Genetic risk score for insulin resistance based on gene variants associated to amino acid metabolism in young adults.

Circulating concentration of arginine, alanine, aspartate, isoleucine, leucine, phenylalanine, proline, tyrosine, taurine and valine are increased in subjects with insulin resistance, which could in part be attributed to the presence of single nucleotide polymorphisms (SNPs) within genes associated with amino acid metabolism. Thus, the aim of this work was to develop a Genetic Risk Score (GRS) for insulin resistance in young adults based on SNPs present in genes related to amino acid metabolism. We performed a cross-sectional study that included 452 subjects over 18 years of age. Anthropometric, clinical, and biochemical parameters were assessed including measurement of serum amino acids by high performance liquid chromatography. Eighteen SNPs were genotyped by allelic discrimination. Of these, ten were found to be in Hardy-Weinberg equilibrium, and only four were used to construct the GRS through multiple linear regression modeling. The GRS was calculated using the number of risk alleles of the SNPs in HGD, PRODH, DLD and SLC7A9 genes. Subjects with high GRS (≥ 0.836) had higher levels of glucose, insulin, homeostatic model assessment- insulin resistance (HOMA-IR), total cholesterol and triglycerides, and lower levels of arginine than subjects with low GRS (p < 0.05). The application of a GRS based on variants within genes associated to amino acid metabolism may be useful for the early identification of subjects at increased risk of insulin resistance.

Soluble receptor for advanced glycation end-products (sRAGE) in childhood obesity: association with gene expression of RAGE and cardiometabolic markers / Receptor soluble para productos finales de glicación avanzada (sRAGE) en la obesidad infantil:asociación con la expresión génica de RAGE y marcadores cardiometabólicos

Introduction: advanced glycation end-products (AGEs) interact with the receptor for AGEs (RAGE). Full-length RAGE is associated with intracellular signal transduction, and soluble-RAGE (sRAGE) lacks the transmembrane and cytoplasmic domains, acting as a competitive inhibitor ofAGEs-RAGE binding. sRAGE levels in healthy children are associated with cell surface expression of RAGE. However, the expression of RAGE hasnot been explored in childhood obesity.Objective: the study aim was to evaluate the sRAGE levels and the gene expression of RAGE in children and its association with cardiometabolicmarkers.Methods: this is a cross-sectional study with 6-11-year children, 20 with overweight and 20 with obesity. Anthropometric measurements includedwaist circumference (cm) (WC), neck circumference (NC), weight (kg), fat mass (%), trunk fat (kg), muscular mass (kg), height (cm), and bodymass index (BMI) (kg/m2). Blood samples following an overnight fast were collected to measure glucose (mg/dl) and lipid profile with colorimetricmethods. sRAGE was determined in serum using the enzyme-linked immunosorbent assay (ELISA). Quantitative reverse transcription (RT-qPCR)was performed to analyze RAGE transcripts in peripheral blood mononuclear cells isolated by Ficoll®-Hypaque.Results: we found higher RAGE (p = 0.0315) and lower sRAGE (p = 0.0305) levels in the obesity group. sRAGE level showed a negative correlation with RAGE (r = -0.35) and BMI (r = -0.24), and positive with HDL-cholesterol (r = 0.29). Regression analysis suggests that HDL-C andRAGE levels are predictors of sRAGE levels.Conclusions: expression of RAGE is associated with lower sRAGE levels in childhood obesity. Moreover, obese children show higher cardiometabolic risk markers, and a positively associated with sRAGE. (AU)

