title: A bis-Schiff base of isatin improves methylglyoxal mediated insulin resistance in skeletal muscle cells.
abstract: Methylglyoxal (MGO) is a highly reactive advanced glycation end products (AGEs) precursor and its abnormal accumulation causes damage to various tissues and organs. In our previous study, we synthesized a novel MGO inhibitor, MK-I-81, a bis-Schiff base derivative of isatin. In this study we demonstrate the mechanism of action of MK-I-81, on insulin resistance in skeletal muscle cells. MK-I-81 reduced AGEs formation and restored proximal insulin signaling by modulating IRS-1 phosphorylation. MK-I-81 also alleviated MGO mediated diminished distal insulin signaling by increasing protein kinase B and glycogen synthase kinase 3-beta phosphorylation. We also observed that MK-I-81 prevented reduced glucose uptake and glycogen synthesis induced by MGO in muscle cells. We found that the mechanism of action by which MK-I-81 reduced insulin resistance was suppression of production of MGO mediated ROS production in C2C12 cells. We evaluated deactivation of PKC-α and receptor for advanced glycation end products (RAGE) after treatment of cells with MK-I-81. MK-I-81 also reduced MGO mediated IRS-1, PKC-α and RAGE interaction in muscle cells. MK-I-81 also promoted nuclear factor erythroid 2-related factor-2 phosphorylation, heme oxygenase-1 and glyoxalase expression levels. We conclude that MK-I-81 can be a potential therapeutic target to address AGEs mediated insulin resistance. A novel Advanced Glycation End products (AGEs) inhibitor, MK-I-81 (a bis Schiff base of isatin), restored AGEs mediated down regulation of insulin signaling via modulating key molecules of proximal and distal insulin signaling. MK-I-81 also increased glucose uptake and glycogen synthesis in muscle cells. Novel bis-Schiff base of isatin showed significant antioxidant activity and also reduced receptor for AGEs (RAGE) expression and PKC-alpha activation therefore; MK-I-81 reduces AGEs induced insulin resistance.
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
authors.forename: Meha Fatima
authors.initials: MF
authors.lastname: Aftab
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
authors.forename: Shabbir Khan
authors.initials: SK
authors.lastname: Afridi
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
authors.forename: Safina
authors.initials: S
authors.lastname: Ghaffar
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
authors.forename: Munazza
authors.initials: M
authors.lastname: Murtaza
authors.affiliation: HEJ Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
authors.forename: Momin
authors.initials: M
authors.lastname: Khan
authors.affiliation: HEJ Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
authors.forename: Aneela
authors.initials: A
authors.lastname: Karim
authors.affiliation: HEJ Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
authors.forename: Khalid Mohammed
authors.initials: KM
authors.lastname: Khan
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan. rizwanas.waraich@gmail.com.
authors.forename: Rizwana Sanaullah
authors.initials: RS
authors.lastname: Waraich
keywords: Advanced glycation end products; Bis-Schiff bases of istain; Diabetes; Insulin receptor substrate 1; Insulin resistance; Insulin signal transduction; Protein kinase