Free Fatty Acids and Sarcopenia Risk in Type 2 Diabetes: Insights From SHAP Analysis

Sarcopenia is a prevalent and disabling complication of Type 2 diabetes mellitus (T2DM), which significantly elevates the risks of falls, fractures, institutionalization, and all-cause mortality. Lipotoxicity mediated by circulating free fatty acids (FFA) is crucial in the pathogenesis of diabetes-related sarcopenia, but the independent association and dose-response pattern between serum FFA levels and sarcopenia risk in T2DM patients remain poorly clarified.

This single-center cross-sectional study enrolled 299 patients with T2DM. Sarcopenia was diagnosed in accordance with the 2019 Asian Working Group for Sarcopenia criteria. Fasting serum FFA levels were measured by enzymatic colorimetry. Sequential multivariate logistic regression, restricted cubic spline (RCS) analysis, receiver operating characteristic (ROC) curve, calibration curve, decision curve analysis (DCA), and SHapley Additive exPlanations (SHAPs) analysis were applied to explore the association and predictive value of FFA.

The overall prevalence of sarcopenia was 23.4%. After full adjustment for confounders, log-transformed FFA remained an independent risk factor for sarcopenia (OR = 2.73, 95% CI: 1.31-5.70, p = 0.007). RCS analysis identified a significant nonlinear relationship with a threshold at 0.6 mmol/L; sarcopenia risk declined slightly with increasing FFA below this threshold, but rose steeply and linearly when FFA exceeded 0.6 mmol/L. FFA showed excellent predictive performance with an AUC of 0.852, satisfactory calibration and significant clinical net benefit. SHAP analysis confirmed FFA as the core predictive feature, and the association was consistent across all prespecified subgroups.

Serum FFA levels are independently and nonlinearly associated with sarcopenia risk in T2DM patients, with a clinically actionable threshold of 0.6 mmol/L. FFA can serve as a simple, accessible, and cost-effective biomarker for early risk stratification of sarcopenia in patients with T2DM.