Introdução: O Índice de Massa Corporal (IMC) possui limitações para avaliação dos riscos à saúde; a literatura propõe que este índice seja utilizado associado a medidas metabólicas, recomendando-se a classificação em fenótipos antropométrico-metabólicos. A avaliação da resistência à insulina periférica tem sido apontada como fator importante para identificar os fenótipos metabólicos desfavoráveis, porém este marcador não é comumente considerado nas definições do fenótipo de obesidade metabolicamente benigna. Estudos de prevalência deste fenótipo relatam estimativas heterogêneas dependendo dos critérios de definição. Estes estudos trazem contribuições relevantes para a compreensão das repercussões desse fenótipo no tratamento, no planejamento de serviços de saúde e no entendimento da epidemiologia da obesidade e suas diferentes manifestações. Objetivo: Investigar o impacto da resistência à insulina nas estimativas de prevalência do fenótipo obesidade metabolicamente benigna em adolescentes obesos que buscaram tratamento. Metodologia: Estudo transversal com base em dados secundários sobre 418 adolescentes obesos que foram atendidos na Liga de Obesidade Infantil do Hospital das Clínicas da Universidade de São Paulo entre janeiro de 2009 e dezembro de 2013. Duas definições foram adotadas para classificar os adolescentes nos fenótipos \"metabolicamente benigno\" e \"metabolicamente adverso\". A primeira se baseou nos valores propostos pelo International Diabetes Federation para diagnosticar síndrome metabólica em crianças e adolescentes. Na segunda acrescentou-se medida de resistência à insulina determinada pelo Homeostasic Model Assessment of Insulin Resistance (HOMA-IR). O valor de corte adotado para o HOMA-IR foi de 3,16. A análise descritiva incluiu a distribuição das frequências absoluta e relativa das variáveis independentes sexo, idade, cor de pele, estadio puberal e escore Z para IMC (Z-IMC). A prevalência de obesidade metabolicamente benigna foi calculada com intervalo de 95% de confiança (IC 95%) e o teste X², com nível de significância de 5%, foi utilizado para avaliar as associações entre as variáveis de exposição e o desfecho. As mesmas análises foram feitas para ambas definições. Aprovação do Comitê de Ética em Pesquisa do Hospital das Clínicas (Número do Processo: 1.230.024). Resultados: Dos 418 participantes, 217 (52%) eram do sexo feminino. A média de idade foi de 13 anos (± 2) e de Z-IMC 3,2 (± 0,5). Metade dos participantes estavam em fase puberal e 39% pós-puberal segundo a escala de Tanner. A prevalência do fenótipo metabolicamente benigno foi de 43% (IC 95%, 38 - 48%) pela definição I e 13% (IC 95%, 9 - 16%) pela definição II. Nas análises multivariadas segundo a definição I, o sexo masculino [razão de prevalência (RP) ajustada 0,32 IC 95% 0,16 - 0,62], o estadio púbere (RP ajustada, 0,24; IC 95%, 0,14 - 0,43) e obesidade severa (RP ajustada, 0,40; IC 95%, 0,16 - 0,62), foram associados de forma independente e significativa com a menor prevalência de OMB. Quando a definição II foi aplicada, foram observados resultados semelhantes de estadio púbere (RP ajustada, 0,34; IC 95%, 0,19 - 0,59) e obesidade severa (RP ajustada, 0,39; IC 95%, 0,20 - 0,79), mas sexo masculino (RP ajustada, 0,63; IC 95%, 0,32 - 1,23) não se mostrou significante na associação com a menor prevalência de OMB. Nenhuma associação entre o fenótipo OMB e a variável cor de pele foi encontrada. Conclusão: Inclusão de medida de resistência à insulina nos critérios de definição da obesidade metabolicamente benigna nessa população levou à expressiva diminuição da prevalência deste fenótipo. Resistência à insulina pode ser um importante marcador da repercussão negativa da obesidade na saúde desses adolescentes / Introduction: The Body Mass Index (BMI) has limitations for assessment of health risks; the literature suggests that this index be used in association with metabolic measures, recommending classification in anthropometric-metabolic phenotypes. The evaluation of insulin resistance has been identified as an important factor to identify unfavorable metabolic phenotypes, but this marker is not commonly considered in the definitions of metabolically healthy obesity phenotype. Prevalence studies report that heterogeneous estimates depending on the criteria of the definition. These studies bring relevant contributions to the understanding of this phenotype in the treatment, planning of health services and understanding of the epidemiology of obesity and its different manifestations. Objective: To investigate the impact of insulin resistance on the estimated prevalence of metabolically healthy obesity phenotype in obese adolescents seeking treatment. Methodology: This is a cross-sectional study based on secondary data, on 418 obese adolescents, who were treated at Childhood Obesity League of Hospital das Clínicas, University of São Paulo between January 2009 and December 2013. Two definitions were used to classify adolescents into \"metabolically healthy\" and \"metabolically unhealthy\" phenotypes. The first one was based on the values proposed by the International Diabetes Federation to diagnose metabolic syndrome in children and adolescents. The second one, the measure of insulin resistance determined