Computational Modeling of PI3K/AKT Pathway in Bipolar Disorder and Type 2 Diabetes: Implications for Lithium Treatment and Curcumin as a Potential Alternative.

Bipolar disorder (BD) exhibits a high comorbidity rate with type 2 diabetes (T2D), suggesting shared pathophysiological mechanisms. Although lithium serves as the first-line treatment for BD, its underlying therapeutic mechanism and potential effects on T2D remain incompletely understood. This study identified the PI3K/AKT pathway as a key link between these disorders. Using an ordinary differential equation (ODE) model that integrates the PI3K/AKT pathway with the phosphatidylinositol (PI) cycle, we simulated lithium's regulatory effects in BD treatment. Our simulations revealed that lithium's primary inhibitory effect on GSK3β stems from direct binding, which restores insulin sensitivity, suggesting potential benefits for both BD and T2D, particularly in their comorbid state. Additionally, molecular docking studies indicated that curcumin, a potentially safer alternative to lithium, exhibits enhanced anti-inflammatory properties by binding to both GSK3β and p38 MAPK. These findings provide novel insights into the molecular mechanisms connecting BD and T2D and propose new therapeutic strategies for their management.