Introdução: A obesidade aumenta o risco da presença de alterações metabólicas, o que contribui para um elevado risco cardiovascular. No entanto, o papel independente da obesidade na gênese da aterosclerose e da doença cardiovascular ainda é controverso. Diversos estudos identificaram indivíduos que apresentam um fenótipo de obesidade sem alterações metabólicas, conhecida como \"obesidade metabolicamente saudável\" (ObMS). Como a definição de ObMS é variável, sua prevalência não é bem definida. A espessura íntima-média carotídea (EIMC) e a calcificação arterial coronariana (CAC) são considerados marcadores precoces de aterosclerose subclínica Apesar de estudos prévios terem avaliado a associação entre índice de massa corporal (IMC) e EIMC e entre IMC e CAC, o papel independente da obesidade, particularmente em indivíduos metabolicamente saudáveis não está claro. Objetivos: Avaliar se a obesidade, independentemente dos fatores de risco cardiovascular, está associada à maior EIMC e à maior CAC. Calcular a prevalência de ObMS utilizando uma definição estrita de saúde metabólica. Métodos: Este estudo é uma análise transversal dos dados da linha de base do Estudo Longitudinal da Saúde do Adulto (ELSA-Brasil). O indivíduo foi classificado como tendo ObMS se tivesse o IMC >=30 kg/m2 e não tivesse nenhum dos componentes da síndrome metabólica, excluindo-se o critério da circunferência abdominal. Resultados: A análise com EIMC incluiu 10.335 participantes e a análise com CAC incluiu 4.320 participantes. A prevalência de obesidade foi de 21,2% (n=2.191) na análise com EIMC e de 24,3% (n=1.050) na análise com CAC. Com uma definição estrita, a prevalência de ObMS foi de 5,6% na análise com EIMC e 5,5% na análise com CAC. A estratificação dos indivíduos de acordo com a saúde metabólica, evidenciou que os indivíduos metabolicamente saudáveis eram mais jovens, predominantemente mulheres e que tinham menor circunferência abdominal. A maioria dos indivíduos com ObMS tinha obesidade grau 1 (84,7% na análise com EIMC e 82,8% na análise com CAC) e raramente tinham obesidade grau 3 (3,2% na análise com EIMC e 5,2% na análise com CAC). A obesidade abdominal foi presente em mais de 99% dos indivíduos obesos. A análise com EIMC evidenciou que a EIMC média da amostra foi de 0,81 mm (±0,20). A EIMC média da subamostra metabolicamente saudável foi de 0,70 (±0,13) mm nos indivíduos não obesos e de 0,76 mm (±0,13) nos obesos (p < 0,001). A EIMC média da subamostra metabolicamente não saudável foi de 0,81 (±0,20) mm nos indivíduos não obesos e de 0,88 mm (±0,20) nos obesos (p < 0,001). Estes achados se mantiveram inalterados mesmo após o ajuste multivariado para possíveis variáveis de confusão. A análise com CAC (CAC=0 versus CAC > 0) não evidenciou diferença significativa de calcificação coronariana nos indivíduos obesos, metabolicamente saudáveis ou não, em relação aos não obesos. Conclusão: Utilizando-se uma definição estrita, a prevalência de ObMS é menor do que 6%. O conceito de obesidade metabolicamente saudável, mesmo utilizando-se uma definição estrita, parece inadequado, visto que nesta população, a obesidade está associada com valores mais elevados de EIMC. Na análise com CAC não evidenciamos diferença estatisticamente significativa / Introduction: Obesity increases the risk of metabolic abnormalities, which contributes to elevated cardiovascular risk. However, the independent role of obesity in the development of atherosclerosis and cardiovascular disease is still debatable. Several studies identified individuals with an obesity phenotype without metabolic abnormalities: \"metabolically healthy obesity\" (MHO). Since the definition of MHO is variable, the prevalence of MHO varies widely. Carotid intima-media thickness (CIMT) and coronary artery calcification (CAC) are considered early markers of subclinical atherosclerosis. Although previous studies have evaluated the association between body mass index (BMI) and CIMT and between BMI and CAC, the independent role of obesity, particularly in metabolically healthy subjects, is still unclear. Objectives: This study sought to evaluate whether obesity, regardless of cardiovascular risk factors, is associated with higher CIMT levels and higher CAC. We also sought to calculate MHO prevalence using a strict definition of metabolic health. Methods: This is a cross-sectional analysis of the baseline data of Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). MHO was defined as BMI >=30 kg/m2 and none of metabolic syndrome components, excluding waist circumference criterion. Results: EIMC analysis included 10,335 subjects and CAC analysis 4,320 subjects. Obesity prevalence was 21.2% (n=2,191) in EIMC analysis and 24.3% (n=1,050) in CAC analysis. This study showed a prevalence of MHO: 5.6% (n=124) in EIMC analysis and 5.5% (n=58) in CAC analysis. When individuals were stratified according to the presence of metabolic health, we found that metabolically healthy subjects were younger, more likely to be women and had lower waist circumference. Most of the MHO subjects had grade 1 obesity (84.7% in EIMC analysis and 82.8% in CAC analysis) and rarely had grade 3 obesity (3.2% in EIMC analysis and 5.2% in CAC analysis). Abdominal obesity was present in more than 99% of obese subjects. EIMC analysis showed that mean CIMT of the sample was 0.81 (±0.20). The mean CIMT of metabolically healthy subsample was 0.70 (±0.13) in non-obese and 0.76 (±0.13) in obese (p < 0.001). The mean CIMT of metabolically unhealthy subsample was 0.81 (±0.20) in non-obese and 0.88 (±0.20) in obese (p < 0.001). Those findings remained essentially unchanged after multivariate adjustment for confounding. CAC analysis (CAC=0 versus CAC > 0) did not show a significant difference in coronary calcification in obese subjects, regardless metabolic status, when compared with non-obese subjects. Conclusion: Using a strict definition, the prevalence of MHO is below 6%. The concept of MHO, even with strict definition, seems inadequate, as even in this population obesity is associated with higher CIMT levels. CAC analysis did not show statiscally significant difference

