Insulin Resistance and Metabolic Dysfunction in Early-Stage Parkinson’s Disease: Evidence from a Preliminary Case-Control Study

<b>Background:</b> Parkinson's disease (PD) is increasingly recognized as a multisystem disorder in which metabolic dysfunction may contribute to disease susceptibility and progression. Peripheral insulin resistance (IR) has been implicated in PD, but data in levodopa-naïve patients are currently limited. Objective: To investigate the prevalence of IR and metabolic dysfunction in early-stage, levodopa-naïve PD patients and their association with clinical features. <b>Methods:</b> We conducted an exploratory case-control study including 20 levodopa-naïve PD patients and 40 age-, sex-, and BMI-matched healthy controls. Participants underwent comprehensive clinical and metabolic assessments, including fasting glucose, insulin, lipid profiles, and HOMA-IR calculation. Peripheral IR was defined using HOMA-IR cut-offs of ≥2.0 (primary analysis) and ≥2.5 (sensitivity analysis). ANCOVA adjusted for age, sex, and BMI was used for between-group comparisons. <b>Results:</b> PD patients exhibited higher fasting insulin (10.7 ± 5.2 vs. 8.0 ± 4.4 µIU/mL; <i>p</i> = 0.020) and HOMA-IR (2.63 ± 1.40 vs. 1.89 ± 1.21; <i>p</i> = 0.014) compared to controls. Using a HOMA-IR ≥ 2.0, IR prevalence was 70% in PD vs. 32.5% in controls (OR = 4.85, 95% CI 1.52-15.50, <i>p</i> = 0.012). ANCOVA analysis confirmed group differences after adjusting for covariates (respectively, <i>p</i> = 0.032 for insulin and <i>p</i> = 0.023 for HOMA-IR). A sensitivity analysis excluding six patients receiving dopaminergic therapy further supported the robustness of the results. No significant correlations were observed between IR and disease severity scores. <b>Conclusions:</b> Early-stage, levodopa-naïve PD patients exhibit a higher prevalence of peripheral insulin resistance compared with matched controls. These findings support the hypothesis that metabolic dysfunction is an intrinsic component of PD pathophysiology and may represent a target for early intervention.