Introducción: los productos finales de glicación avanzada (AGE) interactúan con el receptor de AGE (RAGE). El RAGE de longitud completaestá asociado con la transducción de señales intracelulares y el RAGE soluble (sRAGE) carece de los dominios transmembrana y citoplásmico,actuando como un inhibidor competitivo de la unión de AGE-RAGE. Los niveles de sRAGE en niños sanos están asociados con la expresión deRAGE en la superficie celular. Sin embargo, la expresión de RAGE no se ha explorado en la obesidad infantil.Objetivo: el objetivo del estudio fue evaluar los niveles de sRAGE y la expresión génica de RAGE en niños y su asociación con marcadorescardiometabólicos.Métodos: se trata de un estudio transversal con niños de seis a once años, 20 con sobrepeso y 20 con obesidad. Las medidas antropométricasincluyeron la circunferencia de la cintura (cm) (CC), la circunferencia del cuello (NC), el peso (kg), la masa grasa (%), la grasa del tronco (kg),la masa muscular (kg), la altura (cm) y el índice de masa corporal (IMC) (kg/m2). Se tomaron muestras de sangre después de una noche deayuno para medir glucosa (mg/dl) y el perfil de lípidos con métodos colorimétricos. Los sRAGE se determinaron en suero utilizando un ensayoinmunoabsorbente ligado a enzimas (ELISA). Se realizó una transcripción inversa cuantitativa (RT-qPCR) para analizar los transcritos de RAGE encélulas mononucleares de sangre periférica aisladas por Ficoll®-Hypaque.Resultados: encontramos niveles más altos de RAGE (p = 0,0315) y más bajos de sRAGE (p = 0,0305) en el grupo de obesidad. El nivel de sRAGE mostró una correlación negativa con RAGE (r = -0,35) e IMC (r = -0,24), y positiva con el colesterol HDL (r = 0,29). El análisis de regresión sugiere que los niveles de HDL-C y RAGE predicen los niveles de sRAGE.Conclusiones: la expresión de RAGE se asocia con niveles más bajos de sRAGE en la obesidad infantil. ... (AU)

Soluble receptor for advanced glycation end-products (sRAGE) in childhood obesity: association with gene expression of RAGE and cardiometabolic markers.

Introduction: Introduction: advanced glycation end-products (AGEs) interact with the receptor for AGEs (RAGE). Full-length RAGE is associated with intracellular signal transduction, and soluble-RAGE (sRAGE) lacks the transmembrane and cytoplasmic domains, acting as a competitive inhibitor of AGEs-RAGE binding. sRAGE levels in healthy children are associated with cell surface expression of RAGE. However, the expression of RAGE has not been explored in childhood obesity. Objective: the study aim was to evaluate the sRAGE levels and the gene expression of RAGE in children and its association with cardiometabolic markers. Methods: this is a cross-sectional study with 6-11-year children, 20 with overweight and 20 with obesity. Anthropometric measurements included waist circumference (cm) (WC), neck circumference (NC), weight (kg), fat mass (%), trunk fat (kg), muscular mass (kg), height (cm), and body mass index (BMI) (kg/m2). Blood samples following an overnight fast were collected to measure glucose (mg/dl) and lipid profile with colorimetric methods. sRAGE was determined in serum using the enzyme-linked immunosorbent assay (ELISA). Quantitative reverse transcription (RT-qPCR) was performed to analyze RAGE transcripts in peripheral blood mononuclear cells isolated by Ficoll®-Hypaque. Results: we found higher RAGE (p = 0.0315) and lower sRAGE (p = 0.0305) levels in the obesity group. sRAGE level showed a negative correlation with RAGE (r = -0.35) and BMI (r = -0.24), and positive with HDL-cholesterol (r = 0.29). Regression analysis suggests that HDL-C and RAGE levels are predictors of sRAGE levels. Conclusions: expression of RAGE is associated with lower sRAGE levels in childhood obesity. Moreover, obese children show higher cardiometabolic risk markers, and a positively associated with sRAGE.

