OBJECTIVE: Cardiovascular disease (CVD) remains the leading cause of death globally. Reducing high blood cholesterol, which is a dominant risk factor for CVD events, is an essential goal of medical treatment. Statins are known as first‐choice agents. However, clinical trials report that some statins increased the risk for type 2 diabetes (T2D). Our objective was to investigate the effect of different statins on insulin secretion and content from pancreatic β-cells after chronic and acute exposure and determine the underlying mechanisms. METHODS: The effects of simvastatin, lovastatin and pitavastatin on GSIS and content were studied in clonal pancreatic β-cells (INS-1 832/13) cultured in high glucose (12 mM). Insulin content and secretion were measured after chronic and acute incubation of statins using homogenous time-resolved fluorescence (HTRF) insulin assay kit (Cisbio). Intracellular Ca2+ was measured using fura-2 AM (Invitrogen). RESULTS: Simvastatin (25-200 nM) and lovastatin (50-200 nM) significantly inhibited GSIS and depleted insulin content in a dose-dependent manner after 72-hour exposure. When the secretion level was normalized for content, the inhibitory effect was not observed. Simvastatin (200 nM) also increased the amplitude of intracellular Ca2+ oscillations at low glucose, but this was not reflected in the amplitude of oscillatory insulin release. In contrast, pitavastatin (25-200 nM) did not affect GSIS and only decreased insulin content at the highest dose tested. CONCLUSION: Inhibition of GSIS by simvastatin and lovastatin could be due to depletion of insulin content. Decreased Ca2+ sensitivity may also contribute to inhibition of GSIS by simvastatin. Pitavastatin had less inhibitory effect on GSIS and insulin content as compared to simvastatin and lovastatin indicating that not all lipophilic statins have a detrimental impact on GSIS. We suggest that statins may have differential mechanistic effects on β-cells some of which may contribute to the risk of T2D.

Objetivo: Avaliar a influência da terapia com tibolona no metabolismo dos carboidratos e lipídeos de pacientes na pós-menopausa portadoras de diabetes mellitus tipo 2. Método: estudo prospectivo, longitudinal, aberto e controlado envolvendo 24 mulheres na pós-menopausa portadoras de diabetes mellitus tipo 2, com média de idade de 57,5 ± 4,8 anos, tratadas seqüencialmente com placebo (6 meses) e tibolona-2,5 mg/dia (6 meses). Parâmetros clínicos, antropométricos, bioquímicos, hormonais e ultra-sonográficos foram avaliados no período basal, após 6 (tempo 1) e 12 meses de acompanhamento (tempo 2). Análise estatística foi realizada utilizando-se ANOVA para medidas repetidas, com nível de significância 5%. Resultados: com os 6 meses de uso da tibolona, evidenciamos reduções significativas nos sintomas climatéricos avaliados através do índice de Blatt-Kuperman, assim como no percentual de gordura corporal, circunferência abdominal, pressão arterial diastólica, e níveis séricos de transaminases, triglicerídeos e HDL-colesterol. Não houve variações significativas nos níveis de glicose e insulina de jejum, hemoglobinaglicada, área sobre a curva da glicose, área sobre a curva da insulina, índice QUICKI, colesterol total e LDL-colesterol. A avaliação ultra-sonográfica não revelou variações significativas do volume uterino e espessura endometrial. Efeitos colaterais surgiram apenas durante o primeiro mês de uso da tibolona (cefaléia e mastalgia em 8,3% e sangramento genital em 16,6%). Conclusão: o tratamento com tibolona em curto prazo mostrou-se uma alternativa viável para pacientes na pós-menopausa portadoras de diabetes mellitustipo 2. / Objective: to determine the effects of tibolone on the glycemic and lipid metabolism in postmenopausal women with Type 2 diabetes mellitus. Method: a prospective, longitudinal, open and controlledstudy involving 24 postmenopausal women with Type 2 diabetes mellitussequentially treated with placebo (6 months) and 2.5 mg/day tibolone (6 months). Clinical evaluation, anthropometric parameters, biochemical and hormonal measurements, and transvaginal ultrasonography were performed at baseline and after 6 (time 1) and 12 months of follow-up (time 2). Statistical analysis was performed by repeatedmeasures analysis of variance, with the level of significance set at 5 %. Results: After 6 months the tibolone use, we observed significant reductions in the climacteric symptoms evaluated by the Blatt-Kupperman index, % body fat, abdominal circumference, diastolic arterial pressure, and in the serum levels of aminotransferases, triglycerides and HDL-cholesterol. There were no significant variations in fasting glucose and insulin levels, glycosylated hemoglobin, glucose-area under the curve (AUC), insulin-AUC, quantitative insulin sensitivity check index (QUICKI), total cholesterol and LDL-cholesterol levels. Ultrasonographic evaluation showed no significant changes in uterine volume or endometrial thickness. Side effects were present only during first months of tibolone use (headache and mastalgia in 8.3% and genital bleeding in 16.6%). Conclusion: The short-term treatment with tibolone showed to be a good alternative for postmenopausal women with Type 2 diabetes mellitus.

