Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subject

Elucidating the potential mechanisms involved in the detrimental effect of excess body weight on insulin action is an important priority in counteracting obesity-associated diseases. The present study aimed to disentangle the epigenetic basis of insulin resistance by performing a genome-wide epigenetic analysis in visceral adipose tissue (VAT) from morbidly obese patients depending on the insulin sensitivity evaluated by the clamp technique. The global human methylome screening performed in VAT from 7 insulin-resistant (IR) and 5 insulin-sensitive (IS) morbidly obese patients (discovery cohort) analyzed using the Infinium HumanMethylation450 BeadChip array identified 982 CpG sites able to perfectly separate the IR and IS samples. The identified sites represented 538 unique genes, 10% of which were diabetes-associated genes. The current work identified novel IR-related genes epigenetically regulated in VAT, such as COL9A1, COL11A2, CD44, MUC4, ADAM2, IGF2BP1, GATA4, TET1, ZNF714, ADCY9, TBX5, and HDACM. The gene with the largest methylation fold-change and mapped by 5 differentially methylated CpG sites located in island/shore and promoter region was ZNF714. This gene presented lower methylation levels in IR than in IS patients in association with increased transcription levels, as further reflected in a validation cohort (n = 24; 11 IR and 13 IS). This study reveals, for the first time, a potential epigenetic regulation involved in the dysregulation of VAT that could predispose patients to insulin resistance and future type 2 diabetes in morbid obesity, providing a potential therapeutic target and biomarkers for counteracting this process

Tumor necrosis factor system activity is associated with insulin resistance and dyslipidemia in myotonic dystrophy

Myotonic dystrophy (MyD) is a multisystem autosomal dominant disorder associated with progressive muscle wasting and weakness. The striking metabolic abnormality in MyD is insulin resistance. The mechanism by which target tissues are insensitive to insulin action remains uncertain. In a recent study, plasma soluble tumor necrosis factor receptor (sTNFR)2 levels were found to be associated with muscle tissue mass and insulin resistance. Given these associations, we speculated that disorders of the muscle cell membrane could lead simultaneously to insulin insensitivity and sTNFR2 leakage in MyD. To test this hypothesis, we measured the levels of circulating sTNFR1 and sTNFR2 and insulin resistance in MyD patients. We studied 22 MyD patients and 24 age-, BMI-, and fat mass-matched control subjects. Both MyD men and women showed higher plasma insulin levels in the presence of comparable glucose concentrations than did control subjects. sTNFR2, but not sTNFR1, levels were approximately 1.5-fold higher in MyD patients. In parallel with these findings, the fasting insulin resistance index (FIRI) was also higher in MyD patients. In fact, in the whole population, fasting insulin and FIRI strongly correlated with sTNFR2 in both men (r = 0.77 and r = 0.81, P<0.0001, respectively) and women (r = 0.67 and r = 0.64, P = 0.001, respectively). sTNFR2 levels were also associated with the insulin sensitivity index (S(I)), calculated from an oral glucose tolerance test (OGTT) according to the method by Cederholm and Wibell (r = -0.43, P = 0.006). We constructed a multiple linear regression to predict FIRI, with BMI, waist-to-hip ratio, and sTNFR2 as independent variables. In this model, both BMI (P = 0.0014) and sTNFR2 (P = 0.0048) levels contributed independently to 46% of the variance of FIRI. In another model, in which FIRI was substituted for S(I) from the OGTT, both BMI (P = 0.0001) and sTNFR2 (P = 0.04) levels contributed independently to 48% of the variance of S(I) from the OGTT. Plasma cholesterol and triglyceride concentrations were significantly increased in MyD patients. sTNFR1 and sTNFR2 levels were found to be strongly associated with plasma cholesterol, LDL cholesterol, and triglycerides. sTNFR1 and sTNFR2 also correlated with serum creatine kinase activity in MyD patients (r = 0.57, P = 0.006; r = 0.75, P<0.0001, respectively). In conclusion, here we describe, for the first time to our knowledge, a relationship between insulin action and plasma sTNFR2 concentration in MyD patients. We have also found increased concentrations of plasma triglycerides and cholesterol levels in parallel with sTNFR1 and sTNFR2 concentrations in MyD patients. We speculate that the latter associations are dependent on, and secondary to, increased tumor necrosis factor (TNF)-alpha action. Whether TNF action is implicated in the pathogenesis of MyD or is a simple marker of disease activity awaits further studies

El impacto de la diabetes gestacional sobre el desarrollo fetal: más allá de la glucemia

