Base de dados : MEDLINE
Pesquisa : D08.811.913.696.620.250 [Categoria DeCS]
Referências encontradas : 2861 [refinar]
Mostrando: 1 .. 10   no formato [Detalhado]

página 1 de 287 ir para página                         

  1 / 2861 MEDLINE  
              next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29408271
[Au] Autor:Ben Khelifa S; Martinez R; Dandana A; Khochtali I; Ferchichi S; Castaño L
[Ad] Endereço:Unit of Clinical and Molecular Biology/UR17ES29, Faculty of Pharmacy, Monastir, Tunisia. Electronic address: souhaira34@gmail.com.
[Ti] Título:Maturity Onset Diabetes of the Young (MODY) in Tunisia: Low frequencies of GCK and HNF1A mutations.
[So] Source:Gene;651:44-48, 2018 Apr 20.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance, an early clinical onset and a primary defect in ß-cell function. Mutations in the GCK and HNF1A genes are the most common cause of MODY among Caucasians. The etiology of MODY in Tunisia stills a challenge for researchers. The aim of this study was to screen for mutations in GCK, HNF1A, HNF4A and INS genes in North African Tunisians subjects, in whom the clinical profile was very suggestive of MODY. A total of 23 unrelated patients, with clinical presentation of MODY were tested for mutations in GCK, HNF1A, HNF4A and INS genes, using Denaturing High Performance Liquid Chromatography (DHPLC), Multiplex Ligation-depend Probe Amplification (MLPA) and sequencing analysis. We identified the previously reported mutation c-169C > T in one patient as well as a new mutation c-457C > T in two unrelated patients. No mutations were detected in the HNF1A and INS genes. Despite restrictive clinical criteria used for selecting patients in this study, the most common genes known for MODY do not explain the majority of cases in Tunisians. This suggests that there are others candidate or unidentified genes contributing to the etiology of MODY in Tunisians families.
[Mh] Termos MeSH primário: Diabetes Mellitus Tipo 2/genética
Glucoquinase/genética
Fator 1-alfa Nuclear de Hepatócito/genética
Mutação
[Mh] Termos MeSH secundário: Adulto
Feminino
Frequência do Gene
Fator 4 Nuclear de Hepatócito/genética
Seres Humanos
Masculino
Polimorfismo Genético
Regiões Promotoras Genéticas
Proteínas Serina-Treonina Quinases
Tunísia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HNF1A protein, human); 0 (HNF4A protein, human); 0 (Hepatocyte Nuclear Factor 1-alpha); 0 (Hepatocyte Nuclear Factor 4); EC 2.7.1.2 (Glucokinase); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (germinal center kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180207
[St] Status:MEDLINE