Introducción: Introducción: los productos finales de glicación avanzada (AGE) interactúan con el receptor de AGE (RAGE). El RAGE de longitud completa está asociado con la transducción de señales intracelulares y el RAGE soluble (sRAGE) carece de los dominios transmembrana y citoplásmico, actuando como un inhibidor competitivo de la unión de AGE-RAGE. Los niveles de sRAGE en niños sanos están asociados con la expresión de RAGE en la superficie celular. Sin embargo, la expresión de RAGE no se ha explorado en la obesidad infantil. Objetivo: el objetivo del estudio fue evaluar los niveles de sRAGE y la expresión génica de RAGE en niños y su asociación con marcadores cardiometabólicos. Métodos: se trata de un estudio transversal con niños de seis a once años, 20 con sobrepeso y 20 con obesidad. Las medidas antropométricas incluyeron la circunferencia de la cintura (cm) (CC), la circunferencia del cuello (NC), el peso (kg), la masa grasa (%), la grasa del tronco (kg), la masa muscular (kg), la altura (cm) y el índice de masa corporal (IMC) (kg/m2). Se tomaron muestras de sangre después de una noche de ayuno para medir glucosa (mg/dl) y el perfil de lípidos con métodos colorimétricos. Los sRAGE se determinaron en suero utilizando un ensayo inmunoabsorbente ligado a enzimas (ELISA). Se realizó una transcripción inversa cuantitativa (RT-qPCR) para analizar los transcritos de RAGE en células mononucleares de sangre periférica aisladas por Ficoll®-Hypaque. Resultados: encontramos niveles más altos de RAGE (p = 0,0315) y más bajos de sRAGE (p = 0,0305) en el grupo de obesidad. El nivel de sRAGE mostró una correlación negativa con RAGE (r = -0,35) e IMC (r = -0,24), y positiva con el colesterol HDL (r = 0,29). El análisis de regresión sugiere que los niveles de HDL-C y RAGE predicen los niveles de sRAGE. Conclusiones: la expresión de RAGE se asocia con niveles más bajos de sRAGE en la obesidad infantil. Además, los niños obesos muestran marcadores de riesgo cardiometabólico más elevados y una asociación positiva con sRAGE.

Visceral adiposity index is a better predictor to discriminate metabolic syndrome than other classical adiposity indices among young adults.

BACKGROUND: Visceral adiposity index (VAI) has been identified as a cardiometabolic risk marker in children and adolescents which reflects abdominal fat distribution. The aim of the present study was to evaluated the predictive capacity of VAI, a body shape index (ABSI), atherogenic index of plasma (AIP), and triglycerides and glucose index (TyG index) compared with classical anthropometric measurements to discriminate metabolic syndrome (MetS). METHODS: This retrospective study included 1372 individuals. Anthropometric, clinical, and biochemical measurements were used to screen the prevalence of MetS components and to calculate VAI, ABSI, TyG index, and AIP. RESULTS: The discriminatory capacity among the variables was assessed by the area under the receiver operating characteristic (ROC) curve (AUC). VAI was the variable with the highest AUC with 0.932 CI 95% (0.917-0.948), followed by AIP with 0.914 CI 95% (0.897-0.931), and TyG index with 0.889 CI 95% (0.871-0.908). CONCLUSION: VAI is a promising tool to identify MetS in the late adolescence setting. Among the novel adiposity indexes VAI, AIP, TyG index are able to determine MetS presence, while ABSI is not capable.

[Distribution of triglycerides and glucose (TyG) index and homeostasis model assessment insulin resistance for the evaluation of insulin sensitivity on late adolescence in Mexicans]. / Distribución del índice triglicéridos y glucosa (TyG) y el modelo homeostático para la evaluación de la resistencia a la insulina en la adolescencia tardía en mexicanos.

Introduction: Introduction: when peripheral tissues don't respond well to insulin action, it is defined as insulin resistance (IR). Many methods and indices are available for the estimation of IR, among them the homeostasis model assessment of insulin resistance (HOMA-IR) involves fasting plasma glucose and insulin. Nevertheless, the TyG index has a methodological advantage over the HOMA-IR because it requires only measurements provided by routine laboratory tests. Aim: distribution asessment of the HOMA-IR and TyG indexes in the sample. Also, to determine the predictive capacity of HOMA-IR, using TyG cutoff point as IR-positive diagnostic test. Materials and methods: a cross-sectional analytical study with 1686 participants aged 18 to 21 years from the state of San Luis Potosí, Mexico. Anthropometric assessment involves variables of weight and height. Fasting glucose, insulin and triglyceride concentrations were quantified. In addition, a questionnaire was carried out to know the hereditary family history and the presence of noncommunicable diseases (NCDs). Student's t-test was used to assess the differences in mean statistics between males and females. A receiver operating characteristic (ROC) curve was applied to examine the potential of HOMA-IR to identify IR. Results: 56 % of the study adolescents were females and 44 % were males; mean BMI was 22.62 ± 3.21 kg/m2. In the total sample mean serum glucose, insulin, and triglyceride concentrations were 89.48 ± 9.84 mg/dL, 6.26 ± 5.04 µU/mL, and 95.64 ± 55.78 mg/dL, respectively. A prevalence of 28.2 % of IR was determined, evaluated with the cut-off points for the TyG index. Subsequently, Receiver Operator Curves (ROC) were performed to evaluate the predictive capacity of HOMA-IR. The most outstanding cut-off value was 1.08 for the HOMA-IR index, reaching a sensitivity of 66 % and a specificity of 53 %. The prevalence of HOMA-IR greater than or equal to 1.18 was 47 % in the total population, 19.3 % in males and 28.5 % in females Conclusions: HOMA-IR and TyG can be useful diagnostic parameters for the assessment of IR in late adolescence. To provide a health guide for IR, we propose that a HOMA-IR target value ≤ 1.08 should be considered.