Thesis advisor: Thanh V. Tran / Diabetes management is a major part of treatment but many ethnic/racial minorities with type 2 diabetes do not make the needed adjustment. A key component of healthcare access is health acculturation, defined as a level of success in navigating the mainstream healthcare system. The overall goal of this study is to develop a measure of health acculturation and examine its relationship with diabetes management across several ethnic minority groups in the US. The first purpose is to investigate the relationship between health acculturation and type 2 diabetes management behaviors in a sample of foreign-born Vietnamese, Chinese, Korean and Latino adults. The second purpose is to assess ethnic differences by testing the interaction between health acculturation and ethnicity on diabetes management behaviors. Merged dataset from CHIS 2009 and 2011-2 were used for analysis. Multiple and logistic regression analysis revealed that those with high health acculturation skills performed more diabetes management than their counterparts. Latinos performed better than all Asian subgroups on most diabetes management behaviors regardless of the level of health acculturation. The study has implications for social workers and healthcare providers working with ethnic and minority populations. The results suggest that the health acculturation measure would be a good screening tool to identify immigrant populations who will most benefit from health intervention within the culture of western medicine. In addition, the results help to identify specific skills and tools needed by social workers and healthcare providers to better serve these populations. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Social Work. / Discipline: Social Work.

O objetivo do presente estudo foi avaliar o papel do treinamento físico aeróbio, resistido ou combinado (aeróbio+resistido) no desenvolvimento do diabetes tipo 2 analisando mecanismos associados às complicações no diabetes em camundongos fêmeas com deficiência na produção leptina (ob/ob). Para tanto, foram utilizadas camundongos fêmeas, inicialmente com 4 semanas de idade, divididas em 6 grupos: ob/ob sedentárias com 4 semanas de vida (OS-4), selvagens sedentárias (SS) ou ob/ob sedentárias (OS-12) acompanhadas até a 12ª semana de vida, ob/ob treinamento aeróbio (OA), ob/ob treinamento resistido (OR) e ob/ob treinamento combinado (OC). Os grupos treinados foram submetidos a 8 semanas de treinamento físico dinâmico aeróbio em esteira (50 a 60% da velocidade máxima do teste de esforço) ou resistido em escada (4060% da carga máxima) ou a associação dos dois treinos (combinado). Foram avaliados: peso corporal; glicose, triglicérides e colesterol total sanguíneos; pressão arterial (PA) e frequência cardíaca (FC); sensibilidade barorreflexa (SBR); modulação autonômica cardiovascular; marcadores inflamatórios e hormonais; e parâmetros de estresse oxidativo. Os animais obesos (OS-12) apresentaram aumento de peso corporal, tecido adiposo, de glicemia, de triglicérides e de intolerância à glicose quando comparado aos animais selvagens (SS). Adicionalmente, o grupo OS-12 apresentou piores resultados nos testes aeróbio e de força. Não observamos diferenças entre os grupos SS e OS-12 em relação a PA e FC, porém o grupo OS-12 apresentou diminuição da variabilidade da frequência cardíaca (VFC) (33 ± 4ms2) e da sensibilidade barorreflexa em relação ao grupo SS (VFC: 178 ± 19 ms2). O grupo OS-12 apresentou aumento de angiotensina 2 nos tecidos renal e cardíaco, diminuição da adiponectina e aumento de citocinas inflamatórias no tecido adiposo e no baço em relação ao grupo SS. Somado a isso, os animais obesos apresentam maior dano a proteínas e lipoperoxidação e diminuição das enzimas antioxidantes em tecido renal e cardíaco em relação ao grupo SS. A comparação entre os grupos OS-4 e OS-12 evidenciou aumento de peso corporal, tecido adiposo, glicemia, intolerância à glicose e de parâmetros de estresse oxidativo no grupo OS-12 em relação ao grupo OS-4. A redução na VFC e na SBR foi observada no grupo OS-4 e no grupo OS-12. O treinamento físico por sua vez, diminuiu o ganho de peso e reduziu a glicemia e a intolerância à glicose nos três grupos treinados em comparação ao grupo OS-12. O treinamento físico aeróbio (61 ± 8ms2 e 6 ± 4 mmHg2) e resistido (66 ± 16ms2 e 6 ± 1,4mmHg2) foram eficientes em aumentar a VFC e diminuir a banda de baixa frequência da PA (simpático vascular) em relação ao grupo OS-12, porém o grupo OC (43 ± 7ms2 e 8 ± 0,9mmHg2) foi semelhante ao grupo OS-12 (10 ± 1,1mmHg2) e aos grupos OA e OR. Além disso, as três modalidades melhoraram a SBR. Os três tipos de treinamento reduziram os níveis de angiotensina 2 e aumentaram os níveis de angiotensina 1-7 em tecido adiposo, rim e coração. O treinamento físico aeróbio foi mais eficiente em melhorar o perfil inflamatório em tecido adiposo e no baço, uma vez que os grupos OA e OC apresentaram aumento de adiponectina e apenas o grupo OC apresentou diminuição de IL-6 e PAI-1 em relação ao grupo OS-12. Em