Natural plant-derived polygalacturonic acid-oleanolic acid assemblies as oral-delivered nanomedicine for insulin resistance treatment

Exogenous insulin administration is still the most used treatment for diabetes (mainly used for type-1 diabetes in clinic), however type 2 diabetes (T2D) with the characteristics of insulin resistance accounts for the vast majority proportion (90-95%) of diabetic population, which makes insulin function failure. Currently, many efforts have been devoted to insulin delivery with nanomedicine means, whereas the treatment of insulin resistance in T2D using nanotechnology strategy is rarely reported. In this study, we transformed a plant-derived natural insulin sensitizer into biocompatible nano-transport system, where the natural insulin sensitizer oleanolic acid (OA) was conjugated onto natural polymer polygalacturonic acid (PGA) to form self-assembled micelles as oral administrated nanomedcine for insulin resistance treatment in T2D. In vitro and in vivo investigation demonstrated that OA loaded PGA-OA micelles possess stability to cross the gastrointestinal barriers and improve drug intestinal absorption, remarkably maintaining plasma drug concentration for a longer time. Therefore, this formulation manifested good reversal effect on insulin resistance in the T2D rat model, and thereby exhibited long-term outcomes in glucose level control even after drug withdrawal. Additionally, the molecular mechanism of OA loaded PGA-OA mediated insulin-resistant reversal was found that it was probable mediated by promoting IRS-1/PI3K/AKT signaling pathway and inhibiting the activity of PTP1B enzyme simultaneously. In this regard, such a facile, safe and potent nanomedicine strategy may be promising alternative for long-acting insulin-resistant treatment in T2D therapy.