Made available in DSpace on 2014-12-17T14:16:26Z (GMT). No. of bitstreams: 1 MarcelaAGU_DISSERT.pdf: 6376152 bytes, checksum: 6d7d86fec335062b8c283cdea3878878 (MD5) Previous issue date: 2009-03-30 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Inflammation has been pointed out as an important factor in development of chronic diseases, as diabetes. Hyperglycemia condition would be responsible by toll-like receptors, TLR2 and TLR4, and, consequently by local and systemic inflammation induction. Thus, the objective of present study was to evaluate type 1 Diabetes mellitus (T1DM) pro-inflammatory state through mRNA expression of TLRs 2 and 4 and proinflammatory cytokines IL-1?, IL-6 and TNF-? correlating to diabetic nephropathy. In order to achieve this objective, 76 T1DM patients and 100 normoglycemic (NG) subjects aged between 6 and 20 years were evaluated. T1DM subjects were evaluated as a total group DM1, and considering glycemic control (good glycemic control DM1G, and poor glycemic control DM1P) and considering time of diagnosis (before achieving 5 years of diagnosis DM1< 5yrs, and after achieving 5 years of diagnosis DM1 <5yrs). Metabolic control was evaluated by glucose and glycated hemoglobin concentrations; to assess renal function serum urea, creatinine, albumin, total protein and urinary albumin-to-creatinine ratio were determined and to evaluate hepatic function, AST and ALT serum activities were measured. Pro-inflammatory status was assessed by mRNA expression of TLRs 2 and 4 and the inflammatory cytokines IL-1?, IL-6 and TNF-?. Except for DM1G group (18.4%), DM1NC patients (81.6%) showed a poor glycemic control, with glycated hemoglobin (11,2%) and serum glucose (225,5 md/dL) concentrations significantly increased in relation to NG group (glucose: 76,5mg/dL and glycated hemoglobin: 6,9%). Significantly enhanced values of urea (20%) and ACR (20,8%) and diminished concentrations of albumin (5,7%) and total protein (13,6%) were found in T1DM patients, mainly associated to a poor glycemic control (DM1P increased values of urea: 20% and ACR:49%, and diminished of albumin: 13,6% and total protein:13,6%) and longer disease duration (DM1 <5yrs - increased values of urea: 20% and ACR:20,8%, and diminished of albumin: 14,3% and total protein:13,6%). As regarding pro-inflammatory status evaluation, significantly increased mRNA expressions were presented for TLR2 (37,5%), IL-1? (43%), IL-6 (44,4%) and TNF-? (15,6%) in T1DM patients in comparison to NG, mainly associated to DM1P (poor glycemic control TLR2: 82%, IL-1?: 36,8% increase) and DM1 <5yrs (longer time of diagnosis TLR2: 85,4%, IL-1?: 46,5% increased) groups. Results support the existence of an inflammatory state mediated by an increased expression of TLR2 and pro-inflammatory cytokines IL-1?, IL-6 and TNF-? in T1DM / A inflama??o tem sido descrita como um fator importante no desenvolvimento de doen?as cr?nicas como o diabetes, e a condi??o da hiperglicemia seria a respons?vel pela ativa??o dos receptores toll-like (TLRs), TLR2 e TLR4, e, conseq?entemente, pela indu??o da inflama??o local e sist?mica. Nesse sentido, o presente estudo teve como objetivo de avaliar o estado pr?-inflamat?rio do Diabetes mellitus tipo 1 (DM1) atrav?s da express?o g?nica de TLRs 2 e 4 e das citocinas pr?-inflamat?rias IL-1?, IL-6 e TNF- ?, e correlacionar com o desenvolvimento da nefropatia diab?tica. Foram estudados 76 pacientes diab?ticos tipo 1 e 100 indiv?duos normoglic?micos NG, na faixa et?ria de 6 a 20 anos. Os indiv?duos diab?ticos foram avaliados como um grupo total DM1, e subdivididos em fun??o do controle glic?mico (diab?ticos compensados DM1C, e n?o-compensados DM1NC) e em fun??o do tempo de diagn?stico (diab?ticos com menos de 5 anos de diagn?stico DM1< 5anos, e a partir de 5 anos de diagn?stico DM1 <5 anos). Para a avalia??o do controle metab?lico foram determinadas as concentra??es de glicose e de hemoglobina glicada; para avaliar a fun??o renal as concentra??es s?ricas de ur?ia, creatinina, albumina, prote?na total e a rela??o albumina/creatinina (RAC) urin?ria; e para fun??o hep?tica a atividade s?rica de AST e ALT. O estado pr?-inflamat?rio foi avaliado a partir da express?o do mRNA dos TLRs 2 e 4, e das citocinas IL-1?, IL-6 e TNF-?. Com exce??o do grupo DM1C (18,4%), os pacientes DM1NC (81,6%) apresentaram um controle glic?mico insatisfat?rio, com valores de mediana para glicose (225,5mg/dL) e hemoglobina glicada (11,2%) significativamente superiores ao grupo NG (glicose: 76,5mg/dL e hemoglobina glicada: 6,9%). Foram obtidos valores aumentados para a ur?ia s?rica (20%) e RAC urin?ria (20,8%); e diminu?dos para albumina (5,7%) e prote?na total (13,6%) nos indiv?duos diab?ticos; e associados a um controle glic?mico insatisfat?rio (DM1NC aumento de 20% para ur?ia e 49% para RAC; e diminui??o de 8,6% para albumina e 12,1% para prote?na total) e a um maior tempo de diagn?stico (DM1 <5anos aumento de 20% para ur?ia e 20,8% para RAC; e diminui??o de 14,3% para albumina e 13,6% para prote?na total). No tocante ? avalia??o do estado pr?-inflamat?rio, as express?es de mRNA se apresentaram elevadas para TLR2 (37,5%), IL-1? (43%), IL-6 (44,4%) e TNF-? (15,6%) nos indiv?duos diab?ticos em rela??o aos NG, sendo principalmente associadas aos grupos DM1NC (controle glic?mico insatisfat?rio TLR2: 82%, IL-1?: 43% de aumento) e DM1 <5 anos (maior tempo de diagn?stico TLR2: 85,4%, IL-1?: 46,5% de aumento). O conjunto de resultados suporta a exist?ncia de um quadro inflamat?rio mediado pelo aumento da express?o do TLR2 e das citocinas pr?-inflamat?rias IL-1?, IL-6 e TNF-? no diabetes tipo 1