relação ao estresse oxidativo, os três grupos treinados apresentaram diminuição de marcadores de lesão. Concluindo, nossos achados confirmam o desenvolvimento de disfunção metabólica ao longo da vida de camundongos ob/ob. É interessante notar que com 4 semanas de vida camundongos ob/ob apresentaram uma expressiva redução dos parâmetros da VFC. Este desbalanço autonômico, poderiam estar ocorrendo não só no coração, mas para outros tecidos, como o baço e o tecido adiposo, favorecendo a liberação de citocinas inflamatórias que poderiam induzir a longo prazo lesão de órgão alvo, como observado no presente estudo em coração e rins, por aumento de estresse oxidativo. Os grupos treinados, independente da modalidade, apresentaram melhora metabólica e na regulação autonômica cardiovascular, a qual foi acompanhada de alterações favoráveis no sistema renina-angiotensina, em mediadores inflamatórios e no perfil de estresse oxidativo. Neste sentido, acreditamos que a atenuação da disfunção autonômica (precocemente observada neste modelo de DM) pelo treinamento físico, independente do tipo, possa induzir alterações favoráveis (e dependentes do tipo de treino) no sistema renina angiotensina e em mediadores inflamatórios, reduzindo o estresse oxidativo em tecidos importantes para a regulação cardiovascular / The aim of this study was to evaluate the role of aerobic, resistance or combined (aerobic + resistance) exercise training in the development of type 2 diabetes, analyzing mechanisms associated with diabetes complications in female mice with deficiency in leptin production (ob/ob). Female mice, initially with 4 weeks of age, were divided into 6 groups: ob/ob sedentary with 4 weeks of life (OS-4), sedentary wild type (SS) or ob/ob sedentary (OS-12) followed until 12 week life, ob/ob+aerobic training (OA), ob/ob+resistance training (OR) and ob/ob+combined training (OC). The trained groups were submitted to eight weeks of dynamic aerobic exercise training on a treadmill (50-60% of maximum stress test speed) or resistance exercise on a ladder (40-60% of the maximum load) or an association of these two trainings (combined). Body weight; glucose, triglycerides, and total blood cholesterol; blood pressure (BP) and heart rate (HR); baroreflex sensitivity (BRS); cardiovascular autonomic modulation; inflammatory and hormonal markers; and oxidative stress parameters were evaluated. Obese animals (OS-12) showed increased body and fat weight, blood glucose, triglyceride and glucose intolerance when compared to wild type animals (SS). Additionally, OS-12 group showed decreased capacity in aerobic and strength exercise tests. We did not observe differences between the SS and the OS-12 groups regarding BP and HR, however the OS-12 group showed reduced heart rate variability (HRV) (33 ± 4ms2) and baroreflex sensitivity when compared to the SS group (178 ± 19 ms2). The OS-12 group showed increased angiotensin 2 in kidney and heart tissues, decreased adiponectin and increased inflammatory cytokines in adipose tissue and in the spleen in relation to the SS group. Moreover, obese animals presented increased protein oxidation and lipid peroxidation and decreased antioxidant enzymes in kidney and heart tissues when compared to SS group. The comparison between the OS-4 and the OS-12 groups showed increased body and fat weight, blood glucose, glucose intolerance and oxidative stress in OS-12 compared to OS-4 group. The decrease in HRV and in BRS were observed in OS-4 and OS-12 groups. On the other hand, exercise training decreased weight gain and reduced blood glucose and glucose intolerance in all three trained groups compared to OS-12 group. Aerobic (61 ± 8ms2 and 6 ± 4 mmHg2) and resistance exercise training (66 ± 16ms2 and 6 ± 1.4mmHg2) were efficient in increasing the HRV and decrease the low frequency band of BP (vascular sympathetic modulation) as compared to OS-12 group; however OC group (43 ± 7ms2 and 8 ± 0.9mmHg2) was similar to OS-12 group (10±1.1mmHg2) and to OA and OR groups. In addition, the three types of exercsie training improved BRS. The three types of training reduced levels of angiotensin 2 and increased levels of angiotensin 1-7 in adipose tissue, kidney and heart. The aerobic exercise was more efficient in improving inflammatory profile in adipose tissue and spleen, since OA and OC groups showed an increase in adiponectin and only the OC group showed a decrease in IL-6 and PAI-1 in relation to the group OS-12. Regarding oxidative stress, the three trained groups showed a decrease in damage markers. In conclusion, our findings support the development of metabolic dysfunction during lifespan in ob/ob mice. Interestingly, 4 weeks old ob/ob mice showed a significant reduction in HRV parameters. This autonomic imbalance could be occurring not only in the heart, but in other tissues, such as the spleen and the adipose tissue, promoting the release of inflammatory cytokines. These cytokines could induce long-term target organ damage, as observed in this study in heart and kidney by increased oxidative stress. The trained groups, regardless of the type of training, showed improved metabolic and cardiovascular autonomic regulation, which were accompanied by favorable changes in the renin-angiotensin system, inflammatory mediators and oxidative stress profile. In this sense, we believe that the attenuation of autonomic dysfunction (early observed in this model of DM) by exercise training, regardless of the type of training, can induce positive changes (dependent on the type of exercise training) on the renin angiotensin system and inflammatory mediators, reducing oxidative stress in important tissues for cardiovascular regulation