by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was added. The cut-off value for HOMA-IR was 3.16. The descriptive analysis included the distribution of the absolute and relative frequencies of the independent variables sex, age, pubertal stage and z-score for Body Mass Index (Z-BMI). The prevalence of metabolically healthy obesity was calculated with intervals of 95% of confidence and the X² test at 5% significance level was applied to associations between exposure variables and outcome. The same analyzes was performed for both settings. Approval of the Research Ethics Committee of the Hospital das Clínicas (Process Number: 1.230.024). Results: Of the 418 participants, 217 (52%) were female. The mean age was 13 years (± 2) and Z-BMI 3.2 (± 0.5). Half of the participants were pubertal and 39% post-pubertal according to the Tanner scale. The prevalence of the metabolically healthy phenotype was 43% (CI 95%: 38-48) by definition I and 13% (CI 95%: 9-16) by definition II. In the multivariate analysis using definition I, male gender [prevalence ratio (PR), 0.32; 95% CI, 0.16-0.62], pubertal stage (PR, 0.24; 95% CI, 0.14-0.43) and severe obesity (PR, 0.40; 95% CI, 0.16-0.62) were independently and significantly associated with lower MHO prevalence. When definition II was used, similar results were observed for pubertal stage (PR, 0.34; 95% CI, 0.19-0.59) and severe obesity (PR, 0.39; 95% CI, 0.20-0.79), but male gender (PR, 0.63; 95% CI, 0.32-1.23) was not significantly associated with lower MHO prevalence. No association was found between MHO phenotype and skin color. Conclusion: The inclusion of insulin resistance in the definition criteria of metabolically healthy obesity in this population, led to a significant decrease in the prevalence of this phenotype. Insulin resistance may be an important marker of the negative repercussion of obesity in the health of these adolescents

Os sistemas de monitoração contínua da glicose (SMCG) foram desenvolvidos para monitorar as concentrações intersticiais de glicose em pacientes diabéticos, eliminando a necessidade de repetidas coletas de sangue. Vários estudos em humanos e animais indicam que a glicose intersticial possui correlação com a glicose sanguínea, mas poucos estudos abordam o uso clínico em equinos e há poucos aparelhos padronizados na espécie. O presente estudo teve como objetivo padronizar um novo SMCG intersticial (FreeStyle Libre) em cavalos hígidos e obesos, avaliar a fixação do sensor na pele do cavalo, e avaliar a eficácia do dispositivo no auxílio ao diagnóstico de resistência à insulina durante o teste combinado de glicose e insulina. Para isso foram usados 10 equinos adultos. O sensor foi fixado na região dorsolateral do terço inicial do pescoço de todos os animais. A dosagem de glicemia laboratorial e pelo aparelho foram comparadas em vários tempos. Em cinco cavalos (com escore corporal de 5 a 6) foram apenas realizadas essas dosagens e o acompanhamento por 7 dias da fixação do sensor. Nos outros cinco animais (com escore corporal acima de 7), foi realizado também o teste combinado de glicose e insulina. O aparelho permaneceu fixado entre 3 e 7 dias em 6 dos 10 animais. Houve ótima concordância entre os valores de glicose nos dois sistemas, ocorrendo apenas um pequeno atraso na detecção de variações bruscas de glicemia pelo aparelho testado. Assim conclui-se que o sistema de monitoramento contínuo da glicose FreeStyle Libre pode ser utilizado para avaliação indireta da glicemia por meio da glicose intersticial em cavalos adultos hígidos e obesos, inclusive durante o teste combinado de glicose e insulina. / Continuous glucose monitoring systems (CGMS) have been developed to monitor interstitial glucose concentrations in diabetic patients, eliminating the need for repeated blood sampling. Several studies in humans and animals indicate that interstitial glucose correlates with blood glucose, but few studies address clinical use in horses and there are few standardized devices in the species. The present study aimed to standardize a new interstitial CGMS (FreeStyle Libre) on healthy and obese horses, to evaluate the fixation of the sensor on horse skin, and to evaluate the efficacy of the device in aiding the diagnosis of insulin resistance during the combined test of glucose and insulin. For this, 10 adult horses were used. The sensor was attached to the dorsolateral region of the initial third of the neck of all animals. Dosage of laboratory blood glucose and by the device were compared at various times. In five horses (with a body score of 5 to 6), these measurements were only performed and the 7-day follow-up of the sensor fixation was performed. In the other five animals (with body score above 7), the combined glucose and insulin test was also performed. The device remained fixed for 3 to 7 days in 6 of the 10 animals. There was excellent agreement between the glucose values in both systems, with only a slight delay in the detection of abrupt changes in glycemia by the tested device. Thus, it can be concluded that the FreeStyle Libre glucose monitoring system can be used for indirect evaluation of glycemia through interstitial glucose in healthy and obese adult horses, including during the combined glucose and insulin test.

