Department of Endocrinology and Nutrition, Hospital Clinic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain ; Les Corts Primary Health Care Centre, Transverse group for research in primary care-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain ; Diabetes and Obesity Laboratory-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
PLoS One. 2013 Sep 23;8(9):e75474. doi: 10.1371/journal.pone.0075474. eCollection 2013.
GIP action in type 2 diabetic (T2D) patients is altered. We hypothesized that methylation changes could be present in GIP receptor of T2D patients. This study aimed to assess the differences in DNA methylation profile of GIPR promoter 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 T2D patients were more insulin resistant and had a poorer β cell function than their controls. 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. 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. Our study provides novel findings on GIPR promoter methylation profile which may improve our ability to understand type 2 diabetes pathogenesis.
2 型糖尿病（T2D）患者的 GIP 作用发生改变。我们假设 T2D 患者的 GIP 受体可能存在甲基化变化。本研究旨在评估 T2D 患者和年龄及体重指数（BMI）匹配的对照组之间 GIPR 启动子 DNA 甲基化谱的差异。我们纳入了 93 名仅接受饮食治疗（无任何抗糖尿病药物治疗）的 T2D 患者（病例）。我们为每个病例匹配了一名年龄和 BMI 匹配的对照者（口服葡萄糖耐量试验阴性，非糖尿病患者）。通过 ELISA 测定细胞因子和激素。从全血中提取 DNA，并使用 Sequenom EpiTYPER 系统评估 DNA 甲基化。我们的结果表明，与对照组相比，T2D 患者的胰岛素抵抗更严重，β细胞功能更差。与对照组相比，T2D 患者空腹脂联素水平更低（7.0±3.8 µgr/mL 比 10.0±4.2 µgr/mL）。T2D 患者血清中 IL 12 水平几乎是对照组的两倍（52.8±58.3 pg/mL 比 29.7±37.4 pg/mL）。我们发现，与对照组相比，GIPR 启动子在 T2D 患者中呈低甲基化状态。此外，HOMA-IR 和空腹血糖与 GIPR 启动子的平均甲基化呈负相关，尤其是在 T2D 患者中。这项病例对照研究证实，新诊断的、未接受药物治疗的 T2D 患者比年龄和 BMI 匹配的对照组更具胰岛素抵抗，且β细胞功能更差，这在一定程度上与胰岛素敏化代谢物（脂联素）、促炎谱（IL12）的变化有关，我们还发现 GIPR 的甲基化模式也发生了变化。本研究提供了关于 GIPR 启动子甲基化谱的新发现，可能有助于我们更好地理解 2 型糖尿病的发病机制。