Le diabète de type 2 résulte d’une diminution de la masse fonctionnelle de cellules bêta pancréatiques, possiblement liée à une dédifférenciation cellulaire : les cellules bêta restent présentes, mais leur production d’insuline s’effondre. Ce phénomène, s’il est avéré, ouvrirait la voie à de nouvelles recherches thérapeutiques. Mais s’il est démontré dans certains modèles murins, il n’existe que des arguments très indirects chez l’Humain. Notre objectif est d’apporter de nouveaux arguments pour ce phénomène chez l’humain en modélisant la dédifférenciation de cellules bêta humaines, en utilisant la lignée de cellules bêta pancréatiques humaines EndoC-βH1 et des îlots pancréatiques humains primaires. Nous avons découvert qu’un traitement par FGF2 effondrait la production d'insuline, et des études par RNA-Seq ont révélé un effondrement de plusieurs marqueurs spécifiques de la cellule bêta, incluant INS, MAFB, SLC2A2, SLC30A8 and GCK. Parallèlement, le traitement par FGF2 induisait l'expression de gènes normalement absents d’une cellule bêta, tels les facteurs de transcription MYC, HES1, SOX9 et NEUROG3. La dédifférenciation induite par le FGF2 était temps- et dose-dépendante, et réversible après wash-out. En outre, nous démontrons que la dédifférenciation modifie l’interaction de la cellule bêta avec son environnement : l'expression de TNFRSF11B (ostéoprotégerine), un récepteur tronqué pour RANKL (receptor activator of nuclear factor-kappaB ligand), est induite lors du traitement par FGF2, et les cellules β sont alors protégées contre la signalisation RANKL (TNFSF11) par inhibition de la phosphorylation de P38. Enfin, les analyses des données transcriptomiques ont révélé des niveaux accrus d'ARNm de FGF2 dans les cellules canalaires, endothéliales et stellaires dans les pancréas d’individus diabétiques de type 2, alors que les taux d'ARNm de FGFR1, SOX9 et HES1 sont augmentés dans les îlots pancréatiques d’individus diabétiques de type 2. Nous avons donc développé un modèle de dédifférenciation des cellules bêta humaines induit par le FGF2, identifié de nouveaux marqueurs de dédifférenciation, et trouvé des signes d'augmentation de FGF2, FGFR1 et des marqueurs de dédifférenciation au cours du diabète de type 2. / Clinical and experimental evidences indicate a reduced functional β cell mass in type 2 diabetes. A recent hypothesis implicates β cell dedifferentiation in this reduction of functional β-cell mass. The vast majority of data related to β cell dedifferentiation derive from rodent models, and only indirect evidences are available in human. Our goal was to model human β-cell dedifferentiation using the functional human pancreatic β-cell line, EndoC-βH1, and primary human pancreatic islets. By screening a number of molecules in EndoC-βH1 cells, we found that FGF2 treatment dramatically reduces insulin production and MAFA expression, a β cell specific transcriptional activator. RNASeq of EndoC-βH1 cells treated with FGF2 revealed the down-regulation of additional human β cell specific markers, including INS, MAFB, SLC2A2, SLC30A8 and GCK. In parallel, FGF2 treatment activated the expression of β cell disallowed genes. This is the case for transcription factors such as MYC, HES1, SOX9 and NEUROG3. This is also the case for hormones such as GASTRIN and PYY. Such data were further confirmed by qPCR and immunostaining on primary human islets, attesting that dedifferentiation process occurs in human primary β cells. FGF2-induced dedifferentiation was time- and dose-dependent, and reversible upon wash-out. Furthermore, transcriptomic analysis revealed an increase of TNFRSF11B (osteoprotegerin) expression upon FGF2 treatment. TNFRSF11B is a decoy receptor for the receptor activator of nuclear factor kappa B ligand (RANKL). Our experimental data on EndoC-βH1 demonstrated that FGF2-induced TNFRSF11B protected β cells against TNFSF11 (RANKL) signaling by preventing P38 phosphorylation. Finally, analyses of transcriptomic data revealed increased FGF2 mRNA levels in ductal, endothelial and stellate cells in pancreases from type 2 diabetic patients, whereas FGFR1, SOX9 and HES1 mRNA levels increased in islets from type 2 diabetic patients. In conclusion, we developed a robust model to study β-cell dedifferentiation in a human context. We discovered SOX9, HES1 and MYC as positive markers of human β cell dedifferentiation, demonstrating evidence for dedifferentiation process in human β cell.