INTRODUÇÃO: Síndrome antifosfolípide está associada com aterosclerose acelerada. Embora adipocitocinas exerçam um papel fundamental na interface entre obesidade, inflamação, resistência insulínica e aterosclerose, a exata natureza e relativa contribuição das adipocitocinas, como potenciais marcadores, requer investigação na síndrome antifosfolípide primária (SAFP). OBJETIVO: Este estudo foi desenvolvido para avaliar a possível associação das adipocitocinas com síndrome metabólica (SM), inflamação e outros fatores de risco cardiovascular na SAFP. MÉTODOS: 56 pacientes com SAFP e 72 controles saudáveis pareados por sexo e idade foram incluídos. Adiponectina, leptina, visfatina, resistina, inibidor do ativador de plasminogênio-1 (PAI-1), lipoproteina (a), glicemia, insulina, VHS, PCR, ácido úrico e perfil lipídico foram dosados. SM foi definida de acordo com os critérios da Federação Internacional de Diabetes (IDF) e resistência insulínica foi estabelecida pelo índice de homeostasis model assessment (HOMA). RESULTADOS: Leptina [21,5 (12,9- 45,7) vs 12,1 (6,9-26,8) ng/mL, P=0.001] foi maior em SAFP do que em controles. Adiponectina (P=0,10), resistina (P=0,23), visfatina (P=0,68) and PAI-1 (P=0,77) não diferiu entre os grupos. Em SAFP, leptina e PAI-1 foram positivamente correlacionada com IMC (r=0,61 and 0,29), HOMA-IR (r=O,71 and 0,28) and CRP (r=0,32 and 0,36). Adiponectina foi negativamente correlacionada com IMC (r=-0,28), triglicérides (r=-0,43), HOMA-IR (r=-0,36) e positivamente correlacionada com HDL (r=0,37), aCL IgG (r=0,41), anti- 2GPI IgG (r=0,31) e anti- 2GPI IgM (r=0,38). A análise de pacientes com e sem SM revelou uma associação positiva com leptina (P=0,002) e PAI-1 (P=0,03) e uma associação negativa com adiponectina (P=0,042). No modelo de regressão linear múltipla, observamos que as variáveis que independentemente influenciam a adiponectina foram triglicérides (P<0,001), VLDL-c (P=0,002) e anti-2GPI IgG (P=0,042), leptina foram IMC (P<0,001), glicemia (P=0,046), HOMA-IR (P<0,001) e VHS (P=0,006) e PAI-1 foram PCR (P=0,013) e SM (P=0,048). CONCLUSÕES: O presente estudo demonstra que as adipocitocinas podem estar envolvidas com inflamação, resistência insulínica e SM em pacientes com SAFP / INTRODUCTION: Antiphospholipid syndrome is associated with accelerated atherosclerosis. Although adipocytokines play a key role in the interface between obesity, inflammation, insulin resistance and atherosclerosis, the exact nature and relative contribution of adipocytokines as potential markers warrant further investigation in primary antiphospholipid syndrome (PAPS). OBJECTIVE: This study was undertaken to evaluate a possible association of adipocytokines with metabolic syndrome (MetS), inflammation and other cardiovascular risk factors in PAPS. METHODS: Fifty-six PAPS patients and 72 age- and gender-matched healthy controls were included. Sera samples were tested for adiponectin, leptin, visfatin, resistin, plasminogen activator inhibitor-1 (PAI-1), lipoprotein (a), glucose, insulin, ESR, CRP, uric acid and lipid profiles. MetS was defined according to the guidelines of the International Diabetes Federation (IDF) and insulin resistance was established using the homeostasis model assessment (HOMA) index. RESULTS: Concentrations of leptin [21.5 (12.1-45.7) vs 12.1 (6.9-26.8) ng/mL, P=0.001] were higher in PAPS than in controls. Concentrations of adiponectin (P=0.10), resistin (P=0.23), visfatin (P=0.68) and PAI-1 (P=0.77) did not differ between patients and controls. In PAPS, leptin and PAI-1 levels were positively correlated with BMI (r=0.61 and 0.29), HOMA-IR (r=0.71 and 0.28) and CRP (r=0.32 and 0.36). Adiponectin was negatively correlated with BMI (r=-0.28), triglycerides (r=-0.43) and HOMA-IR index (r=-0.36) and positively correlated with HDL (r=0.37), aCL IgG (r=0.41), anti- 2GPI IgG (r=0.31) and anti- 2GPI IgM (r=0.38). Further analysis of patients with and without MetS revealed a positive association of the syndrome with leptin (P=0.002) and PAI-1 (P=0.03) and a negative association with adiponectin (P=0.042). In the multiple linear regression model, we observed that the variables that independently influence the adiponectin were triglycerides (P<0.001), VLDL-C (P=0.002) and anti-2GPI IgG (P=0.042), leptin were BMI (P<0.001), glucose (P=0.046), HOMA-IR (P <0.001) and ESR (P=0.006) and PAI-1 were CRP (P=0.013) and MetS (P=0.048). CONCLUSION: The findings of the present study provide evidence that adipocytokines may be involved in inflammation, insulin resistance and metabolic syndrome of PAPS patients

A hipótese do presente estudo sugere que a baixa fertilidade de vacas Holandesas (Bos taurus) repetidoras de serviço (RS) está relacionada à baixa qualidade oocitária que, por sua vez, é associada ao quadro de resistência periférica a insulina (RPI). Ainda, a indução de lactação (IL) em vacas Holandesas (Bos taurus) RS pode reverter o quadro de RPI e, consequentemente, melhorar a qualidade oocitária e a produção in vitro de embriões (PIVE). Para testar a hipótese proposta, este estudo objetivou avaliar o efeito da fase da lactação e da gestação [Exp. 1], o efeito da secagem de RS [Exp. 2] e o efeito da IL [Exp. 3] sobre a RPI, a qualidade oocitária e a PIVE em vacas da raça Holandesa (Bos taurus). Nos três estudos foram realizados testes de tolerância à glicose (TTG) para avaliar a RPI através do perfil hormonal sérico de insulina e glicose. Além disso, avaliou-se o perfil bioquímico sérico e folicular e a qualidade oocitária através da PIVE. Verificou-se que, em resposta à infusão de 0,3mg glicose/kg PV, as