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.

Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases

“…An exposure of skeletal muscle cells to MGO or MGO-modified proteins inhibits glucose uptake via an impairment of insulin-stimulated phosphorylation of protein kinase B (PKB) and extracellular signal-regulated protein kinases 1/2 (ERK1/2), without affecting IR tyrosine phosphorylation (375,472). This effect of MGO was inhibited by a bis-Schiff base of isatin, an inhibitor of MGO (7). Importantly, these harmful effects of MGO are independent of ROS, but appear to be a direct consequence of MGO-induced impairment of IRS-1 tyrosine phosphorylation.…”

RAGE in the pathophysiology of skeletal muscle

“…When MGL was reduced in type 2 diabetic patients, IR was improved . Recently, an interesting study proposed a novel MGL‐derived AGE inhibitor, MK‐I81, as a potential therapeutic compound to alleviate AGE‐mediated downregulation of insulin signal transduction and insulin action in skeletal muscle cells restoring insulin sensitivity …”