Foi desenvolvido um estudo observacional de corte transversal, com o objetivo de avaliar o status em Mg de pacientes com diabetes mellitus tipo 2. A amostra foi composta por 51 indivíduos de ambos os gêneros, com idade média de 53,6 ± 10,5 anos, os quais foram selecionados no Ambulatório de Endocrinologia do Hospital Universitário Onofre Lopes (HUOL) Natal/RN. O projeto foi aprovado pelos Comitês de Ética em Pesquisa do HUOL e da Faculdade de Ciências Farmacêuticas da USP. Os pacientes foram submetidos à avaliação antropométrica, dietética, do controle glicêmico, função renal, perfil lipídico, Mg plasmático, eritrocitário, urinário e dietético. Foi observada ingestão adequada de macronutrientes, contudo baixo consumo dietético de Mg e de fibras. Identificou-se, ainda, controle glicêmico e perfil lipídico insatisfatórios e função renal sem alterações significativas. Quanto ao status de Mg, 70,6 % da amostra apresentaram algum dos parâmetros bioquímicos relativos a este mineral abaixo dos valores de referência, sendo estes menores nos indivíduos que tinham mais complicações metabólicas e presença de microalbuminúria. Foram observadas correlações inversas entre o Mg plasmático com a glicemia de jejum (r = -0,281, p = 0,046) e a pós-prandial (r = -0,322, p = 0,021), e correlações positivas entre o Mg urinário com a glicemia de jejum (r = 0,291, p = 0,038), a circunferência abdominal (r = 0,288, p = 0,041) e o IMC (r = 0,282, p = 0,045). Deste modo, foram diagnosticadas alterações no status de Mg, as quais foram mais evidentes nos pacientes que tinham mais complicações, demonstrando a associação dos fatores relacionados com essa doença e o Mg. / A cross-sectional study was carried out to evaluate Mg status in patients with type 2 diabetes mellitus. The sample comprehended 51 individuals, both male and female, aged 53.6 ± 10.5 years, selected from the Endocrinology Clinic of the University Hospital Onofre Lopes (HUOL) in Natal/RN, Brazil. The project was approved by the Commission on Ethics in Research of the HUOL and Faculty of Pharmaceutical Sciences of the University of São Paulo. The patients were assessed concerning anthropometry, diet, blood-glucose control, kidney functioning and lipid profile, besides plasma, erythrocyte, urinary and dietary Mg. An adequate intake of macronutrients and a low consumption of dietary Mg and fibers were observed. Unsatisfactory blood-glucose control and lipid profiles, besides kidney functioning without significant alterations, were also observed. Concerning Mg status, 70.6% of the sample presented biochemical parameters for this mineral below the reference values, and such parameters were lower in individuals with more extensive metabolic complications and microalbuminury. Inverse correlations between plasma Mg with fasting (r = -0.281, p = 0.046) and postprandial plasma glucose (r = -0.322, p = 0.021), and a positive correlation between urinary Mg with fasting plasma glucose (r = 0.291, p = 0.038), waist circumference (r = 0.288, p = 0.041) and body weight index (r = 0.282, p = 0.045) were observed. Therefore, alterations in Mg status were detected in the studied population. Such alterations were more evident in patients with more extensive complications, thus demonstrating the association of factors related to this disease and Mg.

Background: There are naturally occurring health events, such as illness diagnosis, that motivate people to spontaneously adopt healthy behaviours. Such events are often re-ferred to as teachable moments. They have the potential to increase the effectiveness of behaviour change interventions, when people are already motivated to change behaviour. However, it is unclear what makes illness diagnosis a teachable moment for some people but not for others. This project aims to identify the factors determining whether and for whom diagnosis of type 2 diabetes is a teachable moment, and to explore the components of a potential intervention to reduce the risk of type 2 diabetes among high-risk groups. Method: A mixed-methods design, divided into two studies, was employed. The first study was a qualitative study and used semi-structured interviews (n=10 patients and n=13 relatives). It explored the changes occurring in people after diagnosis of type 2 diabetes in oneself or a family member in an effort to identify what factors make diagnosis a teachable moment. The study also explored people's suggestions for a potential diabetes prevention intervention. The second study was a quantitative study and used postal questionnaires (n=85 patients and n=55 relatives). It investigated the relationship between potential teachable moment factors and primary outcomes (physical activity, diet, interest in diabe-tes-related information and education course). Results: This mixed-methods study suggests that the factors that may make diagnosis of type 2 diabetes a teachable moment for patients are outcome expectancy, perceived con-trol, severity, self-concept or social role, gender and time since diagnosis; and for relatives: perceived risk, severity, self-concept or social role, and gender. Although there was lack of complete alignment in factors identified through different methods, this study advances understanding of when interventions may be more (or less) successful. The study makes recommendations for potential interventions to capitalise on the teachable moment crite-ria. Conclusion: The current project highlights the complexity of teachable moment criteria and their relationship with behaviour change. Future research is required to further uncov-er these criteria and their utility for health promotion.