vacas RS no final da lactação secretaram 53% mais insulina e captaram 40% menos de glicose quando comparadas as vacas no terço inicial de lactação (Exp 1). Esses achados são indicativos do estabelecimento do quadro de RPI nas vacas RS em lactação. Durante o período seco, as vacas RS secretaram 96% mais insulina e captaram 56% menos glicose que as vacas no terço inicial da lactação e as vacas RS em lactação, respectivamente (Exp. 2). Ainda, as vacas com lactação induzida secretaram 11% menos insulina e captaram a mesma quantidade de glicose que vacas paridas em fases semelhantes de lactação (Exp 3), demonstrando que o protocolo de IL foi eficiente em alterar o perfil metabólico, revertendo o quadro de RPI presente nas vacas RS. Nos Exp. 1, 2 e 3 foram verificadas maiores concentrações plasmática de triglicérides (TG; P &lt; 0,05), colesterol total (COL; P < 0,05) e LDL (P < 0,05) no soro sanguíneo em vacas RS quando comparadas com vacas no terço inicial de lactação. Durante o período seco (Exp. 2 e 3), observou-se incremento desses metabólitos, destacando aumento na concentração de TG (P < 0,05), COL (P < 0,05) e LDL (P < 0,05) plasmático em vacas secas quando comparadas as vacas em lactação [início e final (RS) da lactação]. No liquido folicular foram observadas variações no perfil bioquímico para COL e TG. Nos Exp. 1, 2 e 3, verificou-se que vacas RS possuem maior concentração de TG (P < 0,05) e COL (P < 0,05) no fluido folicular do que vacas no terço inicial de lactação. Contrariando a hipótese inicialmente proposta, as vacas RS em lactação e as vacas secas apresentaram maior taxa de blastocisto (P < 0,05) e número de blastocistos por OPU (P < 0,05) que as vacas no terço inicial de lactação (Exp. 1, 2 e 3). Através do perfil de insulina circulante em resposta ao TTG foi possível demonstrar o estabelecimento do quadro de RPI em vacas RS (P < 0,05). Além disso, constatou-se agravamento da RPI em vacas secas (P < 0,05). Esse quadro foi associado ao aumento do escore de condição corporal (P < 0,05) e do peso vivo (kg; P < 0,05) nas vacas RS. Em conclusão, não foi verificada associação negativa entre RPI, qualidade oocitária e PIVE em vacas Holandesas (Bos taurus) RS. Apesar da indução de lactação em vacas Holandesas (Bos taurus) RS alterar o metabolismo e diminuir o quadro de RPI, não foi verificado efetivo positivo na qualidade oocitária e na PIVE. / The hypothesis of the present study suggests that low fertility of repeat breeders (RB) Holstein (Bos taurus) cows is related to low oocyte quality, which is associated with peripheral insulin resistance (PIR). Also, induction of lactation (IL) in RB Holstein (Bos taurus) cows can revert PIR and, consequently, improve oocyte quality and in vitro embryo production (IVEP). In order to test the proposed hypothesis, the objective of this study was to evaluate the effect of phase of lactation and gestation [Exp. 1], effect of drying RB [Exp. 2] and effect of IL [Exp. 3] on PIR, oocyte quality and IVEP of Holstein (Bos taurus) cows. In all three studies, glucose tolerance tests (GTT) were performed to evaluate PIR through the serum hormonal insulin and glucose profile. In addition, we evaluated the serum and follicular biochemical profile and oocyte quality through IVEP. It was verified that, in response to a 0.3mg glucose/kg of body weight (BW), RB cows at the end of lactation secreted 53% more insulin and captured 40% less glucose when compared to cows in the initial third of their lactation (Exp. 1). These findings are indicative of the establishment of PIR in RB lactating cows. During the dry period, RB cows secreted 96% more insulin and captured 56% less glucose than cows in the initial third of their lactation and RB lactating cows, respectively (Exp. 2). Also, cows with induced lactation secreted 11% less insulin and captured the same amount of glucose than calved cows in similar lactation phase (Exp. 3), demonstrating that the IL protocol was efficient to alter the metabolic profile, reverting PIR present in RB cows. In Exp. 1, 2 and 3 higher plasmatic concentrations of triglycerides (TG; P<0.05), total cholesterol (COL; P<0.05) and LDL (P<0.05) were verified in the blood serum in RB cows when compared to cows in the initial third of their lactation. During the dry period (Exp. 2 and 3), we observed the increment of these metabolites, and a notable elevation of the plasmatic TG (P < 0.05), COL (P < 0.05) and LDL (P < 0.05) in dry cows when compared to lactating cows [beginning and end (RB) of lactation]. In the follicular fluid, it was possible to observe variations in the biochemical profile for COL and TG. In Exp. 1, 2 and 3, it was verified that RB cows have higher concentration of TG (P < 0.05) and COL (P < 0.05) in the follicular fluid than cows in the initial third of their lactation. Contrary to the initially proposed hypothesis, RB lactating cows and dry cows presented higher blastocyst rate (P<0.05) than cows in the initial third of lactation (Exp. 1, 2 and 3). Through the circulating insulin profile in response to the GTT it was possible to demonstrate the establishment of PIR in RB cows (P<0.05). Also, it was observed worsening of the PIR in dry cows (P<0.05). This condition was associated with an increase in body condition score (P<0.05) and BW (kg; P<0.05) in RB cows. In conclusion, no negative association between PIR, oocyte quality and IVEP was observed in RB Holstein (Bos taurus) cows. Although induction of lactation in RB Holstein (Bos taurus) cows altered the metabolism and reduced PIR, no positive effect was observed in oocyte quality and IVEP.

