Abstract
Dyslipidemia, diabetes mellitus, and insulin resistance (IR) are intricately linked. In recent years, a series of novel lipid indices have emerged. Investigating their correlation with diabetes and IR is critical for early intervention. This study analyzed 19,780 National Health and Nutrition Examination Survey (NHANES) participants (1999-2020), examining the atherogenic index of plasma (AIP), Castelli risk index I (CRI-I) and II (CRI-II), estimated small dense LDL cholesterol (EsdLDL-C), non-HDL cholesterol-to-HDL cholesterol ratio (NHHR), and remnant cholesterol (RC). Covariates were selected via Boruta and LASSO regression. Multivariate logistic regression, restricted cubic splines, ROC, subgroup, and mediation analyses were employed, validated by sensitivity analyses. The prevalence of diabetes was 15.0%. After adjustment, four indices (excluding CRI-II and EsdLDL-C) were associated with diabetes. For Q4 vs Q1, AIP and RC showed significantly elevated risk (OR: 2.52 [2.07-3.07] and 2.13 [1.75-2.58], respectively). Regarding IR, all indices exhibited dose-dependent associations, with AIP (OR: 5.74 [5.00-6.59]) and RC (4.09 [3.58-4.67]) showing the strongest links. For diabetes diagnosis, AIP (AUC: 0.824) and RC (0.822) outperformed other lipid indices (cutoffs: 0.31, 31.0) but were less effective than fasting glucose and HbA1c. For IR, AIP (AUC: 0.837) and RC (0.830) remained superior among lipid indices and showed no significant diagnostic disadvantage vs IR-related indicators. Subgroup analyses indicated stronger AIP/RC-diabetes/IR associations in females. Mediation analyses showed HOMA-IR mediated 43.1% and 50.3% of AIP/RC-diabetes associations, more pronounced in older adults (> 65 years), males and those with BMI ≥ 25 kg/m(2), while fatty acid intake did not affect these mediators. All six indices correlate with IR, but only AIP and RC strongly associate with diabetes, mediated by HOMA-IR. Females show enhanced AIP/RC-diabetes links, while older, male, and overweight groups exhibit greater HOMA-IR mediation. And AIP or RC's diagnostic performance for IR is not inferior to other IR assessment indices. Thus, AIP and RC are prioritized biomarkers for diabetes and IR monitoring.