  2 / 2861 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29416045
[Au] Autor:Basco D; Zhang Q; Salehi A; Tarasov A; Dolci W; Herrera P; Spiliotis I; Berney X; Tarussio D; Rorsman P; Thorens B
[Ad] Endereço:Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland.
[Ti] Título:α-cell glucokinase suppresses glucose-regulated glucagon secretion.
[So] Source:Nat Commun;9(1):546, 2018 02 07.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Glucagon secretion by pancreatic α-cells is triggered by hypoglycemia and suppressed by high glucose levels; impaired suppression of glucagon secretion is a hallmark of both type 1 and type 2 diabetes. Here, we show that α-cell glucokinase (Gck) plays a role in the control of glucagon secretion. Using mice with α-cell-specific inactivation of Gck (αGckKO mice), we find that glucokinase is required for the glucose-dependent increase in intracellular ATP/ADP ratio and the closure of K channels in α-cells and the suppression of glucagon secretion at euglycemic and hyperglycemic levels. αGckKO mice display hyperglucagonemia in the fed state, which is associated with increased hepatic gluconeogenic gene expression and hepatic glucose output capacity. In adult mice, fed hyperglucagonemia is further increased and glucose intolerance develops. Thus, glucokinase governs an α-cell metabolic pathway that suppresses secretion at or above normoglycemic levels; abnormal suppression of glucagon secretion deregulates hepatic glucose metabolism and, over time, induces a pre-diabetic phenotype.
[Mh] Termos MeSH primário: Células Secretoras de Glucagon/metabolismo
Glucagon/secreção
Glucoquinase/genética
Intolerância à Glucose/metabolismo
Glucose/metabolismo
Hipoglicemia/metabolismo
[Mh] Termos MeSH secundário: Difosfato de Adenosina/metabolismo
Trifosfato de Adenosina/metabolismo
Animais
Transporte Biológico
Feminino
Expressão Gênica
Células Secretoras de Glucagon/patologia
Glucoquinase/deficiência
Intolerância à Glucose/genética
Intolerância à Glucose/patologia
Hipoglicemia/genética
Hipoglicemia/patologia
Insulina/metabolismo
Canais KATP/genética
Canais KATP/metabolismo
Fígado/metabolismo
Masculino
Camundongos
Camundongos Knockout
[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 (KATP Channels); 61D2G4IYVH (Adenosine Diphosphate); 8L70Q75FXE (Adenosine Triphosphate); 9007-92-5 (Glucagon); EC 2.7.1.2 (Glucokinase); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180209
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-018-03034-0


  3 / 2861 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28453780
[Au] Autor:Billings LK; Jablonski KA; Warner AS; Cheng YC; McAteer JB; Tipton L; Shuldiner AR; Ehrmann DA; Manning AK; Dabelea D; Franks PW; Kahn SE; Pollin TI; Knowler WC; Altshuler D; Florez JC; Diabetes Prevention Program Research Group
[Ad] Endereço:Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114.
[Ti] Título:Variation in Maturity-Onset Diabetes of the Young Genes Influence Response to Interventions for Diabetes Prevention.
[So] Source:J Clin Endocrinol Metab;102(8):2678-2689, 2017 Aug 01.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Context: Variation in genes that cause maturity-onset diabetes of the young (MODY) has been associated with diabetes incidence and glycemic traits. Objectives: This study aimed to determine whether genetic variation in MODY genes leads to differential responses to insulin-sensitizing interventions. Design and Setting: This was a secondary analysis of a multicenter, randomized clinical trial, the Diabetes Prevention Program (DPP), involving 27 US academic institutions. We genotyped 22 missense and 221 common variants in the MODY-causing genes in the participants in the DPP. Participants and Interventions: The study included 2806 genotyped DPP participants randomized to receive intensive lifestyle intervention (n = 935), metformin (n = 927), or placebo (n = 944). Main Outcome Measures: Association of MODY genetic variants with diabetes incidence at a median of 3 years and measures of 1-year ß-cell function, insulinogenic index, and oral disposition index. Analyses were stratified by treatment group for significant single-nucleotide polymorphism × treatment interaction (Pint < 0.05). Sequence kernel association tests examined the association between an aggregate of rare missense variants and insulinogenic traits. Results: After 1 year, the minor allele of rs3212185 (HNF4A) was associated with improved ß-cell function in the metformin and lifestyle groups but not the placebo group; the minor allele of rs6719578 (NEUROD1) was associated with an increase in insulin secretion in the metformin group but not in the placebo and lifestyle groups. Conclusions: These results provide evidence that genetic variation among MODY genes may influence response to insulin-sensitizing interventions.
[Mh] Termos MeSH primário: Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética
Diabetes Mellitus Tipo 2/genética
Terapia por Exercício
Fator 4 Nuclear de Hepatócito/genética
Programas de Redução de Peso
[Mh] Termos MeSH secundário: Diabetes Mellitus Tipo 2/prevenção & controle
Variação Genética
Glucoquinase/genética
Fator 1-alfa Nuclear de Hepatócito/genética
Fator 1-beta Nuclear de Hepatócito/genética
Proteínas de Homeodomínio/genética
Seres Humanos
Metformina/uso terapêutico
Mutação de Sentido Incorreto
Polimorfismo de Nucleotídeo Único
Comportamento de Redução do Risco
Transativadores/genética
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Basic Helix-Loop-Helix Transcription Factors); 0 (HNF1A protein, human); 0 (HNF1B protein, human); 0 (HNF4A protein, human); 0 (Hepatocyte Nuclear Factor 1-alpha); 0 (Hepatocyte Nuclear Factor 4); 0 (Homeodomain Proteins); 0 (NEUROD1 protein, human); 0 (Trans-Activators); 0 (pancreatic and duodenal homeobox 1 protein); 138674-15-4 (Hepatocyte Nuclear Factor 1-beta); 9100L32L2N (Metformin); EC 2.7.1.2 (Glucokinase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2016-3429