A angiotensina II (AngII) pode ativar as vias de sinalização das proteínas quinases ativadas por mitógenos (MAPKs). Investigamos o papel da obesidade e das MAPKs na resposta à AngII em ratos obesos por injeção de glutamato monossódico (Ob). Artérias mesentéricas de resistência com endotélio intacto e não as artérias sem endotélio, isoladas de Ob, respondem menos à AngII. As respostas à noradrenalina e ao cloreto de potássio estavam inalteradas. Aumento da expressão do receptor AT2 (AT2R), da óxido nítrico sintase (eNOS) e da ERK1/2 podem estar envolvidos na menor resposta pois a inibição do AT2R, da eNOS e da ERK1/2 corrigiram-na. A maior ativação da ERK1/2 nos Ob levou à maior ativação da eNOS e maior geração de NO, diminuindo a resposta à Ang II. Concluímos que na obesidade, a resposta contrátil à Ang II é menor, como possível mecanismo adaptativo frente ao aumento da ativação do sistema renina-angiotensina. Esse mecanismo envolve a participação do endotélio com maior liberação de NO, aumento do número de AT2R, e da fosforilação da eNOS e da ERK1/2. / Angiotensin II (AngII) can activate mitogen-activated protein kinases (MAPKs) pathways. We investigated the role of obesity and MAPKs in AngII response in monosodium glutamate-induced obese rats (Ob). Endothelium-intact but not endothelium-denuded mesenteric resistance arteries isolated from Ob exhibited a lower response to AngII. The response to nordrenaline and potassium chloride were unaltered. Increased expression of AT2 receptor, nitric oxide synthase (eNOS) and ERK1/2 might be involved in the reduced response since inhibition of AT2R, eNOS and ERK1/2 corrected it. Increased activation of ERK 1/2 in Ob might activate eNOS, generating more NO and vasodilation that contributed to reduce the contraction to AngII. We concluded that, in obesity, the lower response to AngII might be an adaptive mechanism against the increased activation of the renin-angiotensin system. This mechanism involves the participation of the endothelium through a greater release of NO, increased AT2R, eNOS and ERK1/2 expressions.

Introdução: A acromegalia é uma doença rara, caracterizada pela produção aumentada de hormônio do crescimento, causada geralmente por um adenoma hipofisário, ocasionando uma série de comorbidades como apneia do sono e resistência insulínica que acarretam um aumento na mortalidade e redução da expectativa de vida. Objetivo: O objetivo deste estudo foi avaliar o impacto da terapêutica da apneia do sono com um dispositivo de pressão positiva contínuas nas vias aéreas (CPAP) e avaliar o impacto desta terapêutica na resistência insulínica pela realização do clamp euglicêmico hiperinsulinêmico (CEH). Pacientes: De 156 acromegálicos regularmente atendidos na unidade de Neuroendocrinologia do HC-FMUSP, foram selecionados 12 indivíduos com apneia do sono de moderada a grave em uso de análogos da somatostatina (AS). Método: Os pacientes foram randomizados em dois grupos com seis integrantes. O grupo A iniciou o tratamento com CPAP, e o grupo B, um adesivo dilatador nasal com efeito de placebo. A avaliação basal incluiu a polissonografia, determinação do GH, IGF-1, HbA1c, ácidos graxos livres, lípides, CEH, bem como os índices de resistência periférica à insulina (HOMA, HOMA2 e QUICKI). Após 3 meses de tratamento, os pacientes foram reavaliados pelos mesmos exames, sendo trocado o tratamento entre os grupos e feita nova avaliação, após mais 90 dias. Resultados: Analisando os resultados finais de todos os pacientes que fizeram uso do CPAP, foi observada uma redução significante na resistência periférica à insulina, verificada pelo índice de sensibilidade derivado do clamp (ISCLAMP, pré e pós- CPAP, 3,83 versus 6,11, p=0,032). Esta redução não foi observada no grupo que fez uso do adesivo nasal (ISCLAMP, pré e pós-adesivo, 5,53 versus 5,19, p=0,455). Não houve diferença significante nos níveis de lípides, HbA1c nem nos índices de resistência periférica à insulina. Conclusão: O tratamento da apneia do sono moderada a grave com CPAP, em pacientes acromegálicos em uso de AS, levou a uma redução da resistência periférica à insulina aferida pelo CEH, dado não observado por meio dos índices HOMA, HOMA2 e QUICKI / Introduction. Acromegaly is a rare disease, characterized by the production of high GH levels usually by pituitary adenoma leading to comorbidities as sleep apnea and insulin resistance, bringing increase of mortality and life span reduction. Objective: This study aims to assess the impact of treatment of sleep apnea with a continuous positive air pressure device (CPAP) on the insulin resistance by performing the hyperinsulinemic euglycemic clamp (HEC). Patients: From 156 acromegalic patients regularly attended on Neuroendocrine Unit of the Hospital das Clínicas, University of São Paulo Medical School, 12 subjects on somatostatin analogs (SA) harboring moderate to severe sleep apnea were selected. Methods: Patients were randomized in two groups of six subjects. Group A started treatment with CPAP while group B started treatment using a nasal dilator adhesive with placebo effect. Basal assessment included polysomnography, determination of GH, IGF-1, HbA1c, free fat acids, lipids assays, HEC as well as insulin resistance indexes (HOMA, HOMA2 and QUICKI). Patients were reevaluated after three months of treatment by the same tests and then the treatment was switched between groups with new assessment 90 days later. Results: A significant reduction on insulin resistance determined by the clamp derived sensibility index was observed after assessing the final data of all patients on CPAP (SICLAMP, pre and post CPAP, 3,83 versus 6,11, p=0,032). This reduction was not seen in the nasal dilator adhesive group (SICLAMP, pre and post adhesive, 5,53 versus 5,19, p=0,455). There was no significant difference on lipids, HbA1c or on peripheral insulin resistance indexes. Conclusion: CPAP treatment of acromegalic patients on AS with moderate to severe sleep apnea leaded to significant reduction on peripheral insulin resistance assessed by the HEC. HOMA, HOMA2 and QUICK did not detect this data