Introdução - Na prevenção primária das doenças cardiovasculares, a adoção de estilo de vida saudável representa uma das estratégias mais importantes. Entretanto, baixos índices de adesão e o abandono da dieta constituem obstáculo importante ao tratamento. Neste sentido, as intervenções cirúrgicas surgiram como um mecanismo promotor da restrição alimentar e têm ganhado importância não só pelo tratamento da obesidade como também no controle dos fatores de risco cardiovascular e na possível redução da mortalidade. Através de estudos clínicos foi possível observar que estas estratégias cirúrgicas promovem profundas modificações estruturais no trato gastrointestinal gerando aumento da saciedade e da sensibilidade à insulina. Em especial para os pacientes diabéticos, por si só associados a maior risco cardiovascular, as cirurgias bariátricas seriam capazes de promover um efeito muito intenso e agudo sobre os marcadores relacionados ao desenvolvimento da aterosclerose. Um evento muito definido no tempo como uma intervenção cirúrgica pode ser muito útil para o estudo e identificação de mecanismos que ainda não estão completamente estabelecidos no processo aterosclerótico. Objetivos - Analisar o comportamento das variáveis laboratoriais, clínicas e estruturais relacionadas ao desenvolvimento e progressão da aterosclerose em indivíduos diabéticos submetidos à cirurgia bariátrica. Métodos - Foram incluídos vinte voluntários diabéticos refratários ao tratamento clínico e que apresentavam obesidade abdominal. Deste grupo, metade foi aleatoriamente selecionada para realização da cirurgia bariátrica e metade foi mantida em tratamento clínico otimizado. Todos os participantes foram submetidos a exames clínicos e bioquímicos nas mesmas ocasiões, até trinta dias antes da cirurgia, três e vinte e quatro meses após a cirurgia. Nestas ocasiões além do perfil lipídico e da glicemia, determinamos os hormônios incretínicos, adipocinas. A avaliação da quantidade de gordura epicárdica e a presença de esteatose hepática será realizada somente após dois anos de seguimento em conjunto com as demais variáveis,. Foram incluídos também 10 indivíduos saudáveis e com IMC dentro da normalidade, como parte do grupo controle. Estes indivíduos foram submetidos à coleta de sangue em dois momentos para avaliação dos mesmos metabólitos. Resultados - No momento pré-intervenção os indivíduos do grupo cirúrgico e clinico eram diferentes em relação ao IMC, Glicemia e Triglicérides, sendo assim, os resultados obtidos foram ajustados minimizando o impacto destas diferenças. Após o seguimento de 3 meses, o grupo cirúrgico apresentou redução significativa nos valores de peso, IMC (33,4 ± 2,6 vs. 27,4±2,8 kg/m2, p < 0,001), HbA1c (9,26 ± 2,12 vs. 6,18±0,63%, p < 0,001), CT (182,9 ± 45,4 vs. 139,8 ± 13 mg/dl, p < 0,001), HDL (33,1 ± 7,7 vs. 38,4 ± 10,6 mg/dL, p < 0,001), TG (369,5 ± 324,6 vs. 130,8 ± 43,1 mg/dL, p < 0,001), Pro-insulina (12.72±9,11 vs. 1,76±1,14 pM, p < 0,001), RBP-4 (9,85±2,53 vs. 7,3±1,35 ng/ml, p < 0,001) e CCK (84,8±33,2 vs. 79,9 ± 31,1, ng/ml, p < 0,001), houve também aumento significativo nos níveis de HDL-colesterol (33,1 ± 7,7 vs. 38,4 ± 10,6 mg/dL, p < 0,001), Glucagon (7,4 ± 7,9 vs. 10,2±9,7 pg/ml, p < 0,001) e FGF- 19 (74,1 ± 45,8 vs. 237,3 ± 234 pg/ml, p=0,001). Um dado interessante foi que os valores de Pro-insulina, RBP-4, HbA1c e HDL- colesterol no grupo cirúrgico atingiram valores similares àqueles do grupo controle três meses após a intervenção, sendo que o FGF-19 apresentava valor duas vezes maior do que o encontrado no grupo de indivíduos saudáveis (237 ± 234 vs. 98 ± 102,1 pg/ml). O grupo clínico não apresentou variação nas variáveis clinicas, apenas nos valores de glucagon com redução significativa no período pós-intervenção (18,1 ± 20,7 vs. 16,8 ± 18,4 pg/ml, p < 0,001). Conclusão - Concluímos que indivíduos diabéticos descompensados e refratários ao tratamento clínico, quando submetidos à cirurgia bariátrica, apresentam uma alteração profunda do ponto de vista clínico, metabólico e hormonal, em relação ao indivíduos de mesmo perfil mantidos em tratamento clínico otimizado. Esta importante alteração, observada já com três meses após a intervenção, pode representar uma importante redução do risco cardiovascular nestes indivíduos. Individualmente, a notável modificação dos valores de FGF-19 associadas à intervenção devem ser estudadas com maior profundidade para compreensão de seu significado e sua potencial utilidade como marcador ou como um dos protagonistas no mecanismo de prevenção cardiovascular / Introduction - The adoption of a healthy lifestyle is one of the most important strategies for the primary prevention of cardiovascular diseases. However, low adhesion rates constitute a major obstacle to treatment. In this scenario, bariatric surgery emerged as an interesting option to promote dietary restriction and have gained importance, not only as obesity treatment but also in the control of cardiovascular risk factors and possible mortality reduction. Data from literature has shown that the surgical strategies can promote deep structural modifications in gastrointestinal tract leading to increased satiety and insulin sensitivity. In diabetic patients, already associated with a higher cardiovascular risk, the surgery would be able to promote a very intense and acute effect on the markers related to the development of atherosclerosis. This procedure, such as a very definite event in time, can be very useful for the study and identification of mechanisms that are not fully established in the atherosclerotic process. Aim - To analyse laboratory, clinical and structural variables related to the development and progression of atherosclerosis in diabetic patients undergoing bariatric surgery. Methods - Twenty diabetic individuals with a BMI between 28-35kg/m2 were randomized to bariatric surgery or clinical treatment and ten healthy subjects (normal BMI) represented the control group. All participants underwent clinical and biochemical tests on the same occasions , up to thirty days before the surgery, three and twenty-four months after surgery. On these occasions beyond the lipid profile and glucose, we determine the incretin hormones, adipokines. Evaluation of the amount of epicardial fat and the presence of hepatic steatosis will be performed only after two years, in conjunction of the other variables. Results - In the baseline surgical group differ from clinical group showing a higher BMI, Glycaemia and Triglycerides. For this matter all results were adjusted to these variables so that it did not interfere with the interpretation of the results. At 3 months, surgical group presented significant differences such as reduction in BMI (33.4 ± 2.6 vs. 27.4 ± 2.8 kg/m2, p < 0.001), triglycerides (369.5±324.6 vs. 130.8 ± 43.1 mg/dL, p < 0.001), Pro-insulin (12.72 ± 9.11 vs. 1.76 ± 1.14 pM, p < 0.001), glycaemia (217 ± 103.1 vs. 102±2, mg/dL, p < 0.001), glycated haemoglobin (9.26±2.12 vs. 6.18±0.63 %, p < 0.001), Total Cholesterol (182.9±45.4 vs. 139.8±13 mg/dl, p < 0.001), RBP-4 (9.85±2.53 vs. 7.3±1.35 ng/ml, p < 0.001) and increment in HDL-cholesterol (33.1±7.7 vs. 38.4±10.6 mg/dL, p < 0.001), glucagon (7.4±7.9 vs. 10.2±9.7 pg/ml, p < 0.001) and FGF-19 (74.1±45.8 vs. 237.3±234 pg/ml, p=0.001). Interestingly, pro-insulin, RBP-4, HbA1c and HDL-cholesterol levels in the surgical group achieved \"control group\" values after 3 months but FGF-19 levels were almost two fold the results in the healthy subjects (237 ± 234 vs. 98±102,1 pg/ml). Clinical group did not differ from baseline according to clinical variables, and only glucagon had a significant reduction 3 months after the intervention (18.1±20.7 vs. 16.8±18.4 pg/ml, p < 0.001). Conclusions - Our results showed that diabetic individuals when subjected to bariatric surgery showed profound metabolic, hormonal and clinical alterations, when compared to similar individuals subjected to optimized clinical treatment. This improvement seen just after tree months could represent an important cardiovascular risk reduction. Individually, the notable modification of FGF -19 values associated with the intervention should be studied in greater depth to understand its meaning and potential utility as a marker or as one of the protagonists in cardiovascular prevention mechanism

