Glycotoxins/Advanced glycation end products (AGES) have implications in development of diabetes and related diseases. In the present study we deciphered the mechanisms of action of URM-II-81, a new derivative of isatin, in alleviation of insulin resistance in human hepatocytes and murine adipocytes. URM-II-81 reduced AGES formation and receptor for advanced glycation end products (RAGE) expression in both cell types. We also observed suppression of methylglyoxal (MGO) mediated ROS production and deactivation of PKC-alpha. URM-II-81 restored proximal insulin signaling by modulating IRS-1 phosphorylation. URM-II-81 also alleviated MGO mediated diminished distal insulin signaling by increasing protein kinase B (PKB) and glycogen synthase kinase 3-beta (GSK-3-beta) phosphorylation. Glycogen synthesis was also increased in hepatocytes after treatment with URM-II-81. In adipocytes URM-II-81 prevented MGO induced reduced glucose uptake. We conclude that URM-II-81 can be a possible treatment target to address glycotoxins induced insulin resistance. (C) 2016 Elsevier Inc. All rights reserved.