Pre-training muscle characteristics of subjects who are obese determine how well exercise training will improve their insulin responsiveness. J Strength Cond Res 31(3): 798–808, 2017—Only half of prediabetic subjects who are obese who underwent exercise training without weight loss increased their insulin responsiveness. We hypothesized that those who improved their insulin responsiveness might have pretraining characteristics favoring a positive response to exercise training. Thirty nondiabetic subjects who were obese volunteered for 8 weeks of either strength training or endurance training. During training, subjects increased their caloric intake to prevent weight loss. Insulin responsiveness by euglycemic clamps and muscle fiber composition, and expression of muscle key biochemical pathways were quantified. Positive responders initially had 52% higher intermediate muscle fibers (fiber type IIa) with 27% lower slow-twitch fibers (type I) and 23% lower expression of muscle insulin receptors. Whether after weight training or stationary bike training, positive responders' fiber type shifted away from type I and type IIa fibers to an increased proportion of type IIx fibers (fast twitch). Muscle insulin receptor expression and glucose transporter type 4 (GLUT4) expression increased in all trained subjects, but these moderate changes did not consistently translate to improvement in whole-body insulin responsiveness. Exercise training of previously sedentary subjects who are obese can result in muscle remodeling and increased expression of key elements of the insulin pathway, but in the absence of weight loss, insulin sensitivity improvement was modest and limited to about half of the participants. Our data suggest rather than responders being more fit, they may have been less fit, only catching up to the other half of subjects who are obese whose insulin responsiveness did not increase beyond their pretraining baseline.

Introduction Insulin resistance in obesity is decreased after successful diet and exercise. Aerobic exercise training alone was evaluated as an intervention in subjects with the metabolic syndrome. Methods Eighteen nondiabetic, sedentary subjects, 11 with the metabolic syndrome, participated in 8 wk of increasing intensity stationary cycle training. Results Cycle training without weight loss did not change insulin resistance in metabolic syndrome subjects or sedentary control subjects. Maximal oxygen consumption (V˙O2max), activated muscle AMP-dependent kinase, and muscle mitochondrial marker ATP synthase all increased. Strength, lean body mass, and fat mass did not change. The activated mammalian target of rapamycin was not different after training. Training induced a shift in muscle fiber composition in both groups but in opposite directions. The proportion of type 2x fibers decreased with a concomitant increase in type 2a mixed fibers in the control subjects, but in metabolic syndrome, type 2x fiber proportion increased and type 1 fibers decreased. Muscle fiber diameters increased in all three fiber types in metabolic syndrome subjects. Muscle insulin receptor expression increased in both groups, and GLUT4 expression increased in the metabolic syndrome subjects. The excess phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser337 in metabolic syndrome muscle tended to increase further after training in spite of a decrease in total IRS-1. Conclusions In the absence of weight loss, the cycle training of metabolic syndrome subjects resulted in enhanced mitochondrial biogenesis and increased the expression of insulin receptors and GLUT4 in muscle but did not decrease the insulin resistance. The failure for the insulin signal to proceed past IRS-1 tyrosine phosphorylation may be related to excess serine phosphorylation at IRS-1 Ser337, and this is not ameliorated by 8 wk of endurance exercise training.

Fundamento. A frequente associação da síndrome metabólica (SMet) com a apneia obstrutiva do sono (AOS) prejudica o balanço simpato-vagal, cujos mecanismos não são totalmente conhecidos. Alterações metabólicas e inflamatórias podem explicar, pelo menos em parte, esta disfunção autonômica. Dieta hipocalórica associada ao treinamento físico (D+TF) é a terapia de primeira escolha no tratamento da SMet e pode impactar na melhora desses parâmetros. Objetivos. Investigar se a sobreposição da AOS na SMet tem um efeito aditivo nas alterações metabólicas e inflamatórias e se essas alterações estão associadas com o desbalanço simpato-vagal. Adicionalmente, investigar o efeito da D+TF nos fatores de risco da SMet, na severidade da AOS, na recuperação da frequência cardíaca pós-esforço máximo (FCrec), no balanço simpato-vagal e nos marcadores metabólicos e inflamatórios. Métodos. Foram estudados 67 pacientes recém-diagnosticados com SMet (ATP-III), não diabéticos e sem uso de medicamentos. Um grupo controle saudável (CS, n=19) também foi recrutado no estudo. A AOS foi definida pelo índice de apneia/hipopneia (IAH) > 15eventos/hora (polissonografia, PSG). Os grupos SMet com AOS (SMet+AOS, n=36) e