  4 / 2861 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
[PMID]:29020906
[Au] Autor:Davis TM; Makepeace AE; Ellard S; Colclough K; Peters K; Hattersley A; Davis WA
[Ad] Endereço:University of Western Australia, Perth, WA tim.davis@uwa.edu.au.
[Ti] Título:The prevalence of monogenic diabetes in Australia: the Fremantle Diabetes Study Phase II.
[So] Source:Med J Aust;207(8):344-347, 2017 Oct 16.
[Is] ISSN:1326-5377
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To determine the prevalence of monogenic diabetes in an Australian community. DESIGN: Longitudinal observational study of a cohort recruited between 2008 and 2011. SETTING: Urban population of 157 000 people (Fremantle, Western Australia). PARTICIPANTS: 1668 (of 4639 people with diabetes) who consented to participation (36.0% participation). MAIN OUTCOME MEASURES: Prevalence of maturity-onset diabetes of the young (MODY) and permanent neonatal diabetes in patients under 35 years of age, from European and non-European ethnic backgrounds, who were at risk of MODY according to United Kingdom risk prediction models, and who were then genotyped for relevant mutations. RESULTS: Twelve of 148 young participants with European ethnic backgrounds (8%) were identified by the risk prediction model as likely to have MODY; four had a glucokinase gene mutation. Thirteen of 45 with non-European ethnic backgrounds (28%) were identified as likely to have MODY, but none had a relevant mutation (DNA unavailable for one patient). Two patients with European ethnic backgrounds (one likely to have MODY) had neonatal diabetes. The estimated MODY prevalence among participants with diagnosed diabetes was 0.24% (95% confidence interval [CI], 0.08-0.66%), an overall population prevalence of 89 cases per million; the prevalence of permanent neonatal diabetes was 0.12% (95% CI, 0.02-0.48%) and the population prevalence 45 cases per million. CONCLUSIONS: One in 280 Australians diagnosed with diabetes have a monogenic form; most are of European ethnicity. Diagnosing MODY and neonatal diabetes is important because their management (including family screening) and prognosis can differ significantly from those for types 1 and 2 diabetes.
[Mh] Termos MeSH primário: Diabetes Mellitus Tipo 2/epidemiologia
Diabetes Mellitus Tipo 2/genética
Diabetes Mellitus/epidemiologia
Diabetes Mellitus/genética
[Mh] Termos MeSH secundário: Diabetes Mellitus/etnologia
Diabetes Mellitus Tipo 2/etnologia
Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos
Feminino
Glucoquinase/genética
Seres Humanos
Estudos Longitudinais
Masculino
Meia-Idade
Mutação
Prevalência
Medição de Risco
Austrália Ocidental/epidemiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
EC 2.7.1.2 (Glucokinase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171013
[St] Status:MEDLINE