Introdução: A lipoproteína de baixa densidade (LDL) e suas formas oxidadas (LDLox) possuem múltiplas propriedades aterogênicas, atuando na deposição de colesterol, indução e manutenção da inflamação, disfunção endotelial, surgimento de células espumosas na parede arterial e conseqüente formação da placa de ateroma. Adicionalmente, LDLox induz apoptose de células endoteliais humanas (HMEC). A lipoproteína de alta densidade (HDL) possui inúmeras atividades antiaterogênicas, incluindo ações antioxidante, anti-inflamatória e anti-trombótica. A HDL é capaz de proteger as HMEC contra apoptose. As subfrações de HDL (sHDL) são heterogêneas em sua composição físico-química e atividades biológicas. A atividade antioxidante das sHDL aumenta com a densidade (HDL2b<HDL2a<HDL3a<HDL3b <HDL3c) e está deficiente em pacientes com SMet. Contudo, a heterogeneidade da atividade anti-apoptótica das sHDL é ainda desconhecida. Objetivos: (i) avaliar a heterogeneidade da atividade protetora das sHDL de indivíduos normolipidêmicos (n=7) e de pacientes com SMet (n=16) contra apoptose de HMEC induzida por LDLox; (ii) definir os mecanismos moleculares envolvidos nesta atividade. Métodos: Através de ultracentrifugação por gradiente de densidade, isolamos cinco diferentes sHDL. HMEC foram incubadas com LDLox (200 ?g apoB/ml) na presença ou não das sHDL (5-100 ?g proteína/ml). Os marcadores de toxicidade (MTT) e de apoptose celular (microscopia de fluorescência, marcagem com anexina V, cit c, AIF, degradação Bid, atividade caspase-3 e fragmentação do ADN) foram analisados. Resultados: Todas sHDL protegeram as HMEC contra a toxicidade e apoptose induzidas pela LDLox. Com mesma concentração de proteína, as subfrações HDL3c (60% proteção - MTT - e >100% - anexina V) e 3b (43% e 67%, respectivamente) de indivíduos normolipidêmicos apresentaram atividade anti-apoptótica mais potente do que as subfrações HDL2a (29% e 28%; p<0,01 vs. HDL3c, respectivamente) e 2b (25% e 62%; p<0,001 vs. HDL3c, respectivamente). Todas sHDL reduziram geração de espécies reativas de oxigênio (ROS) induzida pela LDLox, sendo a HDL3c (54%) mais potente do que HDL2b (21%; p<0.05 vs. HDL3c). Houve correlação positiva entre as atividades anti-apoptótica e antioxidante intracelular com conteúdo de apoA-I e esfingosina 1-fosfato (E1F) das sHDL, senda HDL3b e 3c ricas em E1F. A atividade anti-apoptótica da E1F e das sHDL parece depender da interação com as células endoteliais via apoA-I e seu receptor SR-BI. Finalmente, as HDL3c (n=5) isoladas de pacientes com SMet possuem conteúdo significativamente menor de apoA-I e reduzida atividade anti-apoptótica (60%, p<0,01), quando comparada aos controles normolipidêmicos (n=5). Houve tendência à diminuição da proteção contra a geração de ROS (SMet, n=10). Conclusão: As subfrações HDL3c protegem de forma potente as células endoteliais humanas contra toxicidade e apoptose induzidas pela LDLox, assim como contra geração de ROS. Esta atividade antiapoptótica está reduzida na SMet. / Background: Low density lipoprotein (LDL) and its oxidized forms (oxLDL) have several atherogenic properties, including cholesterol deposition, inflammation, endothelial dysfunction and foam cell formation on the arterial wall, leading to atherosclerotic plaque development. In addition, oxLDL induces human endothelial cell apoptosis (HMEC). High-density lipoprotein (HDL) has number of antiatherogenic activities, as antioxidative, anti-inflammatory and anti-thrombotic actions. HDL displays anti-apoptotic activity and is able to protect endothelial cells against oxLDL-induced apoptosis. HDL subfractions (sHDL) are highly heterogeneous in their physical and chemical composition and biological functions. Antioxidative activity of HDL subfractions increases with increment in density, HDL2b<HDL2a<HDL3a<HDL3b <HDL3c. Important, HDL subfractions from subjects with metabolic syndrome (MetS), display a significantly lower antioxidative activity as compared to healthy controls. However, the heterogeneity of their anti-apoptotic activity was not demonstrated. Objectives: (i) to evaluate the heterogeneity of antiapoptotic activity of sHDL from normolipidemic controls (n=7) and MetS patients (n=16) towards oxLDL-induced apoptosis of HMEC; (ii) to define molecular mechanisms involved in this anti-apoptotic action. Methods: Five major sHDL were fractionated by density gradient ultracentrifugation. HMEC were incubated with mildly oxLDL (200 ?g apoB/ml) in the presence or absence of each sHDL (5-100 ?g protein/ml). Markers of cellular toxicity (MTT) and apoptosis (fluorescent nucleic acid staining, annexin V binding, cytochrome c, AIF and Bid, caspase-3 activity and DNA fragmentation) were observed. Results: All HDL subfractions isolated from normolipidemic subjects protected HMEC against oxLDL-induced toxicity and apoptosis. At equal protein concentrations, HDL3c (60% protection in the MTT test; >100% in annexin V biding) and 3b subfractions (43% and 67%, respectively) were more potent against oxLDL-induced toxicity and apoptosis as compared to HDL2a (29% and 28%; p<0.01 vs. HDL3c, respectively) and 2b subfractions (25% and 62%; p<0.001 vs. HDL3c, respectively). All HDL subfractions attenuated of reactive oxygen species (ROS) generation in HMEC induced by oxLDL. Again, HDL3c (54% inhibition) were more potent as compared to HDL2b (21%; p<0.05 vs. HDL3c). The anti-apoptotic and intracellular antioxidative activities of HDL3 were positively correlated with apoA-I and sphingosine 1-phosphate (S1P) content of sHDL and, possibly, depend on their cellular interaction through apoA-I and its SR-BI receptor. The sHDL3c isolated from MetS patients (n=5) possess reduced content of apoA-I and less potent anti-apoptotic activity (-60%, p<0.01) than controls (n=5). Conclusion: Normolipidemic small dense HDL3 provide potent protection of human endothelial cells from oxLDL-induced apoptosis; this anti-apoptotic activity is reduced in the MetS.