[spa] OBJETIVOS: La diabetes gestacional (DG) es una entidad que se ha relacionado con un mayor riesgo de complicaciones gestacionales. Los objetivos de este estudio fueron: 1) determinar el impacto de la hiperglucemia leve, 2) evaluar las asociaciones entre las complicaciones gestacionales y el grado de tolerancia a la glucosa, obesidad maternal pregestacional, 3) conocer cuál es el rol del sexo fetal en el desarrollo del propio feto en relación a la presencia de DG y obesidad materna pregestacional, y 4)conocer la prevalencia de la DG según los diferentes criterios diagnósticos (criterios de la National Diabetes Data Group y de la Asociación Americana de Diabetes). MÉTODOS: Estudio poblacional prospectivo multicéntrico, que incluyó 9.270 mujeres gestantes con feto único y sin diabetes pregestacional conocida que dio lugar a 4.793 recién nacidos de sexo masculino y 4.477 de sexo femenino. Las mujeres fueron categorizadas según el grado de tolerancia a la glucosa y según IMC pregestacional. Se evaluó el riesgo de macrosomía, tasa de cesáreas y de otras 7 complicaciones gestacionales, mediante modelos de regresión logística múltiple y se calculó el riesgo atribuible en la población. RESULTADOS-CONCLUSIONES: 1) Las mujeres con hiperglucemia leve presentaron una asociación con la presencia de complicaciones similar al grupo control, por lo que no se aconseja un cambio en los criterios diagnósticos. 2) En términos de riesgo absoluto y en términos de freceuncia del riesgo atribuible en la población la contribución de la hiperglucemia leve en las complicaciones gestacionales fue inferior a la presentada por la obesidad materna. 3) Se demostró un dimorfismo sexual en la frecuencia de las complicaciones gestacionales. La presencia de DG sólo se relacionó con morbilidad fetal exclusivamente en el sexo masculino. 4) La prevalencia de DG fue del 8,8% con los criterios NDDG y del 11,6% con los criterios de Carpenter y Coustan (incremento relativo del 31.8%).[eng] OBJECTIVE: Gestational diabetes mellitus (GDM) increases the risk of adverse complications for both mother and child during pregnancy. The objectives of this study were: 1) To evaluate the potential impact of mild hyperglycemia on GDM outcomes; 2) To evaluate the associations among adverse gestational outcomes and glucose tolerance status and maternal obesity; 3) To elucidate whether the adverse gestational outcomes is influenced by maternal obesity and abnormal glucose tolerance differently in male and female fetuses. 4) To know GDM prevalence according to the different diagnostic criteria (National Diabetes Data Group and American Diabetes Association criteria). Methods: A population study in 16 general hospitals from the Spanish National Health Service -that included 9,270 consecutive women with singleton pregnancies and without a former diagnosis of diabetes mellitus delivering 4,793 male and 4,477 female newborns- was conducted. Women were categorized according to glucose tolerance status and pregestational body mass index (BMI). Fetal macrosomia, caesarean section and seven secondary outcomes were evaluated. Logistic regression analyses were performed to predict the effect of maternal BMI category and glucose tolerance on gestational outcomes. The population-attributable fractions (PAf) of predictor variables were also calculated. RESULTS/CONCLUSIONS: 1) The contribution of mild hyperglycemia to adverse GDM outcomes was not significantly different to that of control group. Therefore a change in diagnostic criteria was not warranted in our setting. 2) Pregestational maternal BMI (both the absolute risk and PAf) exhibited a much stronger influence on macrosomia, Caesarean section, pregnancy-induced hypertension and large-for-gestational-age newborns than glucose tolerance status. 3) There was a sexual dimorphism in the risk of abnormal birth weight attributed to maternal glucose tolerance status. A closer surveillance of fetal growth might be warranted in pregnant women with abnormal glucose tolerance carrying a male fetus. 4) Of 9,270 pregnant women screened for GDM, 819 (8.8%) met National Diabetes Data Group criteria. If the threshold for defining GDM had been lowered to ADA criteria, an additional 2.8% of women would have been defined as having the condition (relative increase of 31.8%)

Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subject

Elucidating the potential mechanisms involved in the detrimental effect of excess body weight on insulin action is an important priority in counteracting obesity-associated diseases. The present study aimed to disentangle the epigenetic basis of insulin resistance by performing a genome-wide epigenetic analysis in visceral adipose tissue (VAT) from morbidly obese patients depending on the insulin sensitivity evaluated by the clamp technique. The global human methylome screening performed in VAT from 7 insulin-resistant (IR) and 5 insulin-sensitive (IS) morbidly obese patients (discovery cohort) analyzed using the Infinium HumanMethylation450 BeadChip array identified 982 CpG sites able to perfectly separate the IR and IS samples. The identified sites represented 538 unique genes, 10% of which were diabetes-associated genes. The current work identified novel IR-related genes epigenetically regulated in VAT, such as COL9A1, COL11A2, CD44, MUC4, ADAM2, IGF2BP1, GATA4, TET1, ZNF714, ADCY9, TBX5, and HDACM. The gene with the largest methylation fold-change and mapped by 5 differentially methylated CpG sites located in island/shore and promoter region was ZNF714. This gene presented lower methylation levels in IR than in IS patients in association with increased transcription levels, as further reflected in a validation cohort (n = 24; 11 IR and 13 IS). This study reveals, for the first time, a potential epigenetic regulation involved in the dysregulation of VAT that could predispose patients to insulin resistance and future type 2 diabetes in morbid obesity, providing a potential therapeutic target and biomarkers for counteracting this process