SMet sem AOS (SMet-AOS, n=31) foram subdivididos consecutivamente em dois grupos:D+TF (D, decréscimo de 500 kcal/dia; e TF, 50-70% VO2pico, 3x/sem, 1h) ou seguimento clínico sem intervenção (C), compondo, assim, os seguintes 4 grupos: SMet+AOS/D+TF (n=19), SMet+AOS/C (n=10), SMet-AOS/D+TF (n=14) e SMet-AOS/C (n=13). No período pré e pós 4 meses de D+TF ou período C, foram realizadas as seguintes avaliações: PSG; microneurografia (atividade nervosa simpática muscular, ANSM); teste esforço cardiopulmonar (TECP) para avaliar o consumo de oxigênio (VO2pico) e o comportamento da FC; glicose e insulina de jejum (índice HOMA-IR e índice QUICKI); teste de tolerância oral à glicose para avaliação da área sobre a curva (ASCglicose e ASCinsulina); leptina; adiponectina; TNF-alfa; PCR; IL1-beta ; e IL-6. Adicionalmente, foi realizado o estudo da variabilidade da FC (banda de alta frequência, AF; banda de baixa frequência, BF e o balanço simpato-vagal cardíaco, AF/BF). Resultados. No período pré-intervenção, exceto pela glicemia de jejum, ambos os grupos com SMet foram semelhantes entre si e diferentes do grupo CS nas variáveis peso, fatores de risco da SMet e na BF e AF/BF. SMet+AOS e SMet-AOS apresentaram prejuízo na ANSM e AF comparados ao CS, enquanto que SMet+AOS apresentou prejuízo na ANSM e AF comparado ao SMet-AOS. Comparado com o CS, somente SMet+AOS apresentou prejuízo na glicemia de jejum (P < 0,001), leptina (P=0,03), ASC glicose (P=0,001), ASCinsulina (P=0,02), HOMA-IR (P < 0,001), QUICKI (P < 0,001) e TNF-alfa (P < 0,05). Adicionalmente, ASCglicose (P=0,004) e QUICKI (P=0,04) foram piores no SMet+AOS que SMet-AOS. AANSM se correlacionou positivamente com leptina (R=0,27; P=0,03), ASCglicose (R=0,38; P=0,002), ASCinsulina (R=0,26; P=0,04) e QUICK (R=-0,30; P=0,02). Após a intervenção por D+TF, os grupos SMet+AOS e SMet-AOS apresentaram redução na ANSM e melhora na recuperação da FC após o TECP. Somente o grupo SMet+AOS submetido à D+TF apresentou redução no IAH (37±3,5 vs. 23±3,4 eventos/h, P=0,003), na insulina de jejum (13±1,3 vs. 9±1, ?UI/mL,P=0,02) no HOMA-IR (3,4±0,4 vs. 2,2±0,3 P=0,03) e no QUICKI (0,32±0,01 vs. 0,35±0,01, P=0,04). Os grupos C para a intervenção não apresentaram alterações no período pós-seguimento clínico. Conclusão. Em pacientes com SMet não diabéticos, a presença da AOS leva a um estado inflamatório e prejudica o controle metabólico e autonômico. A AOS também leva uma exacerbação simpática que pode ser explicada, em parte, pelo prejuízo metabólico da glicemia, insulinemia e leptinemia. Nos pacientes com AOS, a intervenção por D+TF diminuiu a IAH e a resistência à insulina. Independente da AOS, D+TF diminuiu o número de pacientes com SMet e melhorou o controle autonômico / Background. The frequent association between metabolic syndrome (MetS) and obstructive sleep apnea (OSA) impairs the sympathovagal balance, which mechanisms are not fully known. Metabolic and inflammatory alterations could be explain, at least in part, this autonomic dysfunction. Hypocaloric diet and exercise training (D+ET) the first choice therapy in the treatment of SMet and may impact the improvement of these parameters. Objectives. Verify whether the overlap of OSA and MetS has an additive effect on metabolic and inflammatory markers and if these alterations are associated with sympathovagal unbalance. Additionally, to investigate the effect of D+ET over MetS risk factors, OSA severity, heart rate recovery after maximal exercise, the sympathovagal balance and metabolic and inflammatory markers. Methods. We studied 67 patients newly diagnosed with MetS (ATP-III), non-diabetic, without medication. A healthy control group (CS, n=19) was also recruited for the study. OSA was defined by the apnea-hypopnea index (AHI) >15 events/hour (polysomnography, PSG). The groups MetS with OSA (MetS+OSA, n=36) and without OSA (MetS-OSA, n=31) were divided in two groups. The intervention by D+ET (D was decrease of 500 kcal/day, and ET, 50-70% of peakVO2, 3x/week, 1h) or control group (C, follow up without intervention): MetS+OSA/D+ET (n=19), MetS+OSA/C (n=10), MetS-OSA/D+ET (n=14) and MetS + OSA/C (n=13). The pre and post period of 4 months of D+ET or C, were measured: PSG; microneurography (muscular sympathetic nerve activity, MSNA); cardiopulmonary exercise test (CPET) for evaluated the oxygen uptake (peakVO2) and heart rate (HR) response; glucose and insulin (HOMA-IR, QUICKI); oral glucose tolerance test for evaluate the area under the curve (AUCglucose and AUCinsulin); leptin; adiponectin; TNF-alpha; PCR; IL1-beta; IL-6. In addition, HR variability (LF=low frequency, HF=high frequency, LF/HF=sympathovagal balance). Results. In pre-intervention, except for fasting glucose, both MetS groups were similar and different from CS group in the weight, MetS risk factors and LF and HF/LF. MetS+OSA and MetS-OSA showed impairment in ANSM and HF compared to CS. In addition, MetS+OSA impairment in ANSM and HF compared to MetS-OSA. Compared to CS, only the MetS+OSA showed differences in fasting glucose (P < 0.001), leptin (P=0.03), glucose ASC (P=0.001), insulin ASC (P=0.02), HOMA-IR (P < 0.001), QUICKI (P < 0.001), TNF-alpha (P < 0.05). In addition, glycemia ASC (P = 0.004) and QUICKI (P = 0.04) were worse in MetS+OSA than to MetS-OSA. The ANSM correlated with leptin (R=0.27, P=0.03), ASC (R=0.38, P=0.002), ASC insulin; (R=0.26; P=0.04) and QUICK (R=-0.30; P=0.02). After intervention by D+TF, the MetS+OSA and MetS-OSA groups showed a reduction in the ANSM and improvement in the recovery of the HR after the TECP.Only the MetS+OSA group submitted to D+ET showed a diminished in AHI (37±3.5 vs. 23±3.4 events/h, P=0.003), fasting insulin (13±1.3 vs. 9±1, P=0.02), HOMA-IR (3.4±0.4 vs. 2.2±0.3 ?UI/mL, P=0.03) and QUICKI (0.32±0.01 vs. 0.35±0.01, P=0.04). The C groups did not change for intervention. Conclusion. In patients with non-diabetic MetS, the OSA leads to an inflammatory state and impairs in metabolic and autonomic control. The OSA also carries a sympathetic exacerbation that can be explained in part by the metabolic glucose, insulin, and leptin impairment. In patients with OSA, D+ET decreased the AHI and insulin resistance. Independently of AOS, D+ET decreased SMet number and improved autonomic control

