Homeostasis Model Assessment for Insulin Resistance Mediates the Positive Association of Triglycerides with Diabetes

Abstract

Elevated circulating triglyceride levels have been linked to an increased risk of diabetes, although the precise mechanisms remain unclear. This study aimed to investigate whether low-density lipoprotein (LDL) cholesterol, homeostatic model assessment (HOMA) for insulin resistance, and C-reactive protein (CRP) served as mediators in this association across a sample of 18,435 US adults. Mediation analysis was conducted using the PROCESS Version 4.3 Macro for SPSS. Simple mediation analysis revealed that all three potential mediators played a role in mediating the association. However, in parallel mediation analysis, where all three mediators were simultaneously included, HOMA for insulin resistance remained a significant mediator (indirect effect coefficient, 0.47; 95% confidence interval [CI], 0.43-0.52; p < 0.05) after adjusting for all tested confounding factors. Conversely, LDL cholesterol (indirect effect coefficient, -0.13; 95% CI, -0.31-0.05; p > 0.05) and C-reactive protein (indirect effect coefficient, 0.01; 95% CI, -0.003-0.02; p > 0.05) ceased to be significant mediators. HOMA for insulin resistance accounted for 49% of the association between triglycerides and diabetes. In conclusion, HOMA for insulin resistance was the dominant mediator underlying the association between triglycerides and diabetes. Therefore, reducing triglyceride levels may hold promise for improving insulin sensitivity in diabetic patients.

Keywords: diabetes; insulin resistance; lipoprotein; mediation analysis.

Figure 1

Flow diagram of the study participants. BMI, body mass index; HbA_1c, hemoglobin A_1c; HOMA for IR, homeostatic model assessment for insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; SBP, systolic blood pressure.

Figure 2

Mediation analysis models. (A) Simple mediation. LDL cholesterol, HOMA for insulin resistance, or C-reactive protein was added as single mediator for the association of triglycerides with diabetes. (B) Parallel mediation. In this analysis, LDL cholesterol, HOMA for insulin resistance, and C-reactive protein were added simultaneously to assess their mediation effects on the association of triglycerides with diabetes. a, association coefficient between triglycerides and the tested mediator; b, association coefficient between the tested mediator and diabetes; c’, also known as direct effect, referring to the association coefficient between triglycerides and diabetes in the presence of the tested mediator (simple mediation) or all tested mediators (parallel mediation); CRP, C-reactive protein; DM, diabetes; HOMA-IR, homeostasis model assessment for insulin resistance; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides. This figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 3

Simple mediation analysis. LDL cholesterol, HOMA for insulin resistance, or C-reactive protein was added as single mediator for the association of triglycerides with diabetes. a, association coefficient between triglycerides and the tested mediator; b, association coefficient between the tested mediator and diabetes; c’, association coefficient between triglycerides and diabetes in the presence of the tested mediator; CI, confidence interval; CRP, C-reactive protein; DM, diabetes; HOMA-IR, homeostasis model assessment for insulin resistance; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides. Green tick = yes. * p < 0.05. This figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 4

Unadjusted parallel mediation analysis. LDL cholesterol, HOMA for insulin resistance, and C-reactive protein were added as parallel mediators for the association of triglycerides with diabetes without adjustment for confounding factors. a, association coefficient between triglycerides and the tested mediator; b, association coefficient between the tested mediator and diabetes; c’, association coefficient between triglycerides and diabetes in the presence of all the tested mediators; CI, confidence interval; CRP, C-reactive protein; DM, diabetes; HOMA-IR, homeostasis model assessment for insulin resistance; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides. Green tick = yes. Red cross = no. * p < 0.05. This figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 5

Parallel mediation analysis with adjustment for confounding factors. LDL cholesterol, HOMA for insulin resistance, and C-reactive protein were placed simultaneously into the analysis as parallel mediators for the association of triglycerides with diabetes. This analysis was adjusted for confounding factors. The latter confounding factors included age, sex, ethnicity, body mass index, poverty–income ratio, education, survey period, lifestyle confounding factors (physical activity, alcohol consumption, and smoking status), clinical confounding factors (systolic blood pressure, total cholesterol, HDL cholesterol, and family history of diabetes), and fasting time. Abbreviations: a, association coefficient between triglycerides and the tested mediator; b, association coefficient between the tested mediator and diabetes; c’, association coefficient between triglycerides and diabetes in the presence of the tested mediators; CI, confidence interval; CRP, C-reactive protein; DM, diabetes; HOMA-IR, homeostasis model assessment for insulin resistance; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides. The green tick represents yes and the red cross represents no. * p < 0.05. This figure was partly produced using Servier Medical Art which was licensed under a Creative Commons Attribution 3.0 unported license.