Le facteur de croissance de l'endothélium vasculaire (VEGF) est une cytokine multifonctionnelle qui a été liée aux maladies cardiovasculaires (MCV) et à des divers troubles/ facteurs de risque cardiovasculaires tel que le syndrome métabolique (SM). L'identification de variants génétiques qui agissent sur les taux de VEGF circulant et leurs associations avec le SM et les molécules d'adhésion et d'inflammation pourraient permettre la compréhension des liens entre les taux de VEGF et les MCV. Par conséquent nous avons recherché l'origine génétique des taux de VEGF, via une étude d'association pangénomique, et les facteurs de variation pré-analytiques et analytiques influant les taux de VEGF mesurés avant d'étudier les implications de cette molécule dans l'inflammation et le SM. Nous avons également examiné le profil du SM dans des populations françaises (cohorte STANISLAS) et iraniennes (cohorte MASHHAD). Les principaux résultats de cette thèse sont : 1) l'identification de variants génétiques rs6921438, rs4416670, rs6993770 et rs10738760 expliquant 47.6% des taux de VEGF circulant, 2) l'association du VEGF et des variants génétiques identifiés avec des molécules d'adhésion et d'inflammation telles que ICAM-1,sélectines E et L,TNF-alpha, IL-6 et CRP au niveau protéique et transcriptomique, 3) l'association du rs10738760 avec le SM, 4) la relation entre le rs6921438 et le HDL-C et le LDL-C, 5) la détermination optimale à la fois des taux de VEGF (le sérum serait plus stable que le plasma) et de son expression génétique en proposant une durée minimale entre le recueil du sang et sa centrifugation, et en évitant des cycles de gel/dégel répétés. 6) la prévalence élevée du SM chez les femmes iraniennes. Nos résultats proposent des liens biologiques entre le VEGF et les molécules d'inflammation et l'adhésion, les lipides et le SM / Vascular endothelial growth factor (VEGF) is a multifunctional cytokine that has been linked to cardiovascular diseases (CVDs) and related predisposing statuses such as metabolic syndrome (MetS).The identification of genetic variants that influence the VEGF circulating levels and their associations with MetS and adhesion and inflammation molecules could enable us to have a comprehensive approach of the relationship of this molecule with CVDs. Therefore, we aimed at first to investigate the genetic background of VEGF levels, via a genome wide association analysis, and the pre-analytical and analytical variation factors of VEGF levels measurements before examining the implication of this molecule in inflammation and in MetS. Also, we examined the differences of MetS between Iranian (MASHHAD cohort) and French (STANISLAS cohort) populations. The main findings of this thesis are: 1) the identification of 4 genetic variants(rs6921438, rs4416670, rs6993770 and rs10738760) that explain 47.6% of circulating VEGF levels, 2) the associations of VEGF and its identified genetic variants with adhesion and inflammation molecules such as ICAM-1, E and L selectins , TNF-alpha, IL-6 and CRP at protein and transcription levels, 3) the association of VEGF-related polymorphism rs10738760 with MetS, 4) the relationship between VEGF regulatory variant, rs6921438, and LDL-C and HDL-C,5) the proposition of the best conditions for measuring both circulating VEGF (serum being the most stable anticoagulant) and its gene expression by reducing time between blood collection and centrifugation, and by avoiding multiple freeze-thaw cycles,6) a high prevalence of MetS in Iranian women. Our results propose the biological connections between VEGF, inflammation and adhesion molecules, lipids and MetS

Chez les patients présentant un syndrome métabolique, le développement des comorbidités cardiaques et rénales associées au diabète de type 2 sont liées à des altérations au niveau vasculaire. Afin d’évaluer l’effet protecteur rénal et cardiaque de nouvelles molécules, le modèle de rat Zucker fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1) semblait approprié. Cependant, son développement lent et les impacts rénaux et cardiaques modestes en limitaient son utilisation. Notre but fut d’exacerber ces altérations par deux méthodes. Nous avons d’abord effectué une néphrectomie unilatérale chez le rat ZSF1 et évalué l’évolution des fonctions cardiaque et rénale en fonction de l’âge. Seule une exacerbation de la dysfonction rénale a été mise en évidence. Néanmoins nous avons pu démontrer l’effet protecteur rénal de l’inhibiteur de l’enzyme de conversion de l’angiotensine lisinopril ainsi que d’un composé antioxydant, le bardoxolone. Notre seconde stratégie a consisté à infuser de l’angiotensine II (AngII) à des rats ZSF1. L’hypertension déjà existante dans ce modèle a été fortement accrue, et le niveau d’aldostérone circulante a été significativement augmenté. Dans ce contexte, les fonctions cardiaque et rénale ont été dégradées de manière importante. Enfin nous avons montré que dans ce modèle, un inhibiteur de l’aldostérone synthase induisait une meilleure protection rénale que l’antagoniste des récepteurs à l’aldostérone éplérénone. Nous avons donc mis en évidence que le rat ZSF1-AngII est un modèle de dysfonction cardio-rénale permettant d’évaluer l’effet protecteur de composés sur les fonctions rénale et cardiaque, dans un contexte de syndrome métabolique / In the context of metabolic syndrome, development of Type 2 Diabetes is associated with (and influenced by) cardiac and renal comorbidities linked to micro- and macro-vasculature alterations. To assess the efficacy of new compounds on targeted organs in the context of metabolic syndrome, the Zucker fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat model could be suitable assuming cardiorenal alterations would develop in a short timeframe. Actually, the ZSF1 rat model recapitulates features of human metabolic syndrome, but develops relatively late (1year-time) and moderate cardiac and renal dysfunctions. The aim of our work was to exacerbate cardiorenal impairments in terms of onset and extent. Two options were explored. On one hand, unilateral nephrectomy was performed in ZSF1 rats, and cardiac and renal functions were longitudinally assessed. This surgical insult only significantly deteriorated renal function, which was prevented by standard of care, lisinopril and new renal protective agent, bardoxolone. On the other hand, subcutaneous infusion of angiotensin II (AngII) was used in the aim to induce hemodynamic and hormonal stress and thus to enhance cardiorenal impairments. AngII-infused ZSF1 rats displayed significant hypertension and increased levels of circulating aldosterone. Moreover, renal and cardiac functions dropped, concomitantly. We showed in this model that an aldosterone synthase inhibitor induced overall better renal protection than the mineralocorticoid receptor antagonist eplerenone. Our data showed that ZSF1-AngII rat is a suitable model to evaluate the cardio and renoprotective effects of drugs in the context of metabolic syndrome

