Mitochondrial Epigenetic Changes Link to Increased Diabetes Risk and Early-Stage Prediabetes Indicator

Abstract

Type 2 diabetes (T2D) is characterized by mitochondrial derangement and oxidative stress. With no known cure for T2D, it is critical to identify mitochondrial biomarkers for early diagnosis of prediabetes and disease prevention. Here we examined 87 participants on the diagnosis power of fasting glucose (FG) and hemoglobin A1c levels and investigated their interactions with mitochondrial DNA methylation. FG and A1c led to discordant diagnostic results irrespective of increased body mass index (BMI), underscoring the need of new biomarkers for prediabetes diagnosis. Mitochondrial DNA methylation levels were not correlated with late-stage (impaired FG or A1c) but significantly with early-stage (impaired insulin sensitivity) events. Quartiles of BMI suggested that mitochondrial DNA methylation increased drastically from Q1 (20 < BMI < 24.9, lean) to Q2 (30 < BMI < 34.9, obese), but marginally from Q2 to Q3 (35 < BMI < 39.9, severely obese) and from Q3 to Q4 (BMI > 40, morbidly obese). A significant change was also observed from Q1 to Q2 in HOMA insulin sensitivity but not in A1c or FG. Thus, mitochondrial epigenetic changes link to increased diabetes risk and the indicator of early-stage prediabetes. Further larger-scale studies to examine the potential of mitochondrial epigenetic marker in prediabetes diagnosis will be of critical importance for T2D prevention.

Figure 1

The diagnosis of healthy (a), prediabetes (b), and T2D (c) among 87 participants using the standards recommended by ADA for fasting glucose (FG) and hemoglobin A1c (A1c).

Figure 2

The correlations of obesity-associated diabetes risk index (BMI) with current diagnostic indices and insulin sensitivity. (a) FG showed no significant correlation with BMI. (b) A1c showed no significant correlation with BMI. (c-d) Decrease of insulin sensitivity was significantly associated with BMI in overweight and obese participants, as indicated by FI (c) and HOMA-IR (d).

Figure 3

Correlation of mitochondrial DNA methylation with insulin sensitivity (HOMA-IR and FI) and current diagnostic indices (FG and A1c). (a-b) HOMA-IR and FI showed significant interaction with ND6 methylation; n = 40. (c) FG showed no correlation with ND6 methylation; n = 40. (d) A1c showed no correlation with ND6 methylation; n = 40. (e) HOMA-IR showed significant interaction with D-loop methylation; n = 40. (f) FG showed no correlation with D-loop methylation; n = 40. (g) A1c showed no correlation with D-loop methylation; n = 40. (h) Cholesterol showed no correlation with D-loop methylation; n = 40. More details about correlation of DNA methylation in mitochondrial D-loop with lipid profile can be found in Supplemental Figure  4.

Figure 4

Changes in mitochondrial DNA methylation and insulin sensitivity versus different levels of diabetes risk factor (BMI) or different stages of disease progression. (a) ND6 methylation showed significant correlation with BMI; n = 40. (b) D-loop methylation showed significant correlation with BMI; n = 40. (c) ND6 methylation increased drastically from low-risk (20 < BMI < 24.9; n = 8) to high-risk (30 < BMI < 34.9; n = 15) stages, with no further significant changes during advanced progression (BMI > 35; n = 17). (d) D-loop methylation increased drastically from low-risk (20 < BMI < 24.9; n = 8) to high-risk (30 < BMI < 34.9; n = 15) stages, with no further significant changes during advanced progression (BMI > 35). (e) HOMA-IR increased drastically from low-risk (20 < BMI < 24.9; n = 8) to high-risk (30 < BMI < 34.9; n = 15) stages and underwent a second significant elevation during advanced progression (from 35 < BMI < 39.9 to BMI > 40; n = 9 and 8, resp.). (f) As an alternative index of insulin resistance, FI increased drastically from low-risk (20 < BMI < 24.9; n = 8) to high-risk (30 < BMI < 34.9; n = 15) stages and underwent a second significant elevation during advanced progression (from 35 < BMI < 39.9 to BMI > 40; n = 9 and 8, resp.). ^∗ p < 0.05; ^∗∗ p < 0.01; ^∗∗∗ p < 0.001; ns: not significant. Red color indicates the dramatic changes in a parameter.