RESUMEN

Overstimulation of pancreatic ß-cells can lead to dysfunction and death, prior to the clinical manifestations of type 2 diabetes (T2D). The excessive consumption of carbohydrates induces metabolic alterations that can affect the functions of the ß-cells and cause their death. We analyzed the role of p53 in pancreatic ß cell death in carbohydrate-supplemented Sprague Dawley rats. For four months, the animals received drinking water containing either 40% sucrose or 40% fructose. The glucose tolerance test was performed at week 15. Apoptosis was assessed with the TUNEL assay (TdT-mediated dUTP-nick end-labeling). Bax, p53, and insulin were assessed by Western blotting, immunofluorescence, and real-time quantitative PCR. Insulin, triacylglycerol, and serum glucose and fatty acids in pancreatic tissue were measured. Carbohydrate consumption promotes apoptosis and mobilization of p53 from the cytosol to rat pancreatic ß-cell mitochondria before blood glucose rises. An increase in p53, miR-34a, and Bax mRNA was also detected (P < 0.001) in the sucrose group. As well as hypertriglyceridemia, hyperinsulinemia, glucose intolerance, insulin resistance, visceral fat accumulation, and increased pancreatic fatty acids in the sucrose group. Carbohydrate consumption increases p53 and its mobilization into ß-cell mitochondria and coincides with the increased rate of apoptosis, which occurs before serum glucose levels rise.

Asunto(s)

Diabetes Mellitus Tipo 2 , Bebidas Azucaradas , Ratas , Animales , Glucosa/metabolismo , Proteína p53 Supresora de Tumor/genética , Diabetes Mellitus Tipo 2/etiología , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo , Ratas Sprague-Dawley , Apoptosis , Insulina , Sacarosa/farmacología , Ácidos Grasos

RESUMEN

AIMS: Obesity and type 2 diabetes mellitus are two pathologies that share metabolic abnormalities in most of the cases; however, there are differences as well. Some studies have reported that approximately 30% of obese patients have normal glucose and lipid levels in blood despite an accumulation of abdominal adipose tissue. Here, we compare the gene expression in adipose tissue of several genes associated with obesity and/or diabetes between obese patients without T2D and obese patients with T2D. METHODS: Omental adipose tissue was collected during the patients elective bariatric surgery. Gene expression was determined by real-time PCR. Phenotypic variables were correlated with gene expression and 2^-ΔΔCt relative expression analysis between groups was performed. RESULTS: The stronger correlations in the obese without T2D or reference group was between ICAM1 and HbA1c; HP and TC and LDL while in the obese with diabetes or case group the correlation occurred between CSF1 and BMI. A correlation between HP and TC was found in the case group as well. The expression of VEGFA, CCND2, IL1R1 and PTEN was downregulated in the obese with T2D group. CONCLUSIONS: This study identified genes whose expression is different between obese subjects with and without diabetes. Those genes are related to inflammation, cholesterol transport, adipocyte differentiation/expansion and browning.

Asunto(s)

Tejido Adiposo/fisiología , Diabetes Mellitus Tipo 2/genética , Obesidad/genética , Adulto , Cirugía Bariátrica , Ciclina D2/genética , Femenino , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Obesidad/cirugía , Fosfohidrolasa PTEN/genética , Fenotipo , Receptores Tipo I de Interleucina-1/genética , Factor A de Crecimiento Endotelial Vascular/genética

RESUMEN

CONTEXT: Little is known about the association between haptoglobin level and cardiometabolic traits. A previous genome-wide association study identified rs2000999 in the HP gene as the stronger genetic contributor to serum haptoglobin level in European populations. OBJECTIVE AND DESIGN: We investigated the association of HP rs2000999 with serum haptoglobin and childhood and adult obesity in up to 540/697 and 592/691 Mexican cases and controls, respectively. Anthropometric and biochemical data were collected. Serum haptoglobin was measured by an immunoturbidimetry assay. HP rs2000999 was genotyped using the TaqMan technology. Mendelian randomization analysis was performed using the Wald and inverse variance weighting methods. RESULTS: Haptoglobin level was positively associated with childhood and adult obesity. HP rs2000999 G allele was positively associated with haptoglobin level in children and adults. HP rs2000999 G allele was positively associated with childhood but not adult obesity. The association between HP rs2000999 and childhood obesity was removed after adjusting for haptoglobin level. In a Mendelian randomization analysis, haptoglobin level genetically predicted by HP rs2000999 showed a significant causal effect on childhood obesity by the Wald and inverse variance weighting methods. CONCLUSION: Our data provide evidence for the first time for a causal positive association between serum haptoglobin level and childhood obesity in the Mexican population. Our study contributes to the genetic elucidation of childhood obesity and proposes haptoglobin as an important biomarker and treatment target for obesity.