INTRODUÇÃO:. A dislipidemia diabética é um dos principais fatores de risco para doença arterial coronária (DAC) O uso de uma nanoemulsão LDL-símile para avaliar clearance do éster de colesterol(EC) e colesterol livre(CL) do intravascular mostrou uma remoção acentuada do CL e um maior depósito em vasos sanguíneos de indivíduos com DAC avançada. OBJETIVOS: Identificar em DM2 a cinética plasmática do CL e EC; se há diferença na cinética de CL e EC em DM2 assintomáticos para DAC com e sem aterosclerose subclínica. MÉTODOS: Estudou-se 12 DM2 e 09 controles pareados para idade e sexo. A aterosclerose subclínca foi avaliada pela presença de Calcificação na artéria coronária (CAC). A Nanoemulsão artificial LDLsímile com dupla marcação radioativa 14C-EC, 3H-CL foi utilizada para o estudo cinético do colesterol, sendo injetada nos participantes e amostras de sangue foram coletadas durante 24 horas para mensuração da radioatividade. Remoção dos lípides da circulação foi calculada por análise compartimental. Mediu-se a taxa de esterificação do 3H-CL no plasma e avaliou-se a capacidade in vitro da HDL de receber lípides a partir das LDL-símile. RESULTADOS: Os diabéticos tiveram IMC, CA e CA/CQ maior que os controles, respectivamente: 31,9 ± 4,6 vs. 27,1± 2,4, p<0,05; 104,9 ± 9,8 vs. 94,2 ± 7,3, p<0,05; 0,98 ± 0,09 vs.0,89 ± 0,06, p<0,01. A glicemia de jejum (171 ± 96 vs. 83 ± 7,5 mg/dl, p <0,05) e hemoglobina glicada (8,9 ± 2,1 vs. 5,6 ± 0,4%, p<0,05) também foram maiores no DM2. A concentração de colesterol total, LDL, HDL, Triglicérides e apolipoproteínas A1,B e E não diferiu entre os grupos. A Taxa fracional de remoção (TFR)14C-EC foi 22% maior DM2 que nos controles (0,07 ± 0,02 vs. 0,05 ± 0,01 h-1, p<0.01). A TFR3H- CL foi semelhante entre os dois grupos, bem como a esterificação. A presença de CAC no grupo DM2 não alterou a remoção de EC e CL nesses pacientes. In vitro a capacidade da HDL em receber EC (4,2 ± 0,8vs. 3,5 ± 0,6 %, p=0,03) e TG (6,8 ± 1,6 vs. 5,0 ± 1,1, p=0.03) foi maior nos DM2. CONCLUSÕES: A remoção acelerada do 14C-EC na população DM2 e a remoção semelhante do 3H-CL quando comparado com grupo controle, pode sinalizar alterações na gênese da dislipidemia diabética. O fato dos DM2 com CAC assintomática não apresentam alterações na remoção de colesterol livre sinaliza uma provável relação do CL com a instabilidade da placa aterosclerótica. / INTRODUTION: The diabetic dyslipidemia is one of the most important risk factor in the development of coronary artery disease (CAD). The LDL-like nanoemulsion is being used to study the clearance of cholesteryl ester(CE) and free cholesterol(FC) from intravascular in patients with advanced CAD and it was shown a higher removal of FC and higher deposit in vases. OBJECTIVE: The aim of this study is to analyze the plasma kinetics of FC and CE in Type 2 Diabetes Mellitus (T2DM); and identify if there are any differences in the removal of FC in the presence of subclinical atherosclerosis in asymptomatic patients with T2DM. METHODS: It was studied 12 T2DM and 09 controls paired by age and gender. The LDL-like nanoemulsion labeled with radioactive: 14C- cholesterol ester (CE), 3H-cholesterol free (CF) was used on plasma kinetics. The nanoemulsion was injected intravenously in all participants and blood sample was collected over 24 hours for radioactivity measurement. The intravascular lipid removal was calculated through compartmental analysis. The intravascular esterification of FC contained in the nanoemulsion was calculated. The ability of HDL to received lipids from LDL-simile were observed in vitro essays. Coronary Calcium Score was detected to identify subclinical atherosclerosis. RESULTS: T2DM patients had a bigger BMI, waist and waist/hip than control, respectively 31.9 ± 4.6 vs. 27.1± 2.4, p<0.05; 104.9 ± 9.8 vs. 94.2±7.3, p<0.05; 0.98± 0.09 vs. 0.89 ± 0.06,p<0.01. Fasting glycemia (171 ± 96 vs. 83 ± 7.5 mg/dl, p <0.05) and glycated hemoglobin( 8.9 ± 2.1 vs. 5.6 ± 0.4%,p<0.05) was higher in T2DM, and there was no differences in the concentration of Total cholesterol, HDL, LDL, Triglycerides and apolipoproteins A1, B and E concentrations. The Fractional Clearance rate (FCR) 14C CE in T2DM was 22% bigger than control ( 0.07 ± 0.02 vs. 0.05± 0.01 h-1, p<0.01). FCR 3H-CF was similar between the groups. The CAC in T2DM did not show differents TFR in CE and FC in these group. In Both groups there was no statistical difference in FC esterification rate. The HDL ability to received CE (4.2 ± 0,8vs. 3.5 ± 0,6 %, p=0,03) and TG (6.8 ± 1.6 vs. 5.0 ± 1.1, p=0.03) from LDL-like nanoemulsion was higher in T2DM. CONCLUSIONS: The higher removal of 14C-CE and similar removal of FC in T2DM can be related to the genese of the diabetic dyslipidemia. The similar removal of FC between the control group and T2DM asymptomatic CAD, with and without subclinical atherosclerosis, could possibly signalize to the relation of FC and the atherosclerotic plaque stability.