Introducción: Introducción: cuando los tejidos periféricos tienen una incapacidad para responder a la acción de la insulina se denomina resistencia a la insulina (RI). Existen diferentes métodos para la identificación de la RI; uno de estos es el índice HOMA-IR, que utiliza los parámetros de laboratorio, glucosa e insulina en ayunas. El índice triglicéridos y glucosa (TyG) presenta la ventaja de solo necesitar análisis de laboratorio de rutina. Objetivo: evaluación de la distribución de los índices HOMA-IR y TyG en la población, así como determinar la capacidad predictiva del índice HOMA-IR utilizando el TyG como prueba diagnóstica para la RI. Materiales y métodos: estudio analítico transversal con 1686 participantes de 18 a 21 años del estado de San Luis Potosí. Se tomaron variables antropométricas de peso y talla y se cuantificó la concentración de glucosa, insulina y triglicéridos en ayuno. Además, se realizó un cuestionario para conocer los antecedentes heredofamiliares y la presencia de enfermedades no transmisibles (ENT). Para la comparación entre mujeres y hombres se realizó una prueba de la t de Student y se realizaron curvas operador receptor (COR) para determinar los valores de corte del HOMA-IR. Resultados: el 56 % de la población fueron mujeres y el 44 % hombres; la media del IMC fue de 22,62 ± 3,21 kg/m2. En la población total de estudio, la media de la concentración sérica de glucosa, insulina y triglicéridos fue de 89,48 ± 9,84 mg/dL, 6,26 ± 5,04 µU/mL y 95,64 ± 55,78 mg/dL, respectivamente. Se determinó una prevalencia del 28,2 % de la RI evaluada con los puntos de corte para el índice TyG. Posteriormente se realizaron curvas operador receptor (COR) para evaluar la capacidad predictiva del HOMA-IR. El valor de corte más destacado fue de 1,08 para el índice HOMA-IR, alcanzando una sensibilidad del 66 % y una especificidad del 53 %. La prevalencia del HOMA-IR mayor o igual a 1,18 fue del 47 % en la población total, del 19,3 % en los hombres y del 28,5 % en las mujeres. Conclusiones: los índices HOMA-IR y TyG pueden ser parámetros de utilidad diagnóstica para la valoración de la RI en la adolescencia tardía. Con el objetivo de brindar una guía de salud para la RI, proponemos que se debe considerar como objetivo un valor de HOMA-IR ≤ 1,08.

Distribución del índice triglicéridos y glucosa (TyG) y el modelo homeostático para la evaluación de la resistencia a la insulina en la adolescencia tardía en mexicanos / Distribution of triglycerides and glucose (TyG) index and homeostasis model assessment insulin resistance for the evaluation of insulin sensitivity on late adolescence in Mexicans

Introducción: cuando los tejidos periféricos tienen una incapacidad para responder a la acción de la insulina se denomina resistencia a la insulina (RI). Existen diferentes métodos para la identificación de la RI; uno de estos es el índice HOMA-IR, que utiliza los parámetros de laboratorio, glucosa e insulina en ayunas. El índice triglicéridos y glucosa (TyG) presenta la ventaja de solo necesitar análisis de laboratorio de rutina. Objetivo: evaluación de la distribución de los índices HOMA-IR y TyG en la población, así como determinar la capacidad predictiva del índice HOMA-IR utilizando el TyG como prueba diagnóstica para la RI. Materiales y métodos: estudio analítico transversal con 1686 participantes de 18 a 21 años del estado de San Luis Potosí. Se tomaron variables antropométricas de peso y talla y se cuantificó la concentración de glucosa, insulina y triglicéridos en ayuno. Además, se realizó un cuestionario para conocer los antecedentes heredofamiliares y la presencia de enfermedades no transmisibles (ENT). Para la comparación entre mujeres y hombres se realizó una prueba de la t de Student y se realizaron curvas operador receptor (COR) para determinar los valores de corte del HOMA-IR. (AU)