L'insuline, hormone clé du contrôle de l'homéostasie métabolique, exerce également des effets trophiques sur la croissance et la prolifération cellulaire. Des études épidémiologiques ont récemment montré que les individus obèses ou diabétiques de type 2 ont un risque plus élevé de développer des cancers et elles ont également suggéré que l’insuline jouerait un rôle dans ce développement tumoral. Ainsi, une signalisation adéquate en aval du récepteur de l’insuline est indispensable pour éviter des processus physiopathologiques. La signalisation de l’insuline est contrôlée par des mécanismes de rétrocontrôle, dont l’adaptateur moléculaire Grb14 qui agit comme un inhibiteur endogène de l’activité catalytique du RI. L’objectif de ma thèse a été d’étudier les conséquences métaboliques et mitogéniques de l’inhibition de Grb14 in#vivo spécifiquement dans le foie de souris. Dans une première étude, nous montrons que sept jours après l’invalidation de Grb14, les souris présentent une activation des voies de signalisation de l’insuline, qui s’accompagne d’une amélioration de la tolérance au glucose et de la production hépatique de glucose. Cependant, de façon paradoxale, la voie de la lipogenèse est très fortement diminuée. En décryptant le mécanisme moléculaire impliqué, nous montrons que l’inhibition de Grb14 permet la libération de la protéine p62/sqstm1 qui active le facteur de transcription Nrf2, ce qui entraine une inhibition du récepteur nucléaire pro-lipogénique LXR. De façon intéressante, l’invalidation de Grb14 chez des souris ob/ob permet de restaurer la glycémie et la stéatose hépatiques à des valeurs comparables aux témoins. Cette étude a ainsi permis de mettre en évidence une nouvelle voie de régulation de la lipogenèse hépatique. Dans une deuxième étude, nous nous sommes intéressés à l'action mitogénique de l'insuline. Nous montrons que 48 heures après l'inhibition de Grb14, les hépatocytes, qui sont des cellules quiescentes, entrent massivement dans le cycle cellulaire. Ce processus est dépendant de l’expression du RI et est médié par la signalisation PI3K/Akt/mTORC1 et la voie Rb/E2F1. Ces données révèlent ainsi que l'insuline est un puissant facteur mitogène dans le foie et que son action est étroitement contrôlée par l’adaptateur Grb14. D’un point de vue physiopathologique, nous avons pu mettre en évidence une diminution de significative de 58% de l’expression de Grb14 dans une collection de 70 CHC humains, apportant ainsi une explication moléculaire à une action pro-tumorigène de l’insuline dans le foie. L’ensemble de ces deux études permet de placer Grb14 au centre de la régulation des actions métaboliques et mitogéniques de l’insuline dans le foie. / Insulin is a key hormone controling metabolic homeostasis which also exerts having trophic effects on cell growth and proliferation. Epidemiological studies have recently shown that obese and type 2 diabetes patients are at higher risk of developing cancers, suggesting that insulin could be involved in tumor development. Proper signaling downstream the insulin receptor is thus essential to prevent pathophysiological processes. Insulin signaling is controlled by feedback mechanisms including the molecular adapter Grb14 which acts as an endogenous inhibitor of the IR catalytic activity. The aim of my PhD was to investigate the metabolic and mitogenic consequences of liver specific Grb14 inhibition in mouse. In the first study, we showed that after seven days of Grb14 invalidation, liver insulin signaling is enhanced, resulting in improved glucose tolerance and diminished hepatic glucose production. However, paradoxically, lipogenesis was greatly decreased. Deciphering the molecular mechanism, we show that Grb14 inhibition leads to the release of its partner p62/SQSTM1, inducing the activation of the Nrf2 transcription factor, which ultimatly inhibited the pro-lipogenic LXR nuclear receptor. Interestingly, Grb14 invalidation in ob/ob mice can restore blood glucose and hepatic steatosis comparable to control values. The study thus highlighted a new pathway controlling lipogenesis that could be targetted to improve metabolic diseases. In the second study, we were interested in insulin mitogenic action. We showed that 48 hours after Grb14 inhibition, hepatocytes that are quiescent cells, massively go through one cell cycle. This process depend on IR expression and is mediated by the PI3K/Akt/mTORC1 pathway and the Rb/E2F1 complex. Our data thus suggest that insulin is a potent mitogenic factor in the liver whose action is closely controlled by the Grb14 adapter in physiological conditions. Importantly, Grb14 expression is significantly decreased in a collection of human HCC, hence bringing out a molecular basis for a pro-tumorigenic action of hyperinsulinemia. Together these two studies reveal that Grb14 is a crucial gatekeeper of insulin metabolic and mitogenic actions in the liver.