An oral hypoglycemic agent for T2DM with the function of alleviating multi-complications

Abstract

Although hypoglycemic drugs with the function of alleviating complications such as GLP-1RA and SGLT2i have been used in clinic, these drugs are still far from meeting the treatment needs. Herein, we report an oral hypoglycemic agent for T2DM with the function of alleviating multi-complications including neuropathy by way of self-polymerizing dietary antioxidant lipoic acid (LA) into a nanodrug called poly-lipoic acid particles (pLAPs). The self-polymerization made the oral T_1/2 and AUC_{0 ~ 72 h} of LA up to 23.2 h and 3761.8 ± 55.9 h*µg/mL, ~ 46 times and ~ 23 times higher than that of LA monomer, respectively. As entering the cells, pLAPs were slowly degraded to LA in response to glutathione to prolong the intracellular retention time of LA from ~ 10 min to > 6 h. This prolongation achieved a continuous activation of the insulin signaling pathway, making a long-lasting and near-normal blood glucose level hypoglycemic effect come true. Thanks to the significant improvement of pharmacokinetics and intracellular retention time, pLAPs restored the oxidative stress and inflammation-related indicators to the normal control levels in the T2DM models with neuropathy and angiopathy, leading to the outstanding therapeutic effect on these complications. Importantly, the promising efficacy of pLAPs was confirmed in the model of spontaneous diabetic rhesus monkeys with neuropathy. Considering its excellent biosafety, the oral hypoglycemic drug with multi-complication alleviation holds clinical potential.