Diabetes mellitus é considerado um importante problema de saúde pública, que, pelas conseqüências decorrentes de suas complicações e tratamento, poderá afetar a qualidade de vida das pessoas acometidas. Os conceitos trazidos pela literatura sobre Qualidade de Vida têm enfocado a percepção das pessoas sobre suas experiências e satisfação em relação a determinadas áreas que compõem a natureza humana. Nas últimas décadas tem crescido o interesse de obter indicadores para avaliar os resultados de intervenções clínicas, de modo a garantir maior resolutividade dos problemas de saúde. Neste contexto surgem os estudos de Qualidade de Vida Relacionada à Saúde, que se constituem em um modelo multidimensional para incluir os vários aspectos da vida humana, no qual a pessoa é fonte primária de informação, para expressar as conseqüências da enfermidade e do tratamento, na sua vida diária. A literatura traz instrumentos gerais e específicos para avaliar a qualidade de vida em relação à saúde. Entendemos que os instrumentos específicos poderão trazer informações direcionadas a realidade que se pretende atuar. Entre os instrumentos específicos de qualidade de vida das pessoas com diabetes, identificou-se o instrumento D-39 para avaliar a qualidade de vida das pessoas com diabetes mellitus. Desta forma, o presente estudo teve como objetivos adaptar o D-39 para a língua portuguesa e desenvolver uma primeira fase do processo de validação, em um estudo piloto. Trata-se de um estudo transversal, de caráter metodológico, com análise psicométrica na simulação do teste de campo para a validade (face, constructo) e a confiabilidade da versão adaptada em uma amostra de brasileiros com diabetes mellitus tipo 2. Este instrumento é composto por 39 itens divididos em cinco domínios (Controle do diabetes, Ansiedade e preocupação, Sobrecarga social, Funcionamento sexual e Energia e mobilidade). O presente estudo foi conduzido em Unidade Básica de Saúde em uma amostra de conveniência, composta por 52 pessoas com diabetes mellitus tipo 2. O processo de adaptação seguiu os seguintes passos metodológicos: tradução do D-39 para a língua portuguesa; avaliação por um Comitê de Juízes; \"back-translation\" da versão para o inglês, comparação das duas versões em inglês; análise semântica dos itens; préteste da versão adaptada e aplicação da versão final em português entre os participantes. Encontramos predomínio de pessoas do sexo feminino (65,4%), convivendo em companhia 9 conjugal ou com filhos (75%), idade entre 45 e 84 anos, média de 62,8 anos (DP=8,6) e baixa escolaridade (71,1%). Em relação à doença, o tempo médio de duração foi de 9,15 anos (DP=4,2); 23 participantes não faziam uso de insulina (23/52; 44,2%) e 29 faziam (29/52; 55,8%). Quanto às comorbidades, identificamos que 84,6% das pessoas apresentavam sobrepeso e obesidade; o valor médio da pressão arterial sistólica foi de 136,15 mmHg (DP=22) e da diastólica 80,57 mmHg (DP=13,34). Na versão adaptada do instrumento D-39, as respostas variaram de 1 a 7; o intervalo possível, para a soma dos 39 itens variou de 49 a 217, e quanto maior o valor, pior a avaliação da qualidade de vida. Obtivemos uma média total do instrumento de 152,5 (DP=38,6). Para a validade de constructo, verificamos a convergência e a divergência entre os itens do D-39. O D-39 possibilitou discriminar entre as pessoas que faziam e as que não faziam uso de insulina. Houve correlações moderadas entre os domínios Controle do diabetes e Ansiedade e Preocupação (0,52), Controle do diabetes e Funcionamento Sexual (0,55), Ansiedade e Preocupação e Energia e Mobilidade (0,46), Sobrecarga Social e Funcionamento Sexual (0,58), Sobrecarga Social e Energia e Mobilidade (0,56), Funcionamento Sexual e Energia e Mobilidade (0,60), e correlação forte entre os domínios Controle do diabetes e Energia e Mobilidade (0,64). A consistência interna, representada pelo alfa de Cronbach, mostrou resultados significantes para o total do instrumento (0,91) e valores variando de 0,58 a 0,85 entre os domínios. Diante dos resultados podemos concluir que a versão adaptada para o português do D-39 mostrou atender aos critérios de validade e confiabilidade exigidos para um instrumento de avaliação da QVRS, mantendo as propriedades da versão original. / Diabetes mellitus is considered an important public health problem which for the decurrent consequences of its complications and treatment, could affect the life quality of the attacked people. The concepts carried by the literature about the Life Quality have focused the perception of the people about their experiences and satisfaction regarding to certain areas which compose the human nature. In the last decades, a major interest concerning to the achievement of new indicators for the results of the evaluation of the clinical intervention have increased in such way to ensure a major resolutivity of the heath problems. In this context appears studies of Health-Related Quality Life related to health which constitute in a multidimensional model to include the several human life aspects, in which the person is primary source of information to express the disease and treatment consequences in his daily life. The literature brings specific instruments to evaluate the health-related quality life. We understand that the specific instruments could bring focused informations on the reality which is intended to act. Among the specific intruments of quality of the people with diabetes, it was identified the instrument D-39 to evaluate the life quality of the people with diabetes mellitus. In this