  5 / 2861 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28919057
[Au] Autor:Zamora RA; Gonzalez-Órdenes F; Castro-Fernández V; Guixé V
[Ad] Endereço:Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Ñuñoa, Santiago, Chile.
[Ti] Título:ADP-dependent phosphofructokinases from the archaeal order Methanosarcinales display redundant glucokinase activity.
[So] Source:Arch Biochem Biophys;633:85-92, 2017 Nov 01.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The genome of Methanosarcinales organisms presents both ADP-dependent glucokinase and phosphofructokinase genes. However, Methanococcoides burtonii has a truncate glucokinase gene with a large deletion at the C-terminal, where the catalytic GXGD motif is located. Characterization of its phosphofructokinase annotated protein shows that is a bifunctional enzyme able to supply the absence of the glucokinase activity. Moreover, kinetic analyses of the phosphofructokinase annotated enzyme from, Methanohalobium evestigatum demonstrated that this enzyme is also bifunctional. The high conservation of the active site residues of all the enzymes from the order Methanosarcinales suggest that they should be bifunctional, as was previously reported for the ADP-dependent kinases from Methanococcales, highlighting the redundancy of the glucokinase activity in this archaeal group. The presence of active glycolytic enzymes would be important when glycogen storage of these organisms needs to be degraded to be used as energy source. Kinetic and structural information allows us to establish a substrate specificity signature that identifies specific GK or PFK, and bifunctional enzymes in this family.
[Mh] Termos MeSH primário: Difosfato de Adenosina/química
Proteínas Arqueais/química
Glucoquinase/química
Methanosarcinales/enzimologia
Fosfotransferases (Aceptor do Grupo Álcool)/química
[Mh] Termos MeSH secundário: Difosfato de Adenosina/metabolismo
Sequência de Aminoácidos
Proteínas Arqueais/genética
Proteínas Arqueais/metabolismo
Sítios de Ligação
Clonagem Molecular
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Glucoquinase/genética
Glucoquinase/metabolismo
Cinética
Methanosarcinales/classificação
Methanosarcinales/genética
Modelos Moleculares
Fosforilação
Fosfotransferases (Aceptor do Grupo Álcool)/genética
Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
Filogenia
Ligação Proteica
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Domínios e Motivos de Interação entre Proteínas
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
Especificidade por Substrato
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Archaeal Proteins); 0 (Recombinant Proteins); 61D2G4IYVH (Adenosine Diphosphate); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC 2.7.1.146 (ADP D-fructose-6-phosphate 1-phosphotransferase); EC 2.7.1.2 (Glucokinase)
[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:170919
[St] Status:MEDLINE


  6 / 2861 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28800453
[Au] Autor:Wang Z; Shi X; Zhang H; Yu L; Cheng Y; Zhang H; Zhang H; Zhou J; Chen J; Shen X; Duan W
[Ad] Endereço:Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
[Ti] Título:Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation.
[So] Source:Eur J Med Chem;139:128-152, 2017 Oct 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Glucokinase (GK) activators are being developed for the treatment of type 2 diabetes mellitus (T2DM). However, existing GK activators have risks of hypoglycemia caused by over-activation of GK in islet cells and dyslipidemia caused by over-activation of intrahepatic GK. In the effort to mitigate risks of hypoglycemia and dyslipidemia while maintaining the promising efficacy of GK activator, we investigated a series of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific partial GK activators, which led to the identification of compound 72 that showed a good balance between in vitro potency and enzyme kinetic parameters, and protected ß-cells from streptozotocin-induced apoptosis. Chronic treatment of compound 72 demonstrated its potent activity in regulation of glucose homeostasis and low risk of dyslipidemia with diabetic db/db mice in oral glucose tolerance test (OGTT). Moreover, acute treatment of compound 72 did not induce hypoglycemia in C57BL/6J mice even at 200 mg/kg via oral administration.
[Mh] Termos MeSH primário: Benzamidas/farmacologia
Diabetes Mellitus Experimental/tratamento farmacológico
Diabetes Mellitus Tipo 2/tratamento farmacológico
Ativadores de Enzimas/farmacologia
Glucoquinase/metabolismo
Tiazóis/farmacologia
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Benzamidas/síntese química
Benzamidas/química
Diabetes Mellitus Experimental/induzido quimicamente
Diabetes Mellitus Experimental/patologia
Diabetes Mellitus Tipo 2/induzido quimicamente
Diabetes Mellitus Tipo 2/patologia
Relação Dose-Resposta a Droga
Descoberta de Drogas
Ativação Enzimática/efeitos dos fármacos
Ativadores de Enzimas/síntese química
Ativadores de Enzimas/química
Teste de Tolerância a Glucose
Células Secretoras de Insulina/efeitos dos fármacos
Células Secretoras de Insulina/patologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Modelos Moleculares
Estrutura Molecular
Estreptozocina
Relação Estrutura-Atividade
Tiazóis/síntese química
Tiazóis/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzamides); 0 (Enzyme Activators); 0 (Thiazoles); 5W494URQ81 (Streptozocin); EC 2.7.1.2 (Glucokinase)
[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:170812
[St] Status:MEDLINE