Introduction: when peripheral tissues don't respond well to insulin action, it is defined as insulin resistance (IR). Many methods and indices are available for the estimation of IR, among them the homeostasis model assessment of insulin resistance (HOMA-IR) involves fasting plasma glucose and insulin. Nevertheless, the TyG index has a methodological advantage over the HOMA-IR because it requires only measurements provided by routine laboratory tests. Aim: distribution asessment of the HOMA-IR and TyG indexes in the sample. Also, to determine the predictive capacity of HOMA-IR, using TyG cutoff point as IR-positive diagnostic test. Materials and methods: a cross-sectional analytical study with 1686 participants aged 18 to 21 years from the state of San Luis Potosí, Mexico. Anthropometric assessment involves variables of weight and height. Fasting glucose, insulin and triglyceride concentrations were quantified. In addition, a questionnaire was carried out to know the hereditary family history and the presence of noncommunicable diseases (NCDs). Student's t-test was used to assess the differences in mean statistics between males and females. A receiver operating characteristic (ROC) curve was applied to examine the potential of HOMA-IR to identify IR. (AU)

Decreased levels and activity of Sirt1 are modulated by increased miR-34a expression in adipose tissue mononuclear cells from subjects with overweight and obesity: A pilot study.

BACKGROUND AND AIMS: Overweight and obesity are important risk factors for chronic disorders. Fat accumulation is one of the central manifestations; it occurs via a complex mechanism where multiple metabolic signals converge. Sirtuins are an enzyme family with deacetylase functions that are implicated in the regulation of several genes. Sirt1 and its upstream regulator (miR-34a) are elements of a converging mechanism that integrates the dynamic metabolic state. In this work, we hypothesized that elevated levels of miR-34a in overweight/obese group inhibits Sirt1 activity. Therefore, we studied the miR-34a/Sirt1 axis in mononuclear cells obtained from adipose tissue. METHODS: Adipose tissue samples were collected from 36 subjects, and they were categorized according to body mass index (BMI) as overweight/obesity and normoweight. Subcutaneous adipose tissue samples were enzymatically dissociated, and mononuclear cells from adipose tissue were isolated by Ficoll Hypaque. Sirt1-positive cells and relative Sirt1 expression were determined by flow cytometry and real-time polymerase chain reaction (qPCR), respectively. Finally, Sirt1 activity was measured with a luminescence assay. RESULTS: The percentage of Sirt1-positive mononuclear cells from adipose tissue decreased along with Sirt1 enzymatic activity in overweight/obese participants. miR-34a expression increased in the overweight/obese group compared to normoweight individuals. There was a negative association between the relative miR-34a expression and Sirt1-positive cells and a synergistic effect on Sirt1-positive cells mediated by the miR-34a inhibitor and Sirt1 agonist. CONCLUSIONS: Our results describe for the first time the presence of miR-34a and Sirt1 in mononuclear cells isolated from subcutaneous adipose tissue. Additionally, these results suggest altered sirtuin function in overweight/obese patients and open the possibility for new therapies that involve these metabolic targets.

P2X4 receptor as a modulator in the function of P2X receptor in CD4+ T cells from peripheral blood and adipose tissue.

