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The association of DNA methylation patterns in TCF7L2 and GIPR genes with Type 2 Diabetes

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Universitat de Barcelona. Facultat de Medicina

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[spa] En nuestra investigación, se plantea la hipótesis que los pacientes diabéticos tipo 2 se diferencian respecto a sujetos no diabéticos de misma edad e índice de masa corporal (IMC) en patrones de metilación específicos que podrían implicar cambios en la expresión génica en los tejidos diana implicados en la fisiopatología de la diabetes tipo 2. En vista de la interacción entre el medio ambiente y la genética, y, que los patrones de metilación pueden cambiar en respuesta a los factores ambientales, se deduce que los patrones de metilación relacionados con la diabetes estarían presentes en los genes clave implicados en la fisiopatología de la diabetes tipo 2, como los genes TCF7L2 y GIPR. Como el patrón de metilación podría influir en la expresión génica, estudiamos la región promotora de los genes seleccionados. Por último, como las marcas epigenéticas pueden ser detectadas a partir de tejidos fácilmente accesibles, se estudiaran las marcas de metilación en el ADN de la sangre total en los dos grupos de sujetos. La primera parte del trabajo demuestra que los pacientes con diabetes tipo 2 de reciente diagnóstico tienen una función de las células β alterada y son más insulino- resistentes que los controles apareados por edad e IMC. Estas diferencias en la función de las células β y la resistencia a la insulina están relacionadas con diferencias en los perfiles de adipoquinas así como metabolitos inflamatorios, que podrían reflejar parte de los mecanismos subyacentes que conducen a la diabetes tipo 2 manifiesta. Posteriormente, hemos demostrado la presencia de alteraciones epigenéticas en pacientes con diabetes tipo 2 en comparación con controles emparejados por edad e IMC en ciertas regiones del genoma que han sido previamente vinculados a la diabetes tipo 2 y a la hiperglucemia, como los genes TCF7L2 y GIPR. Estos nuevos resultados aclaran la visión actual de la asociación entre las alteraciones epigenéticas y regiones genómicas de riesgo conocido para la diabetes tipo 2 y se abren nuevas líneas de investigación sobre este tema.

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[eng] The incidence of type 2 diabetes mellitus (T2D) is increasing worldwide. There are several explanations to this fact, such as the increased prevalence of obesity, population’s ageing, and the lack of physical activity that is practised. However, not all obese and sedentary individuals become type 2 diabetic. Beyond a certain genetic susceptibility and a determined environment, some people will become diabetic, whereas others will not. Recent discoveries in the field of epigenetics have brought an insight in the molecular mechanisms underlying the interaction between environment and genome. Indeed, it is believed that specific changes in the epigenome are associated with the onset and/ or the progression of disease processes such as cancer or diabetes. TCF7L2 is the susceptibility gene for T2D with the largest effect on disease risk that has been discovered to date. However, the mechanisms by which TCF7L2 contributes to the disease remain largely elusive. On the other hand, GIP action in T2D patients is altered. As said above, epigenetic mechanisms, such as changes in DNA methylation patterns, might have a role in the pathophysiology of T2D. In this study, we hypothesized that methylation changes could be present in GIP receptor of T2D patients and in the TCF7L2 gene. This study aimed to assess the differences in DNA methylation profile of GIPR and TCF7L2 promoters between T2D patients and age- and Body Mass Index (BMI)-matched controls. We included 93 T2D patients (cases) that were uniquely on diet (without any anti-diabetic pharmacological treatment). We matched one control (with oral glucose tolerance test negative, non diabetic), by age and BMI, for every case. Cytokines and hormones were determined by ELISA. DNA was extracted from whole blood and DNA methylation was assessed using the Sequenom EpiTYPER system. Our results showed that type 2 diabetic patients were more insulin resistant than their matched controls (mean HOMA IR 2.6 vs 1.8 in controls, P<0.001) and had a poorer beta-cell function (mean HOMA B 75.7 vs. 113.6 in controls, P<0.001). Fasting adiponectin was lower in T2D patients as compared to controls (7.0±3.8 µgr/mL vs. 10.0±4.2 µgr/mL). Levels of IL 12 in serum were almost double in T2D patients (52.8±58.3 pg/mL vs. 29.7±37.4 pg/mL). We found that GIPR promoter was hypomethylated in T2D patients as compared to controls. In addition, HOMA-IR and fasting glucose correlated negatively with mean methylation of GIPR promoter, especially in T2D patients. With reference to the TCF7L2 promoter, results showed that 59% of the CpGs analyzed in TCF7L2 promoter had significant differences between type 2 diabetic patients and matched controls. In addition, fasting glucose, HOMA-B, HOMA-IR, total cholesterol and LDL-cholesterol correlated with methylation in specific CpG sites of TCF7L2 promoter. After adjustment by age, BMI, gender, physical inactivity, waist circumference, smoking status and diabetes status uniquely fasting glucose, total cholesterol and LDL-cholesterol remained significant. This case-control study confirms that newly diagnosed, drug-naïve T2D patients are more insulin resistant and have worse β cell function than age- and BMI-matched controls, which is partly related to changes in the insulin-sensitizing metabolites (adiponectin), in the proinflammatory profile (IL12) and we suggest in the methylation pattern of GIPR. Moreoever, newly diagnosed, drug-naïve type 2 diabetic patients display specific epigenetic changes at the TCF7L2 promoter as compared to age- and BMI-matched controls. Methylation in TCF7L2 promoter is further correlated with fasting glucose in peripheral blood DNA, which sheds new light on the role of epigenetic regulation of TCF7L2 in T2D. Our study provides novel findings on GIPR and TCF7L2 promoters methylation profile which may improve our ability to understand type 2 diabetes pathogenesis.

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The association of DNA methylation patterns in TCF7L2 and GIPR genes with Type 2 Diabetes