Asunto(s)

Predisposición Genética a la Enfermedad , Haptoglobinas/genética , Obesidad Infantil/genética , Polimorfismo de Nucleótido Simple , Alelos , Estudios de Casos y Controles , Niño , Femenino , Genotipo , Haptoglobinas/análisis , Humanos , Masculino , Análisis de la Aleatorización Mendeliana , México , Obesidad Infantil/sangre

RESUMEN

Recently, studies have shown significant association between the rs2000999 polymorphism in the haptoglobin-encoding gene (HP) and low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels, which are important risk factors for cardiovascular diseases. However, the association of rs2000999 with serum lipids in Latin American diabetic populations is still uncharacterized. Here, we analyzed the association of rs2000999 with TC, high-density lipoprotein cholesterol (HDL-C), and LDL-C levels in 546 Mexican adults with type 2 diabetes (T2D) and in 654 controls without T2D. In this observational case-control study we included adults from 4 centers of the Mexican Social Security Institute in Mexico City recruited from 2012 to 2015. TC, HDL-C, LDL-C, triglycerides (TG), and glucose levels were measured by an enzymatic colorimetric method. The variant rs2000999 was genotyped using TaqMan real time polymerase chain reaction. The percentage of Native-American ancestry showed a negative association with the rs2000999 A allele. In contrast, the rs2000999 A allele had a strong positive association with European ancestry, and to a lesser extent, with African ancestry. Linear regression was used to estimate the association between the variant rs2000999 and lipid concentrations, using different genetic models. Under codominant and recessive models, rs2000999 was significantly associated with TC and LDL-C levels in the T2D group and in controls without T2D. In addition, the group with T2D showed a significant association between the variant and HDL-C levels. In summary, the rs2000999 A allele in Mexican population is positively associated with the percentage of European and negatively associated with Native American ancestry. Carriers of the A allele have increased levels of TC and LDL-C, independently of T2D diagnosis, and also increased concentrations of HDL-C in the T2D sample.

Asunto(s)

Enfermedades Cardiovasculares , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Colesterol/sangre , Diabetes Mellitus Tipo 2 , Haptoglobinas , Adulto , Biomarcadores/análisis , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Femenino , Haptoglobinas/análisis , Haptoglobinas/genética , Humanos , Masculino , México/epidemiología , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo

RESUMEN

The organic cation transporters OCT1 and OCT2 and the multidrug and toxin extrusion transporter MATE1, encoded by the SLC22A1, SLC22A2, and SLC47A1 genes, respectively, are responsible for the absorption of metformin in enterocytes, hepatocytes, and kidney cells. The aim of this study was to evaluate whether genetic variations in the SLC22A1, SLC22A2, and SLC47A1 genes could be associated with an altered response to metformin in patients with type 2 diabetes mellitus. A cohort study was conducted in 308 individuals with a diagnosis of type 2 diabetes mellitus of less than 3 years and who had metformin monotherapy. Three measurements of blood glycated hemoglobin (HbA1c ) were obtained at the beginning of the study and after 6 and 12 months. Five polymorphisms were analyzed in the SLC22A1 (rs622342, rs628031, rs594709), SLC22A2 (rs316019), and SLC47A1 (rs2289669) genes by real-time polymerase chain reaction. The results showed a significant association among genotypes CC-rs622342 (ß = 1.36; P < .001), AA-rs628031 (ß = 0.98; P = .032), and GG-rs594709 (ß = 1.21; P = .016) in the SLC22A1 gene with an increase in HbA1c levels during the follow-up period. Additionally, a significant association was found in the CGA and CAG haplotypes with an increase in HbA1c levels compared to the highest-frequency haplotype (AGA). In conclusion, the genetic variation in the SLC22A1 gene was significantly related to the variation of the HbA1c levels, an important indicator of glycemic control in diabetic patients. This information may contribute to identifying patients with an altered response to metformin before starting their therapy.