Obesity is characterized by immune cell infiltration and inflammation. Purinergic receptors such as P2X1, 4 and 7 are expressed on immune cells and their activation contributes with an inflammatory response. However, the simultaneous expression of P2X1, 4 and 7 during overweight or obesity have not been described. Therefore, the aim of this study was to determine single and simultaneously expression and function of the P2X1, 4 and 7 receptors in lymphocytes and CD4 + T cells from peripheral blood (PB) and adipose tissue (AT). Our results showed a higher expression of the P2X4 receptor on CD4 + T cells from PB regarding P2X7 and P2X1 receptor expression. In addition, P2X4 receptor expression on CD4 + T cells from PB and AT was increased in individuals with BMI ≥ 25 Kg/m2. Moreover, a higher simultaneous expression of the P2X4 and P2X7 receptors on CD4 + T cells from AT compared to CD4 + T cells expressing P2X1 and P2X7 receptors simultaneously. Besides, CD4 + T cells expressing P2X4 and P2X7 receptors from PB and AT were augmented in individuals with BMI ≥ 25 Kg/m2. In addition, the percentage of lymphocytes and also CD4 + T cells expressing P2X4 receptor were elevated both in PB and AT compared to cells expressing P2X7 or P2X1. However, CD4 + T cells expressing P2X4 and P2X7 were augmented in AT compared to PB. The function of the receptors showed a lower shedding of CD62 L in adipose tissue mononuclear cells (ATMC) compared with peripheral blood mononuclear cells (PBMC) and a greater participation of P2X4 in the mobilization of intracellular calcium. We concluded that it was possible to determine for the first time the simultaneous expression of purinergic receptors in ATMC, where the P2X4 receptor has a greater participation in the activation of CD4 + T cells possibly modulating the function of the other two receptors.

Increased levels of adipose tissue-resident Th17 cells in obesity associated with miR-326.

miRNAs are important immune regulators in the control of the CD4 + T cells phenotype. miR-326 regulates the differentiation towards Th17 cells and the inhibition of miR-155 is associated with low levels of Treg cells. However, miRNAs expression and transcription factors associated with these lymphocyte subsets in obesity-induced adipose tissue inflammation is still unknown. The aim of this work was to identify Th17 cells in subcutaneous adipose tissue (SAT), proinflammatory cytokine production and their association with the miRNAs and transcription factors involved. We collected SAT samples obtained by lipoaspiration from individuals with normal weight, overweight and obesity. We obtained the stromal vascular fractions and then a Ficoll gradient was performed to obtain adipose tissue mononuclear cells (ATMC). Th17 cells were evaluated by flow cytometry and the expression of miR-326, miR-155, RORC2 and FOXP3 by qRT-PCR. We also analyzed cytokines from the supernatants of the ATMC culture and measured the FOXP3 methylation percentage by bisulfite conversion by PCR. According to the results, the frequency of Th17 cells and RORC2 expression was higher in individuals with obesity and associated with miR-326 expression. The ATMC from this group secreted a proinflammatory cytokine profile by in vitro assay. In contrast, lower levels of mRNA FOXP3 expression was detected in ATMC from individuals with obesity that correlated with methylation percentage of FOXP3 gene but no association with miR-155 was detected. Our results suggested that miR-326 participates in the polarization towards Th17 promoting the inflammatory state in the obesity-induced adipose tissue.

Altered levels of sirtuin genes (SIRT1, SIRT2, SIRT3 and SIRT6) and their target genes in adipose tissue from individual with obesity.

INTRODUCTION: Sirtuins regulate energy metabolism and insulin sensitivity through their ability to act as energy sensors and regulators in several metabolic tissues. AIM: To evaluate the expression levels of sirtuin genes SIRT1, SIRT2, SIRT3 and SIRT6 and their target genes (PPAR-α, PGC1-α, NRF1, DGAT1, PPAR-γ and FOXO3a) in subcutaneous adipose tissue collected from individuals with normoweight, overweight and obesity. METHODS: Adipose tissue samples, obtained by lipoaspiration during liposuction surgery, were processed to obtain RNA, which was reverse-transcribed to cDNA. Then, we measured the expression levels of each gene by qPCR. RESULTS: We found differences in the mRNA expression of SIRT1, SIRT2, SIRT3 and SIRT6 and their target genes (PPAR-α, PGC1-α, NRF1, DGAT1, PPAR-γ and FOXO3a) in adipose tissue from overweight or obese subjects when compared to normoweight subjects. All genes analyzed, except SIRT2, showed correlation with BMI. CONCLUSIONS: Our findings in human subcutaneous adipose tissue show that increased body mass index modifies the expression of genes encoding sirtuins and their target genes, which are metabolic regulators of adipose tissue. Therefore, these could be used as biomarkers to predict the ability of adipose tissue to gain mass of adipose tissue.