furthermore, the protective effect of sir-2.3 knock-out is enhanced by block of glycolysis and eliminated by a null mutation in daf-16/FOXO transcription factor, supporting the involvement of the insulin/IGF pathway. However, data in Caenorhabditis elegans cell culture suggest that the effects of sir-2.3 knock-out act downstream of the DAF-2/IGF-1 receptor. Analysis of ROS in sir-2.3 knock-out reveals that ROS become elevated in this mutant under ischemic conditions in dietary deprivation (DD), but to a lesser extent than in wild type, suggesting more robust activation of a ROS scavenging system in this mutant in the absence of food. This work suggests a deleterious role of SIRT4 during ischemic processes in mammals that must be further investigated and reveals a novel pathway that can be targeted for the design of therapies aimed at protecting neurons from death in ischemic conditions.
[Mh] Termos MeSH primário: Proteínas de Caenorhabditis elegans/genética
Fatores de Transcrição Forkhead/genética
Hidrolases/genética
Isquemia/genética
Proteínas Mitocondriais/genética
Células Receptoras Sensoriais/metabolismo
Sirtuínas/genética
[Mh] Termos MeSH secundário: Animais
Azidas/toxicidade
Caenorhabditis elegans/genética
Morte Celular/efeitos dos fármacos
Técnicas de Inativação de Genes
Glicólise/efeitos dos fármacos
Seres Humanos
Insulina/genética
Isquemia/patologia
Mitocôndrias/genética
Mitocôndrias/patologia
Necrose/genética
Necrose/patologia
Espécies Reativas de Oxigênio/metabolismo
Receptor IGF Tipo 1/genética
Receptor de Insulina/genética
Células Receptoras Sensoriais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Azides); 0 (Caenorhabditis elegans Proteins); 0 (Forkhead Transcription Factors); 0 (Insulin); 0 (Mitochondrial Proteins); 0 (Reactive Oxygen Species); 0 (daf-16 protein, C elegans); EC 2.7.10.1 (DAF-2 protein, C elegans); EC 2.7.10.1 (Receptor, IGF Type 1); EC 2.7.10.1 (Receptor, Insulin); EC 3.- (Hydrolases); EC 3.- (sir-2.3 protein, C elegans); EC 3.5.1.- (SIRT4 protein, human); EC 3.5.1.- (Sirtuins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170917
[Lr] Data última revisão:
170917
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170819
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006965


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[PMID]:28767692
[Au] Autor:Caporarello N; Parrino C; Trischitta V; Frittitta L
[Ad] Endereço:Endocrine Unit, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
[Ti] Título:Insulin receptor signaling and glucagon-like peptide 1 effects on pancreatic beta cells.
[So] Source:PLoS One;12(8):e0181190, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glucagon-like peptide-1 (GLP-1) is a potent gluco-incretin hormone, which plays a central role on pancreatic beta cell proliferation, survival and insulin secreting activity and whose analogs are used for treating hyperglycemia in type 2 diabetes mellitus. Notably, abnormal insulin signaling affects all the above-mentioned aspects on pancreatic beta cells. The aim of our study was to investigate whether the protective effects of GLP1-1 on beta cells are affected by altered insulin receptor signaling. To this end, several effects of GLP-1 were studied in INS-1E rat beta cells transfected either with an inhibitor of insulin receptor function (i.e., the Ectonucleotide Pyrophosphatase Phosphodiesterase 1, ENPP1), or with insulin receptor small interfering RNA, as well as in control cells. Crucial experiments were carried out also in a second cell line, namely the ßTC-1 mouse beta cells. Our data indicate that in insulin secreting beta cells in which either ENPP1 was up-regulated or insulin receptor was down-regulated, GLP-1 positive effects on several pancreatic beta cell activities, including glucose-induced insulin secretion, cell proliferation and cell survival, were strongly reduced. Further studies are needed to understand whether such a scenario occurs also in humans and, if so, if it plays a role of clinical relevance in diabetic patients with poor responsiveness to GLP-1 related treatments.
[Mh] Termos MeSH primário: Peptídeo 1 Semelhante ao Glucagon/farmacologia
Receptor de Insulina/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Glucose/farmacologia
Insulina/metabolismo
Células Secretoras de Insulina/citologia
Células Secretoras de Insulina/efeitos dos fármacos
Células Secretoras de Insulina/metabolismo
Células Secretoras de Insulina/secreção
Mutagênese Sítio-Dirigida
Diester Fosfórico Hidrolases/genética
Diester Fosfórico Hidrolases/metabolismo
Pirofosfatases/genética
Pirofosfatases/metabolismo
Interferência de RNA
RNA Interferente Pequeno/metabolismo
Ratos
Receptor de Insulina/antagonistas & inibidores
Receptor de Insulina/genética
Estaurosporina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insulin); 0 (RNA, Small Interfering); 89750-14-1 (Glucagon-Like Peptide 1); EC 2.7.10.1 (Receptor, Insulin); EC 3.1.4.- (Phosphoric Diester Hydrolases); EC 3.1.4.1 (ectonucleotide pyrophosphatase phosphodiesterase 1); EC 3.6.1.- (Pyrophosphatases); H88EPA0A3N (Staurosporine); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170803
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181190


  10 / 11553 MEDLINE  
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[PMID]:28765322
[Au] Autor:Hosoe J; Kadowaki H; Miya F; Aizu K; Kawamura T; Miyata I; Satomura K; Ito T; Hara K; Tanaka M; Ishiura H; Tsuji S; Suzuki K; Takakura M; Boroevich KA; Tsunoda T; Yamauchi T; Shojima N; Kadowaki T
[Ad] Endereço:Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
[Ti] Título:Structural Basis and Genotype-Phenotype Correlations of INSR Mutations Causing Severe Insulin Resistance.
[So] Source:Diabetes;66(10):2713-2723, 2017 Oct.
[Is] ISSN:1939-327X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The insulin receptor ( ) gene was analyzed in four patients with severe insulin resistance, revealing five novel mutations and a deletion that removed exon 2. A patient with Donohue syndrome (DS) had a novel p.V657F mutation in the second fibronectin type III domain (FnIII-2), which contains the α-ß cleavage site and part of the insulin-binding site. The mutant INSR was expressed in Chinese hamster ovary cells, revealing that it reduced insulin proreceptor processing and impaired activation of downstream signaling cascades. Using online databases, we analyzed 82 missense mutations and demonstrated that mutations causing DS were more frequently located in the FnIII domains than those causing the milder type A insulin resistance ( = 0.016). In silico structural analysis revealed that missense mutations predicted to severely impair hydrophobic core formation and stability of the FnIII domains all caused DS, whereas those predicted to produce localized destabilization and to not affect folding of the FnIII domains all caused the less severe Rabson-Mendenhall syndrome. These results suggest the importance of the FnIII domains, provide insight into the molecular mechanism of severe insulin resistance, will aid early diagnosis, and will provide potential novel targets for treating extreme insulin resistance.
[Mh] Termos MeSH primário: Resistência à Insulina/fisiologia
Receptor de Insulina/genética
[Mh] Termos MeSH secundário: Adolescente
Pré-Escolar
Síndrome de Donohue/genética
Feminino
Genótipo
Seres Humanos
Lactente
Resistência à Insulina/genética
Masculino
Mutação/genética
Mutação de Sentido Incorreto/genética
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.10.1 (Receptor, Insulin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170803
[St] Status:MEDLINE
[do] DOI:10.2337/db17-0301



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