Replication of Integrative Data Analysis for Adipose Tissue Dysfunction, Low-Grade Inflammation, Postprandial Responses and OMICs Signatures in Symptom-Free Adults.

We previously reported preliminary characterization of adipose tissue (AT) dysfunction through the adiponectin/leptin ratio (ALR) and fasting/postprandial (F/P) gene expression in subcutaneous (SQ) adipose tissue (AT) biopsies obtained from participants in the GEMM study, a precision medicine research project. Here we present integrative data replication of previous findings from an increased number of GEMM symptom-free (SF) adults (N = 124) to improve characterization of early biomarkers for cardiovascular (CV)/immunometabolic risk in SF adults with AT dysfunction. We achieved this goal by taking advantage of the rich set of GEMM F/P 5 h time course data and three tissue samples collected at the same time and frequency on each adult participant (F/P blood, biopsies of SQAT and skeletal muscle (SKM)). We classified them with the presence/absence of AT dysfunction: low (<1) or high (>1) ALR. We also examined the presence of metabolically healthy (MH)/unhealthy (MUH) individuals through low-grade chronic subclinical inflammation (high sensitivity C-reactive protein (hsCRP)), whole body insulin sensitivity (Matsuda Index) and Metabolic Syndrome criteria in people with/without AT dysfunction. Molecular data directly measured from three tissues in a subset of participants allowed fine-scale multi-OMIC profiling of individual postprandial responses (RNA-seq in SKM and SQAT, miRNA from plasma exosomes and shotgun lipidomics in blood). Dynamic postprandial immunometabolic molecular endophenotypes were obtained to move towards a personalized, patient-defined medicine. This study offers an example of integrative translational research, which applies bench-to-bedside research to clinical medicine. Our F/P study design has the potential to characterize CV/immunometabolic early risk detection in support of precision medicine and discovery in SF individuals.

Full-field electroretinogram behavior in Vogt-Koyanagi-Harada disease: a 24-month longitudinal study in patients from acute onset evaluated with multimodal analysis.

PURPOSE: To prospectively evaluate the dynamic changes of the full-field electroretinogram (ff-ERG) and its association with inflammatory signs in patients with Vogt-Koyanagi-Harada disease (VKHD) followed up after acute onset. METHODS: Twelve acute VKHD patients, who were followed up for at least 24 months, were enrolled at a tertiary center from June 2011 to January 2017. Treatment consisted of intravenous methylprednisolone followed by 1 mg/kg/day of oral prednisone with a slow tapering associated with late non-steroidal immunosuppressive therapy in previously defined cases. Inflammation was systematically evaluated with clinical and posterior segment imaging (PSI) exams (fluorescein angiography, FA, indocyanine green angiography, ICGA, enhanced depth imaging optical coherence tomography, EDI-OCT). A ff-ERG was performed upon enrollment as well as at predefined intervals. Scotopic ff-ERG parameters changes between the 12th and 24th months defined the ERG-stable or ERG-worsening groups. "Flare" was defined as an appearance or worsening of inflammatory signs (after the initial 6 months following disease onset) under the predefined treatment protocol. RESULTS: ff-ERG parameters initially improved in all eyes; in the evaluation between the 12th and 24th months, ff-ERG results were stable in 17 eyes (71 %) and worsened in 7 eyes (29 %). Subnormal ff-ERG results were observed in 15 eyes (62 %) at the 24th month. On the other hand, the flare was observed in 8 eyes (33 %) as cells in the anterior chamber and in 24 eyes (100 %) as any PSI inflammatory sign. The ERG-worsening group presented thicker subfoveal choroid at the first month (p = 0.001) and fluctuations in choroidal thickness more often during follow-up when compared to the ERG-stable group (p = 0.02). CONCLUSIONS: Scotopic ff-ERG parameters worsened between the 12th and 24th months in a quarter of the patients. Subclinical inflammation detected as an increase in CT seems to be related to worsening in visual function measured with ffERG.

Utility of combined inflammatory biomarkers for the identification of cognitive dysfunction in non-diabetic participants of the ELSA-Brasil.