Asunto(s)

Glucemia/efectos de los fármacos , Glucemia/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Metformina/uso terapéutico , Factor 1 de Transcripción de Unión a Octámeros/genética , Polimorfismo de Nucleótido Simple/genética , Anciano , Estudios de Cohortes , Femenino , Genotipo , Hemoglobina Glucada/genética , Humanos , Hipoglucemiantes/uso terapéutico , Riñón/efectos de los fármacos , Masculino , Persona de Mediana Edad

RESUMEN

AIM: To determine the association between the rs1256031 polymorphism and risk of developing type 2 diabetes. MATERIALS AND METHODS: Cases and controls study. 597 individuals with type 2 diabetes and 605 without it participated. Genotyping of the rs1256031 polymorphism of the ERß gene was performed by real-time PCR using TaqMan assay. For the multivariate analysis, a multiple logistic regression was performed that included the main confounding variables. RESULTS AND CONCLUSION: A multiple logistic regression analysis was performed, adjusting for age, WHR, BMI and gender. The dominant model showed a protective effect compared to the TT genotype (OR = 0.596, IC95% [0.458-0.776]). DISCUSSION: The proportions of native American, European and African ancestry were characterized and no difference was found in the study groups. The protective effect obtained in the dominant model could to be due a regulatory function in the transcription or the processing of the primary transcript. Our result are the first to report an association between the polymorphism rs1256031 and the reduction of the risk of T2D in the Mexican population. The rs1256031 polymorphism show reduced risk of developing T2D and is potential markers for predicting T2D.

Asunto(s)

Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Receptor beta de Estrógeno/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/sangre , Receptor beta de Estrógeno/sangre , Femenino , Genotipo , Humanos , Masculino , México/epidemiología , Persona de Mediana Edad

RESUMEN

Obesity and type 2 diabetes mellitus (T2DM) result from sedentary lifestyle, high-carbohydrate diets and genetic predisposition. Epigenetics is a form of genetic regulation in specialized cells that does not involve changes in the deoxyribonucleic acid (DNA) sequence, but it can be inherited to one or more generations through mitosis or meiosis. Children whose mothers develop gestational diabetes are more likely to become obese and diabetic in adult life. DNA methylation is a major mechanism in the regulation of transcription and gene expression of several genes. High levels of glucose and insulin during pregnancy modify the risk of developing T2DM, suggesting that the expression pattern is modified due to cell memory in a specific tissue. If T2DM is linked to adaptation in utero, the obvious primary prevention is to protect the fetal development. Future epidemiological studies need to employ more accurate indicators or markers of development to show the relationship between a specific disease and the exposure to environmental factors. The mechanisms by which malnutrition, and intrauterine growth retardation produce changes in the metabolism of glucose and insuline are worth to explore in order to control obesity and T2DM.

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La obesidad y la diabetes mellitus tipo 2 (DMT2) son consecuencia del sedentarismo, dietas altas en carbohidratos y la predisposición genética. La epigenética se define como una forma de regulación génica en células especializadas que no implica cambios en la secuencia del ácido desoxirribonucléico (ADN) y que puede transmitirse durante una o más generaciones a través de mitosis o meiosis. Los hijos de madres con diabetes gestacional son más propensos a desarrollar obesidad y diabetes en la vida adulta. La metilación del ADN es un mecanismo importante en la regulación de la transcripción y expresión de varios genes. Los niveles altos de glucosa e insulina durante el embarazo influyen en el riesgo de desarrollo de DMT2, lo cual sugiere que los patrones de expresión a través de la memoria celular en los tejidos específicos se modifican. Si la DMT2 es consecuencia de una adaptación in utero, obviamente la prevención primaria consiste en proteger el desarrollo fetal. Los estudios epidemiológicos futuros necesitan emplear indicadores o marcadores del desarrollo más exactos que demuestren la relación entre una enfermedad y la exposición específica a factores medioambientales. Se deben explorar los mecanismos por los que la desnutrición y el retraso del crecimiento in utero producen cambios en el metabolismo de la glucosa y la insulina a fin de enfrentar la obesidad y la DMT2.

Asunto(s)

Diabetes Mellitus Tipo 2/genética , Epigénesis Genética , Obesidad Infantil/genética , Niño , Diabetes Mellitus Tipo 2/etiología , Humanos , Obesidad Infantil/complicaciones