Combined Effects of ESRα DNA Methylation and Progesterone on Glucose Metabolic Disorders: The Henan Rural Cohort Study

Abstract

To explore the independent and combined effects of ESRα methylation and progesterone on impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM), a case-control study including 901 subjects was conducted. Generalized linear models were performed to assess the independent and combined effects of ESRα methylation and progesterone on IFG or T2DM. Methylation level of cytosine-phosphoguanine (CpG) 1 in the estrogen receptor α (ESRα) gene was positively related to IFG in both men (odds ratio (OR) (95% confidence interval (CI)): 1.77 (1.05, 3.00)) and postmenopausal women (OR (95% CI): 1.82 (1.09, 3.04)), whereas the association between CpG 1 and T2DM was not significant. Positive associations of progesterone with IFG and T2DM were observed in both men (OR (95% CI): 2.03 (1.18, 3.49) and 3.00 (1.63, 5.52)) and postmenopausal women (OR (95% CI): 2.13 (1.27, 3.56) and 3.30 (1.85, 5.90)). Participants with high CpG 1 methylation plus high progesterone had an increased risk of IFG and T2DM, both in men and postmenopausal women. ESRα methylation and progesterone were positively associated with IFG, and the positive association between progesterone and T2DM was also found. Importantly, we firstly found the combined effects of ESRα methylation and progesterone on IFG and T2DM.

Keywords: DNA methylation progesterone; combined effect; estrogen receptor alpha; impaired fasting glucose; type 2 diabetes mellitus.

Figure 1

Basic characteristics of the study population by gender. (A–L) display the distribution of the indices BMI, SBP, PP, TC, TG, HDL-C, LDL-C, FPG, HbA1c, INS, progesterone, CpG 1 methylation in men and postmenopausal women, respectively. BMI, body mass index; CpG, cytosine-phosphoguanine; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; HbA1c, glycosylated hemoglobin A1c; INS, insulin; IFG, impaired fasting glucose; LDL-C, low-density lipoprotein cholesterol; NGT, normal glucose tolerance; PP, pulse pressure; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride; T2DM, type 2 diabetes mellitus. * Compared with NGT, p < 0.05.

Figure 2

Associations of ESRα methylation (CpG 1) and progesterone with glucose homeostasis markers in men and postmenopausal women. Adjusted for BMI, smoking status, alcohol intake, physical activity, per capita monthly income, level of education, family history of T2DM, SBP, PP, TC, TG, HDL-C, and LDL-C; CI, confidence interval; CpG, cytosine-phosphoguanine; ESRα, estrogen receptors α; FPG, fasting plasma glucose; HOMA: homeostasis model assessment; HbA1c, glycosylated hemoglobin A1c; IR: insulin resistance; INS, insulin; Ln-, natural log-transformed; T, tertiles.

Figure 3

Combined effects of ESRα methylation (CpG 1) and progesterone on IFG and T2DM in men and postmenopausal women. ^a: adjusted for BMI, smoking status, alcohol intake, physical activity, per capita monthly income, level of education, family history of T2DM, SBP, PP, TC, TG, HDL-C, and LDL-C; CI, confidence interval; CpG, cytosine-phosphoguanine; OR, odds ratio; M, ESRα methylation; P, progesterone; Ref., reference, with (1, 1) as the reference.