L’arthrose est une maladie dégénérative de l’articulation caractérisée par une dégradation du cartilage, une inflammation de la membrane synoviale et un remodelage de l’os sous-chondral. En conditions physiologiques, les chondrocytes, seul type cellulaire du cartilage, sont en hypoxie (≈ 2% d’oxygène). Le cartilage étant un tissu avascularisé, il existe un gradient de concentration en oxygène au sein des différentes couches du cartilage. Lors du développement de l’arthrose, la dégradation du cartilage provoque une rupture de ce gradient, exposant ainsi les cellules des couches profondes à des concentrations en oxygène beaucoup plus élevées et induisant des modifications de leur métabolisme, ce qui induit leur dysfonction. Le syndrome métabolique est défini par un ensemble de perturbations glucidiques, lipidiques et vasculaires menant au développement de maladies cardiovasculaires et au diabète de type 2. Récemment, un lien entre arthrose et syndrome métabolique a été suggéré, introduisant une notion d’arthrose métabolique. Au cours de cette étude, nous nous sommes intéressés au lien entre arthrose, syndrome métabolique et stress oxydant induit par de fortes concentrations de glucose. Dans la première partie de ce travail, nous avons étudié les effets in vitro de 25 mM de glucose sur une lignée de chondrocytes humains immortalisés (T/C28a2), en hypoxie (2% d’oxygène) et en normoxie (21% d’oxygène). Nous avons montré que le glucose à 25 mM induisait la production d’espèces réactives de l’oxygène (ERO) et de l’azote, l’activation de la caspase 3, la production d’interleukine 6 (IL-6), la diminution de l’activité lysyl oxydase (LOX), qui est impliquée dans les liaisons de pontage des fibres de collagène et d’élastine, ainsi que l’activation du système thiorédoxine (Trx). Ce dernier est un système de défense anti-oxydant endogène composé de la thiorédoxine, de la thiorédoxine réductase (TR) et de Txnip, qui intervient dans le maintien de l’homéostasie cellulaire en réduisant les protéines oxydées, contrôlant ainsi l’environnement redox des cellules. Les effets du glucose 25 mM ont été observés dans les deux conditions d’oxygène étudiées, cependant la réponse cellulaire en normoxie était plus précoce qu’en hypoxie. Nous avons également pu mettre en évidence un rôle de régulateur négatif de la Trx-1 sur la production d’IL-6 faisant intervenir la voie de signalisation p38MAPK. Dans la deuxième partie de ce travail, nous nous sommes intéressés aux effets de l’apport exogène de resvératrol sur les modifications induites par le glucose à 25 mM. Le resvératrol (3,4’,5-trihydroxystilbène) est un polyphénol de la famille des stilbènes, connu pour ses multiples propriétés anti-oxydantes, anti-inflammatoires, anti-diabétiques et anti-cancer. Nous avons pu observer que le resvératrol à 25 μM était capable de diminuer les effets délétères provoqués par le glucose à 25 mM. Cependant, la biodisponibilité du resvératrol est très limitée, empêchant son utilisation en thérapeutique humaine. Par conséquent, dans la troisième partie de cette étude, nous nous sommes intéressés au développement de nouvelles formulations galéniques de resvératrol (nano-émulsions (NE)) et à leurs effets sur un modèle de cellules endothéliales aortiques bovines (BAEC), sur les T/C28a2 ainsi que sur des chondrocytes humains en culture primaire provenant de cartilage de patients arthrosiques. Nous avons montré qu’une des NE permettait d’augmenter le passage intracellulaire de resvératrol dans les deux modèles étudiés et d’en potentialiser les effets protecteurs contre un stress oxydant. Cette NE s’est également montrée efficace dans le rétablissement de l’activité LOX dans les cellules de patients arthrosiques. En conclusion, nous avons montré que le glucose à 25 mM avait des effets délétères sur les chondrocytes de la lignée T/C28a2 et que l’apport exogène de resvératrol permettait de lutter contre ses effets. (...) / Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, inflammation of synovial membrane and subchondral bone remodelling. Under physiological conditions, chondrocytes - the only cell type found in cartilage - are under hypoxia (around 2% of oxygen). As cartilage is an avascular tissue, an oxygen gradient is established from the superficial to the deeper layers. During OA development, cartilage degradation is responsible for a break in this gradient; consequently, cells from the deepest layers are exposed to higher oxygen concentrations inducing modifications in cell metabolism leading to their dysfunction. Metabolic syndrome (MetS) is defined by a cluster of factors (impairment of glucose and lipid metabolism, vascular dysfunctions…) leading to cardiovascular diseases and type 2 diabetes development. Recently, a link between OA and MetS has been suggested, introducing a notion of metabolic OA. We have focused our study on the link between OA, MetS and oxidative stress induced by high glucose concentrations. In the first part of this study, we have determined the in vitro effects of 25 mM glucose on an immortalized human chondrocyte cell line (T/C28a2), under hypoxia (2% oxygen) and normoxia (21% oxygen). We demonstrated that 25 mM glucose induced radical oxygen species (ROS) and nitric oxide production, caspase 3 activation, interleukin 6 (IL-6) production, decrease in lysyl oxidase (LOX) activity (involved in type II collagen crosslinks), and activation of the thioredoxin (Trx) system. Trx system is an endogenous anti-oxidant system, composed by thioredoxin, thioredoxin reductase (TR) and Txnip; it is involved in cellular homeostasis by reducing oxidized proteins, thereby controlling cellular redox environment. Effects of 25 mM glucose have been observed under both oxygen conditions; nevertheless, cellular response under normoxia underwent earlier than under hypoxia. We have also highlighted Trx-1 as a negative regulator of IL-6 production through p38MAPK signalling pathway. In the second part of this study, we have focused our work on the effects of the addition of an exogenous antioxidant, i.e. resveratrol, on the modifications induced by 25 mM glucose. Indeed, resveratrol (3,4’,5-trihydroxystilbene) is a polyphenol of the stilbene family, known for its multiple anti-inflammatory, anti-oxidative, anti-diabetes and anti-cancer properties. We have observed that 25 μM resveratrol was able to decrease deleterious effects induced by 25 mM glucose. However, resveratrol bioavailability is very low, avoiding its use in human therapeutic strategy. Consequently, in the third part of this study, we have developed new galenic formulations of resveratrol, i.e. nano-emulsions (NEs) and determined their effects on a bovine aortic endothelial cells (BAEC) model, on T/C28a2 cells and also on primary cultures of human chondrocytes from osteoarthritic cartilages. One of our NEs was able to increase resveratrol intracellular passage in both cellular models, and to increase the protective effects of resveratrol against oxidative stress. This NE was also efficient in the normalization of LOX activity in osteoarthritic chondrocytes. To conclude, we have demonstrated that 25 mM glucose induced deleterious effects on chondrocytes of the T/C28a2 cell line, and that an exogenous supply in resveratrol allowed to counteract these effects. Development of a new galenic formulation of resveratrol opens new interesting prospects in human therapeutic strategy against OA associated with MetS.

