A bis-Schiff base of isatin improves methylglyoxal mediated insulin resistance in skeletal muscle cells
| Autor: | Meha Fatima Aftab, Khalid Mohammed Khan, Rizwana S. Waraich, Aneela Karim, Shabbir Khan Afridi, Munazza Murtaza, Momin Khan, Safina Ghaffar |
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| Rok vydání: | 2015 |
| Předmět: |
medicine.medical_specialty
biology business.industry Organic Chemistry Methylglyoxal medicine.disease Bioinformatics IRS1 chemistry.chemical_compound Insulin receptor Insulin resistance Endocrinology chemistry Downregulation and upregulation Glycation Internal medicine Drug Discovery biology.protein Molecular Medicine Medicine business Glycogen synthase Protein kinase B |
| Zdroj: | Archives of pharmacal research. |
| ISSN: | 1976-3786 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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