  7 / 2861 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28783164
[Au] Autor:Ivarsdottir EV; Steinthorsdottir V; Daneshpour MS; Thorleifsson G; Sulem P; Holm H; Sigurdsson S; Hreidarsson AB; Sigurdsson G; Bjarnason R; Thorsson AV; Benediktsson R; Eyjolfsson G; Sigurdardottir O; Olafsson I; Zeinali S; Azizi F; Thorsteinsdottir U; Gudbjartsson DF; Stefansson K
[Ad] Endereço:deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
[Ti] Título:Effect of sequence variants on variance in glucose levels predicts type 2 diabetes risk and accounts for heritability.
[So] Source:Nat Genet;49(9):1398-1402, 2017 Sep.
[Is] ISSN:1546-1718
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sequence variants that affect mean fasting glucose levels do not necessarily affect risk for type 2 diabetes (T2D). We assessed the effects of 36 reported glucose-associated sequence variants on between- and within-subject variance in fasting glucose levels in 69,142 Icelanders. The variant in TCF7L2 that increases fasting glucose levels increases between-subject variance (5.7% per allele, P = 4.2 × 10 ), whereas variants in GCK and G6PC2 that increase fasting glucose levels decrease between-subject variance (7.5% per allele, P = 4.9 × 10 and 7.3% per allele, P = 7.5 × 10 , respectively). Variants that increase mean and between-subject variance in fasting glucose levels tend to increase T2D risk, whereas those that increase the mean but reduce variance do not (r = 0.61). The variants that increase between-subject variance increase fasting glucose heritability estimates. Intuitively, our results show that increasing the mean and variance of glucose levels is more likely to cause pathologically high glucose levels than increase in the mean offset by a decrease in variance.
[Mh] Termos MeSH primário: Glicemia/metabolismo
Diabetes Mellitus Tipo 2/genética
Predisposição Genética para Doença/genética
Variação Genética
[Mh] Termos MeSH secundário: Alelos
Índice de Massa Corporal
Diabetes Mellitus Tipo 2/sangue
Jejum
Feminino
Frequência do Gene
Glucoquinase/genética
Glucose-6-Fosfatase/genética
Hemoglobina A Glicada/metabolismo
Seres Humanos
Islândia
Masculino
Penetrância
Polimorfismo de Nucleotídeo Único
Fatores de Risco
Proteína 2 Semelhante ao Fator 7 de Transcrição/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Glycated Hemoglobin A); 0 (TCF7L2 protein, human); 0 (Transcription Factor 7-Like 2 Protein); EC 2.7.1.2 (Glucokinase); EC 3.1.3.9 (Glucose-6-Phosphatase); EC 3.1.3.9. (G6PC2 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170808
[St] Status:MEDLINE
[do] DOI:10.1038/ng.3928