Introdução: Atualmente o estudo da vitamina D é motivo de especial atenção pelos profissionais da área da saúde, não só pelos já consagrados benefícios à saúde óssea, mas também por inúmeros outros, como a melhora da função cognitiva, imunológica, depressão e até redução no risco de doenças cardiovasculares e câncer. Ademais, com o aumento da longevidade, a hipovitaminose D - de alta prevalência em idosos e mulheres após a menopausa - ganha importância na saúde pública. Diante deste cenário, torna-se necessário a realização de estudos que avaliem a prevalência de hipovitaminose D e os fatores a ela associados. Objetivo: estimar, em mulheres acima de 35 anos residentes em Pindamonhangaba, SP, as concentrações séricas de 25 hidroxivitamina D e segmentar as prevalências em dois valores: acima de 20 e acima de 30 ng/mL; identificar os possíveis fatores associados a esses dois limites propostos. Método: Em amostragem aleatória estratificada foram selecionadas 1200 mulheres de 35 a 74 anos, cadastradas no Programa de Saúde da Família da cidade de Pindamonhangaba; em 681 delas foram realizadas coletas sanguíneas para determinação da vitamina D. A variável dependente estudada foi a concentração sérica de 25(OH)D e, as independentes foram pressão arterial, circunferência abdominal e IMC depressão, ansiedade, estresse, insônia, hábito de tonar sol e suplementação de vitamina D referidos, além da determinação das concentrações séricas de cortisol, glicose, colesterol total/frações e triglicerídeos. Resultados: Da população estudada, 73,4% tinham concentrações de 25(OH)D >=20ng/mL e 34,8%, >=30ng/mL. O uso suplementos de vitamina D e o habito de tomar sol associaram-se positivamente às concentrações séricas de 25(OH)D >=30ng/mL (OR=1,58, IC95%: 1,08-2,33 e OR=1,28, IC95%: 1,03-1,58, respectivamente), mas apenas o uso de suplementos de vitamina D mostrou associação com as medidas >=20ng/mL (OR=1,20, IC95%: 1,02-1,40). Ter depressão leve associou-se positivamente a 25(OH)D >=30ng/mL (OR=1,41, IC95%: 1,12-1,79), mas nenhuma associação foi notada com medidas >=20ng/mL. As medidas de 25(OH)D >=30 e 20ng/mL associaram-se negativamente às medidas séricas de glicose >=100 mg/dL (OR=0,72, IC95% 0,58- 0,90 e OR=0,90, IC95% 0,82-0,99, respectivamente). As medidas séricas de HDL <=50mg/dL e triglicérides >=150mg/dL associaram-se negativamente às medidas de 25(OH)D >=30ng/mL (OR=0,79, IC95% 0,63-0,99 e OR=0,77, IC95% 0,62-0,97, respectivamente). Houve associação negativa entre as medidas >=30ng/mL e o diagnóstico de síndrome metabólica, tanto pelo ATPIII (OR 0,72, IC95%: 0,58-0,90) quanto pelo IDF (OR=0,73, IC95%: 0,60-0,91), mas nenhuma associação com as medidas >=20ng/mL. Conclusão: A hipovitaminose D é altamente prevalente na população de mulheres acima de 35 anos de idade. As medidas séricas >=20ng/mL associaram-se negativamente a glicemia >=100mg/dL. As medidas >=30mg/dL associaram-se negativamente a glicemia >=100mg/dL, triglicérides >=150mg/dL, HDL <= 50mg/dL e diagnostico de síndrome metabólica e, positivamente à depressão. / Introduction: Currently the study of vitamin D is a special concern of the health professionals, not only for the already established benefits to bone health, but also for innumerable others, such as the improvement of cognitive, immunological function, depression and even reduction in the risk of cardiovascular diseases and cancer. Moreover, with increasing longevity, vitamin D deficiency - highly prevalent in the elderly and postmenopausal women - gains importance in public health. In view of the aforementioned reasons, it is necessary to conduct studies that evaluate the prevalence of hypovitaminosis D and its associated factors. Objective: to estimate the prevalence of having 25hidroxivitamino D over 20 and 30 ng/mL and identify its associated factors in climacteric women resident in Pindamonhangaba, SP, Brazil. Method: In randomized stratified sampling, 1,200 women aged 35-74 years enrolled in the Pindamonhangaba\'s Family Health Program were selected; in 681 of them, blood samples were taken for clinical analysis. The dependent variable studied was the serum concentration of 25(OH)D and the independent variables were blood pressure, waist circumference and BMI depression, anxiety, stress, insomnia, sunbathing and vitamin D supplementation, as well as determination of serum cortisol, glucose, total cholesterol and fractions and triglycerides levels. Results: Of the study population, 73.4% had 25(OH)D >=20ng/mL and 34.8% >=30ng/ml. Vitamin D supplements use and sunbathing were both positively associated with 25(OH)D >= 30ng/mL (OR=1.58; 95%CI:1.08-2.33 and OR =1.28; 95%CI:1.03-1.58, respectively), but only in the use of vitamin D supplements the association with 25(OH)D >=20ng/ml was found (OR=1.20, 95%CI: 1.02- 1.40). Mild depression was positively associated with 25(OH)D >=30ng/mL (OR=1.41, 95%CI: 1.12-1.79), but no association was noted with measurements >=20ng/mL. Both 25(OH)D >=30 and >=20ng/mL were negatively associated with blood glucose >=100mg/dL (OR=0.72, 95%CI 0.58-0.90 and OR=0.90, 95%CI 0.82-0.99, respectively). Serum HDL <= 50mg/dL and triglycerides >=150mg/dL were negatively associated with 25(OH)D >=30ng/mL (OR=0.79, 95%CI 0.63-0.99 and OR=0.77, 95%CI 0.62-0.97, respectively). A negative association was present between 25(OH)D >=30 ng/mL and metabolic syndrome by ATPIII (OR= 0.72, 95%CI: 0.58-0.90) and IDF criteria (OR=0.73, 95%CI: 0.60-0.91), but there was no association with 25(OH)D >=20ng/mL. Conclusion: Hypovitaminosis D is highly prevalent in study population. Serum 25(OH)D >=20mg/dL was negatively associated with glycemia >=100mg/dL, and the 30mg/dL limit was negatively associated with glycemia >=100mg/dL, triglycerides >=150mg/dL, HDL <=50mg/dL and metabolic syndrome and positively associated to depression. Serum measurements >=20ng/mL were not significantly associated with the investigated factors.

