A new glycotoxins inhibitor attenuates insulin resistance in liver and fat cells

• Published in: Biochemical and biophysical research communications Vol. 476; no. 4; pp. 188 - 195
• Main Authors: Afridi, Shabbir Khan, Aftab, Meha Fatima, Murtaza, Munazza, Ghaffar, Safina, Karim, Aneela, Mughal, Uzma Rasool, Khan, Khalid Mohammed, Waraich, Rizwana Sanaullah
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.08.2016
• Subjects: 3T3-L1 Cells; adipocytes; Adipocytes - cytology; Adipocytes - drug effects; Adipocytes - metabolism; advanced glycation end products; Animals; Cell Proliferation - drug effects; Diabetes; Enzyme Activation - drug effects; glucose; Glucose - metabolism; Glycation End Products, Advanced - antagonists & inhibitors; glycogen; Glycogen Synthase Kinase 3 - metabolism; Glycotoxins; Hep G2 Cells; hepatocytes; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; insulin; Insulin - metabolism; Insulin Receptor Substrate Proteins - metabolism; Insulin Resistance; Insulin signal transduction; Isatin - analogs & derivatives; Isatin - pharmacology; liver; Liver - drug effects; Liver - metabolism; mechanism of action; Mice; non-specific serine/threonine protein kinase; phosphorylation; Phosphorylation - drug effects; Protein kinase; protein kinase C; Protein Kinase C-alpha - metabolism; Reactive Oxygen Species - metabolism; Schiff bases of istain; tau-protein kinase; Glycotoxins; Insulin resistance; Diabetes; Protein kinase; Schiff bases of istain; Insulin signal transduction
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.05.085

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-α. 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. A novel glycotoxin inhibitor, URM-II-81, modulated key molecules of proximal and distal insulin signaling and hence alleviated glycotoxin mediated diminished insulin signaling. URM-II-81 also increased glycogen synthesis and glucose uptake in liver and fat cells, respectively. Novel derivative of isatin showed significant reduced receptor for AGEs (RAGE) expression, antioxidant activity and PKC-alpha activation, therefore; URM-II-81 reduced glycotoxin induced insulin resistance. [Display omitted] •A new glycotoxins inhibitor enhanced insulin signaling in hepatocytes and adipocytes.•URM-II-81 enhanced glucose uptake in adipocytes.•URM-II-81 improved glycogen synthesis in hepatocytes.