  8 / 2861 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28525638
[Au] Autor:Sklenarova J; Petruzelkova L; Kolouskova S; Lebl J; Sumnik Z; Cinek O
[Ad] Endereço:Department of Pediatrics, Second Faculty of Medicine, Charles University and University Hospital Motol, 150 06 Prague, Czech Republic.
[Ti] Título:Glucokinase Gene May Be a More Suitable Target Than the Insulin Gene for Detection of ß Cell Death.
[So] Source:Endocrinology;158(7):2058-2065, 2017 Jul 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Detection and quantification of unmethylated circulating insulin (INS) DNA presumably released from ß cells has been previously used for assessing their destruction. As the targets within the INS gene suffer from suboptimal specificity, we sought to improve the assay parameters by using the glucokinase gene (GCK) tissue-specific pancreatic promoter. The amount of methylated and unmethylated GCK DNA was measured using a droplet polymerase chain reaction assay and compared with the previously published INS-targeted assay. The method was tested using synthetic target sequences and DNA from pancreatic islets, blood, brain, kidney, large intestine, liver, lung, small intestine, and stomach. Circulating serum DNA was obtained from children with recent-onset type 1 diabetes (T1D) (n = 25), autoantibody-positive first-degree relatives of T1D patients (n = 14), and healthy controls (n = 20). The unmethylated GCK DNA was found to be more islet specific than unmethylated INS DNA. The proportion of the unmethylated GCK DNA was lower than INS in all tested extrapancreatic tissues, except kidney. Although the amounts of methylated DNA measured by the two assays were similar, the INS assay detected considerably more unmethylated DNA. Whereas none of the assays showed significant increase in the amount of unmethylated DNA, the ratio of unmethylated/methylated GCK DNA was borderline significantly increased in autoantibody-positive relatives compared with T1D patients (P = 0.04) and controls (P = 0.06). Targeting the assay into the GCK gene improved analytical parameters of the assay. As the amount of unmethylated target DNA in properly treated samples is very low, the clinical utility of this method remains to be evaluated.
[Mh] Termos MeSH primário: Diabetes Mellitus Tipo 1/diagnóstico
Glucoquinase/genética
Células Secretoras de Insulina/fisiologia
Insulina/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Estudos de Casos e Controles
Morte Celular/genética
Criança
Pré-Escolar
Metilação de DNA
Análise Mutacional de DNA/métodos
Diabetes Mellitus Tipo 1/genética
Diabetes Mellitus Tipo 1/patologia
Feminino
Glucoquinase/análise
Seres Humanos
Lactente
Insulina/análise
Células Secretoras de Insulina/patologia
Masculino
Reação em Cadeia da Polimerase
Valor Preditivo dos Testes
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insulin); EC 2.7.1.2 (Glucokinase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE
[do] DOI:10.1210/en.2016-1923