INTRODUCTION: Insulin resistance and low-grade inflammation are pathophysiological mechanisms shared by type 2 diabetes and dementia. A cluster of biomarkers that could help diagnosing cognitive dysfunction prior to the installation of insulin resistance is desirable. This ELSA sub-study examined whether a cluster of selected inflammatory biomarkers was associated with worse cognitive scores in non-diabetic participants. METHODS: A sample of 998 non-diabetic participants of ELSA-Brasil had their cognitive function assessed by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), a verbal fluency test and a trail making test. An inflammatory cluster was formed by using the k-means method. ANOVA was used to compare the tertiles of a composite global cognitive z-score with clinical and laboratory variables. Logistic regression modelling with forward stepwise model selection was performed considering cognitive performance as the outcome and the cluster as the independent variable of main interest. Models were stratified by sex and adjusted for age, insulin resistance and other confounders. RESULTS: The mean age was 45.7 ± 4.9 years and 54.8% were women, who had a higher frequency of university level, healthier behaviors and lower systolic and diastolic blood pressure (BP) levels, fasting plasma glucose, non-HDL cholesterol and E-selectin levels than men. Individuals in the highest tertile of the composite global cognitive z-score were more likely to be women, with university level, and lower mean values of body mass index, BP levels, and HOMA-IR than those in lower tertiles. Using logistic regression model, the cluster category of the highest grade of inflammation showed to be associated with worse cognitive performance in women only. CONCLUSION: The association between a cluster of inflammation and worse cognitive performance seems to be useful to identify middle-aged women at risk for cognitive decline, independently of their state of insulin resistance.

Envolvimento da inflamação subclínica e do estresse oxidativo na resistência à insulina associada a obesidade / Involvement of the subclinical inflammation and oxidative stress in the obesity-associated insulin resistance

A epidemia global da obesidade é um dos mais importantes problemas de saúde pública. Excessiva adiposidade é um crucial fator de risco no surgimento de várias doenças metabólicas, incluindo hipertensão, diabetes mellitus do tipo 2 e doença do fígado gorduroso não alcoólico. Essas condições patológicas estão estritamente associadas com a resistência à insulina. Baseado nos esforços das últimas décadas, ocorreu marcante desenvolvimento na investigação sobre resistência à insulina induzida pela obesidade, especialmente em termos do mecanismo envolvido neste processo. Dentre esses, a inflamação subclínica ou crônica de baixo grau é o mais aceito atualmente. Este estado inflamatório é caracterizado por altos níveis circulantes de citocinas inflamatórias, incluindo TNFα e ILß, e aumentado infiltração de macrófagos em tecidos periféricos. No entanto, tem ocorrido grande interesse no papel que o estresse oxidativo desempenha na indução da resistência à insulina. Sob ativação, muitas células imunes geram radicais livres e, da mesma maneira, a síntese de espécies reativas de oxigênio promovem um status inflamatório. Estudos têm mostrado níveis elevados de espécies reativas e estresse oxidativo em indivíduos e animais obesos e/ou resistentes a insulina; isso parece estar associado a redução da função e da atividade e biogênese mitocondrial causada pelo aumento de lipídeos circulantes e maior deposição de gordura ectópica. Essa revisão discorre sobre o mecanismo fisiopatológico de como a inflamação subclínica induz resistência à insulina na obesidade. Ainda, descreve o papel que o estresse oxidativo desempenha neste processo, bem como a produção de radicais livres na obesidade

The global epidemic of obesity is a major public health problem. Excess adiposity is a major risk factor in the progress of various metabolic disorders including dyslipedima, hypertension, type 2 diabetes, and nonalcoholic fatty liver disease. These pathological states are strongly associated with insulin resistance. On the basis of efforts over the last decades, there have been remarkable developments in the investigation of obesity-induced insulin resistance, especially in terms of the mechanisms involved in this process. Among these, low-grade chronic inflammation is the most accepted actually. This inflammation state is characterized by high circulating levels of inflammatory cytokines, including TNFα and ILß, and increased macrophage infiltration in peripheral tissues. However, there has been a profound interest in the role that oxidative stress plays to induce insulin resistance. Upon activation, many immune cells generate free radicals, and in the same way, the synthesis of reactive oxygen species promotes an inflammatory status. Studies have shown high levels of reactive species and oxidative stress in obese and / or insulin resistant people and animals; it appears to be associated with reduced function and mitochondrial activity and biogenesis caused by increased circulating lipids and increased deposition of ectopic fat. This review discourse on the pathophysiological mechanism of how the subclinical inflammation induce obesity-associated insulin resistance. Also discuss the role that oxidative stress plays to induce insulin resistance, as well as the relation of the free radicals and cytokines in the obesity.

