Oral nanomedicine for cure of T2DM through whole-process regulation of glucose uptake/metabolism and mitochondrial repair in hepatocytes

Serious drug dependence or resistance is a big challenge of insulin-or metformin-based strategies for type 2 diabetes mellitus (T2DM) therapy, which could be resolved by metal ions with coenzyme activity or polypeptides with repair ability. As two essential trace elements, Zn and Se play important roles respectively in glucose uptake mediated by cell membrane translocation of GLUT4 and ROS clearance and insulin sensitization mediated by selenoprotein. However, the complex stability and the repairing mechanism clarification of polypeptide-metal combination strategy still need more exploration. In this work, polypeptide-bimetallic complexes (peptides-Se/Zn) with more chelating sites and more satisfactory digestive stability than polypeptide-single-metallic complexes were firstly obtained, and then were gastrointestinally delivered by porous CaSiO₃ and hydroxypropylmethyl cellulose phthalate (HPMCP) into T2DM hepatocytes for whole-process regulation of glucose uptake and metabolism. The release of Zn²⁺ activates the IRS1/PI3K/Akt pathway and the simultaneous release of Se⁴⁺ activates the cAMP/AMPK pathway, which together upregulates GLUT4 membrane formation and glucose uptake. Moreover, peptides-Se/Zn repaired the mitochondrial activity through directly repairing mitochondrial membrane by peptides and up-regulating glutathione peroxidase (GPX) and glycolysis by Zn²⁺/Se⁴⁺, which is beneficial for more efficient glucose uptake and glycometabolism capacity. In summary, the polypeptide-bimetallic nano-platform realized the repair of hepatocyte mitochondria and the whole-process regulation of glucose uptake and metabolism, thus reshaping hepatocyte function and realizing blood glucose reversal, exhibiting great significance in exploring the feasibility and mechanism of polypeptide metal complexes as T2DM drug candidates.