Insulin resistance compromises midbrain organoid neural activity and metabolic efficiency predisposing to Parkinson’s disease pathology

Growing evidence indicates that Type 2 Diabetes (T2D) is associated with an increased risk of developing Parkinson’s disease through shared disease mechanisms. Studies show that insulin resistance, which is the driving pathophysiological mechanism of T2D plays a major role in neurodegeneration by impairing neuronal functionality, metabolism, and survival. To investigate insulin resistance caused pathological changes in the human midbrain, which could predispose a healthy midbrain to PD development, we exposed iPSC-derived human midbrain organoids from healthy individuals to either high insulin concentrations, promoting insulin resistance, or to more physiological insulin concentrations restoring insulin signalling function. We combined experimental methods with metabolic modelling to identify the most insulin resistance-dependent pathogenic processes. We demonstrate that insulin resistance compromises organoid metabolic efficiency, leading to increased levels of oxidative stress. Additionally, insulin-resistant midbrain organoids showed decreased neural activity and reduced amount of dopaminergic neurons, highlighting insulin resistance as a significant target in PD prevention. ### Competing Interest Statement JCS is a co-inventor on a patent covering the generation of the here-described midbrain organoids (WO2017060884A1). Furthermore, JCS is a co-founder and shareholder of the company OrganoTherapeutics which makes use of midbrain organoid technology. GGG is a lead scientist in OrganoTherapeutics. The other authors declare no competing interests.