Inflamacion subclinica en diabetes tipo 1 infanto-juvenil / Subclinical inflammation in children and adolescents with type 1 diabetes / Inflamação subclínica em crianças e adolescentes com diabetes tipo 1

En ninos y adolescentes con diabetes tipo 1 (DT1) puede aparecer precozmente un estado de inflamacion subclinica. El objetivo del trabajo fue determinar los niveles plasmaticos de moleculas proinflamatorias en una poblacion infanto-juvenil con DT1, sin evidencias clinicas de complicaciones vasculares y correlacionar estos parametros entre si y con el grado de control glucemico y tiempo de evolucion de la enfermedad. Se estudiaron 42 pacientes con DT1 (21M/21F), de 10 a 13 anos, que se compararon con un grupo control. Se evaluaron: recuento de leucocitos, formas solubles de E-selectina (sE-S) y molecula de adhesion celular vascular 1 (VCAM-1), mieloperoxidasa (MPO), TNF-á, Fibrinogeno (Fg) y uPCR. Los datos se expresaron como mediana y rango intercuartil. Los diabeticos presentaron niveles aumentados de: sE-S [108 (69-150) vs. 68 (52-86) ng/mL, p=0,003], VCAM-1 [785 (732-835) vs 712 (658-758) ng/mL, p=0,04], uPCR [1,00 (0,67-1,70) vs. 0,20 (0,18-0,87) mg/L, p=0,01]. No se observaron diferencias en las moleculas estudiadas segun el grado de control glucemico y tiempo de evolucion de la enfermedad. La uPCR se correlaciono con glucemia en ayunas, HbA1c, sE-S y VCAM1. Los niveles elevados de uPCR, sE-S y VCAM-1 sugieren un estado proinflamatorio asociado a activacion endotelial en ninos con DT1, potenciando el riesgo de enfermedad vascular.

In children and adolescents with type 1 diabetes (T1D), clinical manifestations of vascular complications are uncommon; however, endothelial disturbance and a pro-inflammatory state can emerge early. The objectives of this work were: I) to determine plasma levels of proinflammatory molecules in a T1D pediatric population with no clinical evidence of vascular complications; II) to correlate these parameters with each other, and with glycemic control degree and disease duration. Forty-two patients with T1D (21 M/21W), aged 10 and 13 years and an evolution time not more than 6 years were compared with a control group. The biochemical parameters evaluated were: WBC, sE-S and VCAM-1, MPO, TNF-á, hsCRP and plasma Fg. Glycemic control was performed by determining fasting glucose and HbA1c. Data were expressed as the median and interquartile range. Increased levels of sE-S [108 (69-150) vs. 68 (52-86) ng/mL, p=0.003], VCAM-1 [785 (732-835) vs. 712 (658-758) ng/mL, p=0.04], hsCRP [1.00 (0.67-1.70) vs. 0.20 (0.18- 0.87) mg/L, p=0.01] were found in diabetic patients compared with the control group. No differences in the studied molecules were observed when diabetic patients were grouped according to glycemic control degree and evolution of the disease. hsCRP correlated with fasting glucose, HbA1c, sE-S and VCAM-1. High hsCRP, sE-S and VCAM-1 levels suggest a proinflammatory state associated with endothelial activation in children and adolescents with T1D, potentiating the risk of vascular disease.

Em crianças e adolescentes com diabetes tipo 1 (DT1), um estado de inflamação subclínica pode aparecer de forma precoce. O objetivo do trabalho foi determinar os níveis plasmáticos de moléculas pró-inflamatórias em uma população infanto-juvenil com DM1 sem evidências clínicas de complicações vasculares e correlacionar estes parâmetros, entre si com o grau de controle glicêmico e tempo de evolução da doença. Foram estudados 42 pacientes com DM1 (21M/21F), de 10 a 13 anos, que foram comparados com um grupo controle. Foram avaliadas a contagem de leucócitos, formas solúveis de E-selectina (sE-S) e molécula de adesão celular vascular 1 (VCAM-1), mieloperoxidase (MPO), TNF-á, fibrinogênio (Fg) e PCRus. Os dados foram expressos como mediana e intervalo interquartil. Os pacientes diabéticos apresentaram níveis aumentados de SE-S [108 (69-150) vs. 68 (52-86) ng/mL, p=0,003], VCAM-1 [785 (732-835) vs. 712 (658-758) ng/mL, p=0,04], PCRus [1,00 (0,67-1,70) vs. 0,20 (0,18-0,87) mg/L, p=0,01]. Não foram observadas diferenças nas moléculas estudadas segundo o grau de controle glicêmico e tempo de evolução da doença. O PCRus foi correlacionado com glicemia em jejum, HbA1c, sES e VCAM1. Os níveis elevados de PCRus, sE-S e VCAM-1 sugerem um estado pró-inflamatório associado com a ativação do endotélio em crianças com DM1, aumentando o risco de doença vascular.