way, the aim of this study was to adapt to Portuguese and to develop a prime phase of the validation process in a pilot study. It deals with a transversal study with a methodological character with psychometric analysis in the simulation of the field test for the validity (face and construct) and the reliability of the adapted version in a sample of Brazilians with Type 2 diabetes mellitus. This instrument is composed of 39 items divided in five domains (Diabetes Control, Anxiety and Preoccupation, Social Burden, Sexual Behavior and Energy and Mobility). This study was performed in Basic Health Unity in a convenience sample, composed by 52 people with Type 2 diabetes mellitus. The adaptation process followed the following methodological steps: translation of the D-39 to Portuguese; evaluation by a Committee of Judges; \"back-translation\" of the version to english, comparison of both English versions; semantical analysis of the items; pre-test of the adapted version and application of the final version in Portuguese among the participants. It was found predominance of female people (65,4%), living together partners with conjugal bonds or with children (75%), age between 45 and 84 years of age, average = 62,8 anos (DP = 8,6) and low scholarity (71,1%). The average time of disease was 9,15 years (DP = 4,2); concerning to the 11 treatment 23 participants did not use insulin (23/52; 44,2%) and 29 participants used insulin (29/52; 55,8%). Concerning to the comorbities it was identified that 84,6% of the people were overweight and obesity; the average valor systolic arterial pressure was 136,15 mmHg (DP=22) and diastolic arterial pressure 80,57 mmHg (DP=13,34). In the adapted version of the instrument D-39, the answers varied from 1 to 7; the possible interval, for the 39 items varied from 49 to 217, and how much the larger value is, the worse the evaluation of the quality life will be. It was obtained average total average of the instrument of (152,5 DP = 38,6). For the construct validity, it was verified the convergence and the divergency among the items of the D-39. The D-39 it made possible to discriminate well among the people who used and those who did not use the insulin. It had moderate correlations among the domains Diabetes Control and Anxiety and Preoccupation (0,52), Diabetes Control and Sexual Behavior (0,55), Anxiety and Preoccupation and Energy and Mobility (0,46), Social Burden and Sexual Behavior (0,58), Social Burden and Energy and Mobility (0,56), Sexual Behavior and Energy and Mobility (0,60) and strong correlation among the domains Diabetes Control and Energy and Mobility (0,64). The internal consistency, represented by Cronbach\'s alpha, showed significant results for the total of the instrument (0,91) and values varying from 0,58 to 0,85 among the domains. According to these results, it was concluded that the adapted version to Portuguese of the D- 39 answer the validity and reliability criterion and required for an evaluation instrument of the Health-Related Quality of Life (HRQL), maintaining the properties of the original version.

INTRODUCTION: Type 2 diabetes mellitus (T2DM), once thought to be an adult disease, now affects large numbers of children. The prevalence of T2DM in children increased 35% between 2001 and 20091 and while it appears to now be leveling off, it is clear that much of the burden of disease falls disproportionately on ethnic minorities. It is well known that there are changes occurring in the microvasculature well before diabetes is diagnosed, and these changes are thought to contribute to micro- and macrovascular complications. Therefore, prediabetes, which is a time of mild hyperglycemia that exists between normal glucose metabolism and overt diabetes, provides a target for behavior modification and potentially the prevention of complications. The mainstay of treatment for diabetes has been lifestyle intervention and treatment with metformin. Research has shown that both intensive lifestyle interventions and metformin are effective for the treatment of T2DM. However, much of this knowledge comes from studies on adults and is simply inferred to youth. Thus, at this time it is still unknown to what extent treatments including lifestyle intervention and metformin should be used, or how they should be utilized, in youth. This is especially true for youth with prediabetes, as this is likely where prevention of the disease needs to occur to have the greatest overall benefit. PROPOSED STUDY: Thus, the proposed study will directly compare two groups treated with standard of care and either metformin daily or intensive lifestyle intervention with a CrossFit™ training modality. The primary outcome is treatment failure and development of diabetes. A secondary outcome is achievement of normoglycemia and its durability. CONCLUSIONS: This study will be the first to examine the longer term outcomes of the use of metformin in youth as well as the effects of high intensity functional training (HIFT) using the CrossFit™ modality. While there is accumulating evidence about the safety of the use of metformin in youth, most studies are of short duration and this study will provide longer term results. Additionally, CrossFit™, a relatively new exercise modality, has not been tested in the literature on youth and as a form of combined aerobic and resistance training, it may provide and effective and interesting means of lifestyle intervention and reversion to normoglycemia in adolescents. In conclusion the results from this study will provide significant clinical relevance.