Gastric Inhibitory Polypeptide Receptor Methylation in Newly Diagnosed, Drug-Naïve Patients with Type 2 Diabetes: A Case-Control Study

Abstract

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.

Differential Methylation of TCF7L2 Promoter in Peripheral Blood DNA in Newly Diagnosed, Drug-Naïve Patients with Type 2 Diabetes

“…We found that several CpGs had significant differences between type 2 diabetic patients and controls, although overall the methylation pattern did not show a clear differential pattern related to T2D. These results are consistent with previous data of promoter methylation patterns from peripheral blood DNA where a global directional change in methylation levels that would affect all neighboring CpGs systematically and that would be characteristic of the disease has not been identified [18] , [28] . On the other hand, a recent study found some T2D-related methylation patterns in peripheral blood DNA [17] but their analysis did not cover the genomic region we studied.…”

“…Cases and controls were recruited from the same primary health center. Eligibility criteria for inclusion of cases and controls were applied as previously cited [18] . Briefly, eligibility criteria for cases were the following: clinical diagnosis of T2D, adequate glycemic control after a period of minimum six months of low-carbohydrate diet and lifestyle interventions, no pharmacological therapy for T2D needed to achieve the glycemic control.…”

Blood-Based DNA Methylation Biomarkers for Type 2 Diabetes: Potential for Clinical Applications

“…TCF7L2 is involved in glucose homeostasis and was reported to be differentially methylated in 13 of its promoter CpGs (eight hypermethylated and five hypomethylated) between treatment-naïve patients with T2D and matched controls (42). Furthermore, methylation at specific CpG sites of the TCF7L2 promoter correlated significantly with fasting glucose concentrations, total cholesterol, LDL-cholesterol, as well as the homeostatic model assessment for insulin resistance (HOMA-IR) (47).…”

“…Canivell et al performed DNA methylation profiling of the GIPR promoter in peripheral blood DNA and identified differential methylation at nine CpG sites located upstream of the first exon between patients with T2D and controls. On average, these nine CpG sites were hypomethylated in patients with T2D and significantly correlated with waist circumference and fasting glucose concentrations (47). SLC30A8 encodes a pancreas-specific, zinc efflux transporter, and reduced levels or activity of SLC30A8 hinder glucose-induced insulin secretion, as zinc is required for the crystallization of insulin within secretory granules (65).…”

The role of DNA methylation in the pathogenesis of type 2 diabetes mellitus

“…The authors found that GIPR promoter was hypomethylated in patients with T2DM compared to the control individuals. The mean methylation levels of the GIPR promoter were negatively correlated with fasting glucose and HOMA-IR in the patients with T2DM, where the reduced DNA methylation of the GIPR promoter was associated with increased HOMA-IR and increased fasting glucose levels [ 60 ].…”