O desenvolvimento de síndrome metabólica como decorrência do uso de psicofármacos vem recebendo grande atenção da literatura nos últimos anos. O uso de antipsicóticos atípicos foi fortemente associado a ganho de peso, desenvolvimento de diabetes tipo 2 e aumento da mortalidade em pacientes esquizofrênicos. Já o uso de antidepressivos, embora associado a alterações de peso, não foi suficientemente estudado quanto ao risco de desenvolvimento de síndrome metabólica. Este estudo objetivou investigar alterações do peso corporal e de parâmetros relacionados à síndrome metabólica em pacientes com transtorno de pânico tratados com clomipramina, fluoxetina ou placebo. Foi realizado um estudo randomizado, duplo-cego e controlado com 83 pacientes seguidos ao longo de 24 semanas. Foram obtidas medidas de peso, relação cintura-quadril, glicemia, e níveis séricos de colesterol total, HDL e LDL colesteróis e triglicérides. Os resultados deste estudo permitiram concluir que, no tratamento do transtorno de pânico, não foram observadas alterações significativas de peso ou dos parâmetros bioquímicos associados à síndrome metabólica / The development of metabolic syndrome as a result of psychopharmacological treatment has been a highlight in medical literature on recent years. Atypical antipsychotics have been strongly associated with weight gain, type 2 diabetes and elevated mortality rates in schizophrenic patients. Although related to weight gain, antidepressants have not been as well studied concerning the risk of metabolic syndrome development. The objective of this study was to investigate changes in weight and in parameters associated with the metabolic syndrome in patients with panic disorder treated with clomipramine, fluoxetine or placebo. We conducted a randomized, double-blind, controlled study with 83 patients during 24 weeks. Measures were obtained for weight, waist-hip rate, glicemia and serum levels of total, HDL and LDL cholesterols, and triglycerides. The results of this study allowed the conclusion that, in the treatment of panic disorder, changes on weight or on the biochemical parameters related to metabolic syndrome were not significant

Submitted by Ricardo Cedraz Duque Moliterno (ricardo.moliterno@uefs.br) on 2016-10-18T22:30:52Z No. of bitstreams: 1 DISSERTA??O TACIANE.pdf: 1332823 bytes, checksum: 16624f495ae47a3674ddd9369197c8bf (MD5) / Made available in DSpace on 2016-10-18T22:30:52Z (GMT). No. of bitstreams: 1 DISSERTA??O TACIANE.pdf: 1332823 bytes, checksum: 16624f495ae47a3674ddd9369197c8bf (MD5) Previous issue date: 2015-03-31 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Metabolic syndrome is a set of changes consisting of dyslipidemia, glucose intolerance, hypertension, obesity and hyperinsulinemia. The study of this syndrome is of great importance to public health, since it can lead to negative outcomes that could increase their risk of cardiovascular disease in the general population. OBJECTIVE: Investigate the occurrence of metabolic syndrome and associated factors in adults treated in public health services in the city of Feira de Santana - BA. METHOD: epidemiological study, cross-sectional and exploratory conducted in 479 adults aged at least 20 years, seen at public health services in the fair city of Santana - BA. Information was obtained through structured questionnaires, anthropometric clinical and oral, and biochemists. The diagnosis of metabolic syndrome took into account the criteria proposed by the National Cholesterol Education Program - Adult Treatment Panel III / (NCEP-ATP III) and the International Diabetes Federation (IDF). Prevalence ratios were estimated (PR) and their respective confidence intervals of 95% (95% CI) and statistical significance level of 5%. Multivariate analysis was constructed using Poisson regression. RESULTS: Presented in the form of a scientific paper: "Metabolic syndrome and its associated factors in adults", to be submitted to the Journal Brazilian Archives of Endocrinology and Metabolism. The occurrence of MS ranged from 57% (NCEP / ATP III) to 62% (IDF). In the bivariate analysis female, advanced age, overweight, and some comorbidities proved to be independently associated with MS. In the hierarchic analysis, only BMI ? 30 kg / m? (NCEP-ATPIII) and no measurement of blood pressure periodically (IDF) remained independently associated with metabolic syndrome. CONCLUSIONS: The metabolic syndrome is a public health problem among individuals in this study. The body mass index ? 30 kg / m2 not regular blood pressure measurements are important predictors of the metabolic syndrome in adults. / A S?ndrome Metab?lica ? um conjunto de altera??es constitu?do por dislipidemia, intoler?ncia ? glicose, hipertens?o arterial, obesidade e a hiperinsulinemia. O estudo desta s?ndrome ? de grande relev?ncia para a sa?de p?blica, uma vez que pode ocasionar desfechos negativos capazes de aumentar o risco de doen?as cardiovasculares na popula??o em geral. OBJETIVO: Investigar a ocorr?ncia de S?ndrome Metab?lica e seus fatores associados em indiv?duos adultos atendidos em servi?os de sa?de p?blica no Munic?pio de Feira de Santana ? BA.M?TODO: Estudo epidemiol?gico, transversal, e de car?ter explorat?rio realizado em 479 adultos com idade m?nima de 20 anos, atendidos em servi?os de sa?de p?blica no munic?pio de Feira de Santana ? BA. As informa??es foram obtidas mediante aplica??o de question?rios estruturados, exames cl?nicos antropom?tricos e bucais, e bioqu?micos. O diagn?stico da s?ndrome metab?lica levou em considera??o os crit?rios propostos pelo National Cholesterol Education Program - Adult Treatment Panel III / (NCEP-ATP III) e pela Internacional Diabetes Federation (IDF). Foram estimadas raz?o de preval?ncia (RP) e seus respectivos intervalos de confian?a de 95% (IC 95%) e n?vel de signific?ncia estat?stica de 5%. A an?lise multivariada foi constru?da usando a regress?o de Poisson. RESULTADOS:Apresentados em forma de artigo cient?fico: ?S?ndrome metab?lica e seus fatores associados em indiv?duos adultos?, a ser submetido ? Revista Arquivos Brasileiros de Endocrinologia e Metabologia. A ocorr?ncia da SM variou entre 57% (NCEP/ATP III) a62% (IDF). Na an?lise bivariada, sexo feminino, faixa et?ria avan?ada, excesso de peso, e algumas comorbidades mostraram-se independentemente associados com SM. Na an?lise hierarquizada, apenas ?ndice de massa corporal ? 30kg/m? (NCEP-ATPIII) e n?o aferi??o da press?o arterial periodicamente (IDF)permaneceram independentemente associados ? s?ndrome metab?lica.CONCLUS?ES: A s?ndrome metab?lica representa um problema de Sa?de P?blica entre os indiv?duos desse estudo. O ?ndice de massa corporal ? 30kg/m2 a n?o aferi??o regular da press?o arterial s?o potenciais preditores da s?ndrome metab?lica em adultos.

