Detrimental influence of diabetic conditions on human midbrain organoid fidelity
Accumulating evidences indicate shared disease mechanisms between type 2 diabetes (T2D) and Parkinson’s disease (PD). T2D seems to be a significant risk factor for the development of PD. The Substantia nigra in the midbrain, which is the most affected brain region in PD, is densely packed with insulin receptors, suggesting a significant role of insulin in midbrain metabolism and functionality. In addition, brain glucose uptake occurs partially in an insulin independent-manner, allowing glucose intracellular flow even when an insulin resistant state has been reached.
In the present study we aimed at understanding the effect of T2D associated insulin resistance and chronic hyperglycemia on midbrain organoid fidelity. Accordingly, we exposed human midbrain organoids to physiological (low glucose, low insulin) or diabetic cell culture conditions. This shall to better provide evidences that high levels of insulin, which would lead to insulin resistance, compromise dopaminergic neuron maturity and complexity. While particularly hyperglycemia seems to be responsible for oxidative damage. Finally, we demonstrate that diabetic culture conditions strongly alter the cellular metabolism and reduce mitochondrial functionality. All these effects might contribute to the increased vulnerability of dopaminergic neurons to degenerate and hence increase the risk for PD.