The Saudi Journal of Medical Insights

Background: A compelling body of evidence suggests a significant intersection between Parkinson’s disease (PD) and
insulin resistance (IR), implicating metabolic dysfunction in PD pathophysiology beyond a simple comorbidity.
Objective: This systematic review aimed to comprehensively evaluate and synthesize the contemporary literature from the
past five years on the association between PD and IR.
Methods: The review was conducted according to PRISMA guidelines. A systematic search of five major databases
identified studies published within the last five years. Eligibility criteria included original research investigating the PD-IR
relationship in human patients or derived cellular models. Two reviewers independently performed study selection, data
extraction, and risk-of-bias assessment using Joanna Briggs Institute tools. Results: Four studies were included, comprising
clinical (retrospective cohort, cross-sectional), experimental (in vitro), and bioinformatics designs. Clinical findings showed
a higher prevalence of impaired fasting glucose in PD (43.4%) versus atypical parkinsonism (18.2%) and linked
hyperglycemia/IR to more severe axial motor symptoms. Experimental data using PD patient-derived midbrain organoids
demonstrated intrinsic insulin signaling dysregulation and rescued dopaminergic neuron loss via insulin pathway
modulation. Bioinformatics analysis identified shared genetic pathways (e.g., insulin signaling, immune response) between
PD, IR, and narcolepsy. Conclusion: Current evidence converges to suggest that central insulin resistance is a potential
disease-modifying factor in PD, contributing to neurodegeneration and specific motor deficits. The findings support the
rationale for targeting metabolic pathways as a novel therapeutic strategy in PD. Future longitudinal studies and clinical
trials of insulin-sensitizing agents are warranted.