Submitted by Ricardo Cedraz Duque Moliterno (ricardo.moliterno@uefs.br) on 2017-11-27T20:53:26Z No. of bitstreams: 1 edilenemqa-tese.pdf: 4986958 bytes, checksum: 98721b3ed915b46fe60ca445665ea3ca (MD5) / Made available in DSpace on 2017-11-27T20:53:26Z (GMT). No. of bitstreams: 1 edilenemqa-tese.pdf: 4986958 bytes, checksum: 98721b3ed915b46fe60ca445665ea3ca (MD5) Previous issue date: 2016-09-26 / Metabolic syndrome (MS) is a complex disorder with a strong genetic basis and multifactorial etiology. Insulin resistance (IR) causes MS and it can be triggered by intestinal inflammation like the use of lactose in patients intolerant of this carbohydrate. It was found that variants in the lactase gene are associated with lactase non persistence LNP and MS in a population sample of Salvador/Bahia; and whether these variants are modifying the response to diet-therapeutic intervention in patients with this syndrome; also compared the biochemical test of lactose tolerance (LTT) with genetic diagnosis; and tested the association of mutations in the lactase gene with cofactors SM (TGL, HDL-C, blood pressure, glucose levels, waist circumference), with anthropometric variables (Arm Circumference, Body Mass Index, Hip Circumference, hip-waist ratio,lean massand fat mass percentages) and other factors associated with MS: insulin, total cholesterol, LDL-C, VLDL-C, C-reactive protein, HOMA-IR, renal function (creatinine, urea, uric acid, microalbuminuria) and vitamin D. There were two studies: a case-control with 257 cases (MS) and 210 controls and other clinical trial study, which was conducted with three types of diet in patients with metabolic syndrome: diet 1 - No lactose; Diet 2 - Lactose and energy restriction; Diet 3 - Only energy restriction. In all groups were also evaluated for nine SNPs in the lactase (LCT) gene. The genotyping of SNPs was carried out by TaqMan assays. Data were analyzed using SPSS, 20.0, and the Hardy-Weinberg Equilibriumhaplotype frequencies were calculated using Arlequin, 2000 program. The results showed that all diets improve several MSaspects after two months of intervention, especially in the diet 1, that also decreased inflammation, insulin resistance and dyslipidemia (LDL-C). In addition,it was the diet that most took out patients of the MS: 2.72 times more likely to get out of MS than diet 3. LNP was high in both cases and controls. There was compatibility between clinical diagnosis for LNP by Lactose Tolerance Test and two of the studied SNPs, they were rs4988253 and rs182549, those that have proved functional studies. Thus, it is suggested the analysis of LCT gene polymorphisms before the nutritional therapeutics for patients with MS, as well as to take out the lactose in their diet. / A S?ndrome Metab?lica (SM) ? uma desordem complexa, de forte base gen?tica e de etiologia multifatorial. Dentre as suas causas, encontra-se a Resist?ncia ? Insulina (RI) que pode ser desencadeada pela inflama??o intestinal, pelo uso de lactose em pacientes intolerantes a este carboidrato. Verificou-se quais variantes no gene da lactase est?o associados ? IL e SM em amostra da popula??o de Salvador/Bahia; e tamb?m se estas variantes s?o modificadoras da resposta ? interven??o dietoter?pica em portadores desta s?ndrome; comparou-se tamb?m o teste bioqu?mico de toler?ncia ? lactose (TTL) com o diagn?stico gen?tico; e testou-se a associa??o das muta??es no gene da lactase com os cofatores da SM (TGL, HDL-c, press?o arterial, glicemia, circunfer?ncia da cintura), com vari?veis antropom?tricas (circunfer?ncia do bra?o, ?ndice de massa corporal, circunfer?ncia do quadril, raz?o cintura quadril, percentual de massa magra e massa gorda) e com outros fatores associados ? SM: insulina, colesterol total, LDL-C, VLDL, Prote?na C reativa, HOMA-IR, fun??o renal (creatinina, ur?ia, ?cido ?rico, microalbumin?ria) e vitamina D. Foram realizados dois estudos: um caso-controle com 257 casos (SM) e 210 controles e outro estudo de tipo ensaio cl?nico, que foi realizado com tr?s tipos de dieta com os pacientes com SM: dieta 1 ? sem lactose; dieta 2 ? sem lactose e com restri??o energ?tica; Dieta 3 ? apenas restri??o energ?tica. Em ambos os grupos tamb?m foram avaliados 9 SNPs no gene da lactase. A genotipagem dos SNPs foi realizada pela tecnologia de ensaios TaqMan. Os dados foram analisados pelo programa SPSS ver 20.0 e a adequa??o das frequ?ncias genot?picas ao Equilibrio de Hardy-Weinberg e c?lculo da frequ?ncia dos hapl?tipos formados pelos polimorfismos foram obtidos atrav?s do programa Arlequin ver 2000. Os resultados mostraram que todas as dietas melhoram o quadro da SM ap?s dois meses de interven??o, com destaque para a dieta 1, que tamb?m diminuiu a inflama??o, resist?ncia ? insulina e a dislipidemia (LDL-C). Al?m disso foi a dieta que mais tirou paciente da SM: apresentou 2,72 vezes mais chances de sair da SM que a dieta 3. A intoler?ncia ? lactose foi alta tanto em casos como em controles. Houve compatibilidade do TTL com os SNPsrs4988253 e rs182549, os ?nicos que possuem estudos funcionais. Assim, sugere-se an?lise de polimorfismos do gene da lactase antes da prescri??o nutricional para pacientes com SM, bem como, a retirada da lactose da dieta.