  9 / 2861 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28516783
[Au] Autor:Martinez JA; Xiao Q; Zakarian A; Miller BG
[Ad] Endereço:Department of Chemistry and Biochemistry, Florida State University , Tallahassee, Florida 32303, United States.
[Ti] Título:Antidiabetic Disruptors of the Glucokinase-Glucokinase Regulatory Protein Complex Reorganize a Coulombic Interface.
[So] Source:Biochemistry;56(24):3150-3157, 2017 Jun 20.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The glucokinase regulatory protein (GKRP) plays an essential role in glucose homeostasis by acting as a competitive inhibitor of glucokinase (GCK) and triggering its localization to the hepatocyte nucleus upon glucose deprivation. Metabolites such as fructose 6-phosphate and sorbitol 6-phosphate promote assembly of the GCK-GKRP complex, whereas fructose 1-phosphate and functionalized piperazines with potent in vivo antidiabetic activity disrupt the complex. Here, we establish the molecular basis by which these natural and synthetic ligands modulate the GCK-GKRP interaction. We demonstrate that a small-molecule disruptor of the protein-protein interaction utilizes a two-step conformational selection mechanism to associate with a rare GKRP conformation constituting 3% of the total population. Conformational heterogeneity of GKRP is localized to the N-terminus and deleting this region eliminates the ability of sorbitol 6-phosphate to promote the GCK-GKRP interaction. Stabilizing ligands favor an extended N-terminus, which sterically positions two arginine residues for optimal Coulombic interaction with a pair of carboxylate side chains from GCK. Conversely, disruptors promote a more compact N-terminus in which an interfacial arginine residue is stabilized in an unproductive orientation through a cation-π interaction with tyrosine 75. Eliminating the ability to sample this binding impaired conformation enhances the intrinsic inhibitory activity of GKRP. Elucidating the molecular basis of ligand-mediated control over the GCK-GKRP interaction is expected to impact the development and future refinement of therapeutic agents for diabetes and cardiovascular disease, which result from improper GKRP regulation of GCK.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores
Proteínas Adaptadoras de Transdução de Sinal/química
Glucoquinase/antagonistas & inibidores
Hipoglicemiantes/farmacologia
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Relação Dose-Resposta a Droga
Glucoquinase/metabolismo
Seres Humanos
Hipoglicemiantes/química
Ligantes
Modelos Moleculares
Estrutura Molecular
Ligação Proteica/efeitos dos fármacos
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (GCKR protein, human); 0 (Hypoglycemic Agents); 0 (Ligands); 0 (Recombinant Proteins); EC 2.7.1.2 (Glucokinase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171007
[Lr] Data última revisão:
171007
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170519
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00377


  10 / 2861 MEDLINE  
              first record previous record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28512030
[Au] Autor:Cheruvallath ZS; Gwaltney SL; Sabat M; Tang M; Wang H; Jennings A; Hosfield D; Lee B; Wu Y; Halkowycz P; Grimshaw CE
[Ad] Endereço:Takeda California, 10410 Science Center Drive, San Diego 92121, USA. Electronic address: zacharia.cheruvallath@takedasd.com.
[Ti] Título:Discovery of potent and orally active 1,4-disubstituted indazoles as novel allosteric glucokinase activators.
[So] Source:Bioorg Med Chem Lett;27(12):2678-2682, 2017 06 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Guided by co-crystal structural information obtained from a different series we were exploring, a scaffold morphing and SBDD approach led to the discovery of the 1,4-disubstituted indazole series as a novel class of GKAs that potently activate GK in enzyme and cell assays. anti-diabetic OGTT efficacy was demonstrated with 29 in a rodent models of type 2 diabetes.
[Mh] Termos MeSH primário: Diabetes Mellitus Experimental/tratamento farmacológico
Diabetes Mellitus Tipo 2/tratamento farmacológico
Descoberta de Drogas
Ativadores de Enzimas/farmacologia
Glucoquinase/metabolismo
Indazóis/farmacologia
[Mh] Termos MeSH secundário: Administração Oral
Regulação Alostérica/efeitos dos fármacos
Animais
Diabetes Mellitus Experimental/metabolismo
Diabetes Mellitus Tipo 2/metabolismo
Relação Dose-Resposta a Droga
Ativadores de Enzimas/administração & dosagem
Ativadores de Enzimas/química
Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores
Canais de Potássio Éter-A-Go-Go/metabolismo
Teste de Tolerância a Glucose
Seres Humanos
Indazóis/administração & dosagem
Indazóis/química
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Obesos
Modelos Moleculares
Estrutura Molecular
Bloqueadores dos Canais de Potássio/farmacologia
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Enzyme Activators); 0 (Ether-A-Go-Go Potassium Channels); 0 (Indazoles); 0 (Potassium Channel Blockers); EC 2.7.1.2 (Glucokinase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170518
[St] Status:MEDLINE



página 1 de 287 ir para página                         
   


Refinar a pesquisa
  Base de dados : MEDLINE Formulário avançado   

    Pesquisar no campo  
1  
2
3
 
           



Search engine: iAH v2.6 powered by WWWISIS

BIREME/OPAS/OMS - Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde