Wide Metabonomics and Lipidomics of Type 2 Diabetes Mellitus Risk in Chinese Adult Twins

Abstract

Background: Type 2 diabetes mellitus (T2DM) is a metabolic disorder with a growing global prevalence. Lipidomic and metabolomic analyses have been used to investigate the relationship between circulating metabolites and T2DM characteristics. However, few studies have explored this relationship specifically in twin populations.

Methods: The data came from China's National Twin Registry (CNTR). 420 participants (210 twin pairs) were included. A mixed-effects model was applied to explore the relationship between individual metabolite/lipid levels and T2DM-related characteristics, such as homeostasis model assessment of T2DM, fasting insulin, fasting glucose, HbA1c, and insulin resistance (HOMA-IR). To compare metabolite/lipid levels in twins with inconsistent T2DM (one twin had T2DM while the other did not), the empirical Bayesian paired T-test was used. Lastly, bivariate structural equation models (SEM) were employed to investigate the genetic/environmental correlation between metabolite/lipid levels and T2DM. To ensure the statistical reliability of the results, all P values were corrected using the False Discovery Rate (FDR) method.

Results: Mixed linear model results showed that a higher level of But-2-enoic (β=0.18, 95% confident interval [95% CI]: 0.14 to 0.22, adjusted P-value [Padj] = 0.002), a type of unsaturated fatty acid, And phosphatidylethanolamines (PE), including PE(39:6) (β=0.12, 95% CI: 0.09 to 0.15, Padj = 0.007), PE(40:7) (β=0.09, 95% CI: 0.07 to 0.11, Padj = 0.008), were found to be significantly associated with T2DM. In the empirical Bayesian paired T-test, a total of 71 metabolite levels associated with T2DM were identified, among which triglyceride (TG) (e.g., TG(53:3), TG(55:3), TG(55:5), etc.), L-Leucine (β=0.06, 95% CI: 0.01 to 0.12, Padj = 0.02), Deoxycholic acid 3-sulfate (β=0.23, 95% CI: 0.05 to 0.42, Padj = 0.02), PE(38:2) (β=0.08, 95% CI: 0.01 to 0.07, Padj = 0.04), and sphingomyelins [SM(d44:6)] (β=0.04, 95% CI: 0.01 to 0.06, Padj = 0.004) were found to be significantly elevated in affected twins as compared to their unaffected co-twins. The bivariate SEM analysis revealed that genetic correlations of 1 and 0.53 for D-Glucose and But-2-enoic acid, -0.04 and -0.37 for L-Lactic acid and phosphatidylcholines [PC(32:1p)], and 0.19 and 0.12 for PE(39:6) and PE(40:7). The environmental factors also contributed to the associations between T2DM and metabolite/lipid levels, with point estimates of 0.27 and 0.29 for D-Glucose and But-2-enoic acid, 0.4 and -0.14 for GM3(d41:1) and L-Lactic acid, and -0.33, -0.25, -0.44, and −0.18 for PC.

Conclusion: In summary, our findings reveal regional aggregation of metabolite/lipid levels in T2DM, which highlights a potential pathway for future research. Furthermore, we demonstrate that PC and PE levels are partially subject to genetic control, while the association between metabolite/lipid levels and T2DM is partly explained by shared genes and environmental influences. The study sheds light on the complex relationship between metabolite/lipid levels and T2DM and provides a foundation for further research in this area.

Funding: The CNTR wase supported from the National Natural Science Foundation of China (82173499, 82073633, 81973126, 81573223), the Special Fund for Health scientific research in public welfare (201502006, 201002007), and the Peking University Outstanding Discipline Construction Project of Epidemiology and Biostatistics.

Declaration of Interest: The authors declare no conflict of interest.

Ethical Approval: This study was approved by the Biomedical Ethics Committee at Peking University, Beijing, China (IRB00001052-13022, IRB00001052-14021, IRB00001052-22032). All enrolled subjects provided written informed consent.

Keywords: Twin study, Type 2 diabetes, Lipids, Metabolites