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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.

Graphical Abstract

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.

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References

  1. Abdel-Rahman E, Bolton WK (2002) Pimagedine: A novel therapy for diabetic nephropathy. Expert Opinion on Investigational Drugs 11:565–574

    CAS  Article  PubMed  Google Scholar 

  2. Boden G (2011) Obesity, insulin resistance and free fatty acids. Current opinion in Endocrinology, Diabetes, and Obesity 18:139–143

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  3. Boel E, Selmer J, Flodgaard HJ, Jensen T (1995) Diabetic late complications: Will aldose reductase inhibitors or inhibitors of advanced glycosylation endproduct formation hold promise? Journal of Diabetes and Its Complications 9:104–129

    CAS  Article  PubMed  Google Scholar 

  4. Bohlender JM, Franke S, Stein G, Wolf G (2005) Advanced glycation end products and the kidney. American Journal of Physiology 289:F645–659

    CAS  PubMed  Google Scholar 

  5. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820

    CAS  Article  PubMed  Google Scholar 

  6. Brownlee M, Vlassara H, Kooney A, Ulrich P, Cerami A (1986) Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science 232:1629–1632

    CAS  Article  PubMed  Google Scholar 

  7. Bucciarelli LG, Wendt T, Rong L, Lalla E, Hofmann MA, Goova MT, Taguchi A, Yan SF, Yan SD, Stern DM, Schmidt AM (2002) Rage is a multiligand receptor of the immunoglobulin superfamily: Implications for homeostasis and chronic disease. Cellular and Molecular Life Sciences 5:1117–1128

    Article  Google Scholar 

  8. Cai W, Ramdas M, Zhu L, Chen X, Striker GE, Vlassara H (2012) Oral advanced glycation endproducts (ages) promote insulin resistance and diabetes by depleting the antioxidant defenses age receptor-1 and sirtuin 1. Proceedings of the National Academy of Sciences of the United States of America 109:15888–15893

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  9. Cassese A, Esposito I, Fiory F, Barbagallo AP, Paturzo F, Mirra P, Ulianich L, Giacco F, Iadicicco C, Lombardi A, Oriente F, Van Obberghen E, Beguinot F, Formisano P, Miele C (2008) In skeletal muscle advanced glycation end products (ages) inhibit insulin action and induce the formation of multimolecular complexes including the receptor for ages. Journal of Biological Chemistry 283:36088–36099

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  10. Cheng AS, Cheng YH, Chiou CH, Chang TL (2012) Resveratrol upregulates nrf2 expression to attenuate methylglyoxal-induced insulin resistance in hep g2 cells. Journal of Agriculture and Food Chemistry 60:9180–9187

    CAS  Article  Google Scholar 

  11. Cheng AS, Cheng YH, Lee CY, Chung CY, Chang WC (2015) Resveratrol protects against methylglyoxal-induced hyperglycemia and pancreatic damage in vivo. Nutrients 7:2850–2856

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  12. Fiory F, Lombardi A, Miele C, Giudicelli J, Beguinot F, Van Obberghen E (2011) Methylglyoxal impairs insulin signalling and insulin action on glucose-induced insulin secretion in the pancreatic beta cell line INS-1E. Diabetologia 54:2941–2952

    CAS  Article  PubMed  Google Scholar 

  13. Freedman BI, Wuerth JP, Cartwright K, Bain RP, Dippe S, Hershon K, Mooradian AD, Spinowitz BS (1999) Design and baseline characteristics for the aminoguanidine clinical trial in overt type 2 diabetic nephropathy (action ii). Controlled Clinical Trials 20:493–510

    CAS  Article  PubMed  Google Scholar 

  14. Fukunaga M, Miyata S, Higo S, Hamada Y, Ueyama S, Kasuga M (2005) Methylglyoxal induces apoptosis through oxidative stress-mediated activation of p38 mitogen-activated protein kinase in rat schwann cells. Annals of the New York Academy of Sciences 1043:151–157

    CAS  Article  PubMed  Google Scholar 

  15. Goldin A, Beckman JA, Schmidt AM, Creager MA (2006) Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 114:597–605

    CAS  Article  PubMed  Google Scholar 

  16. Guo Q, Mori T, Jiang Y, Hu C, Osaki Y, Yoneki Y, Sun Y, Hosoya T, Kawamata A, Ogawa S, Nakayama M, Miyata T, Ito S (2009) Methylglyoxal contributes to the development of insulin resistance and salt sensitivity in sprague-dawley rats. Journal of Hypertension 27:1664–1671

    CAS  Article  PubMed  Google Scholar 

  17. Hancer NJ, Qiu W, Cherella C, Li Y, Copps KD, White MF (2014) Insulin and metabolic stress stimulate multisite serine/threonine phosphorylation of insulin receptor substrate 1 and inhibit tyrosine phosphorylation. Journal of Biological Chemistry 289:12467–12484

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  18. Huttunen HJ, Fages C, Rauvala H (1999) Receptor for advanced glycation end products (rage)-mediated neurite outgrowth and activation of nf-kappab require the cytoplasmic domain of the receptor but different downstream signaling pathways. Journal of Biological Chemistry 274:19919–19924

    CAS  Article  PubMed  Google Scholar 

  19. Kazi AA, Lang CH (2010) Pras40 regulates protein synthesis and cell cycle in C2C12 myoblasts. Molecular Medicine 16:359–371

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  20. Khan KM, Khan M, Ali M, Taha M, Rasheed S, Perveen S, Choudhary MI (2009) Synthesis of bis-Schiff bases of isatins and their antiglycation activity. Bioorganic & Medicinal Chemistry 17:7795–7801

    CAS  Article  Google Scholar 

  21. Kihm LP, Wibisono D, Muller-Krebs S, Pfisterer F, Morath C, Gross ML, Morcos M, Seregin Y, Bierhaus A, Nawroth PP, Zeier M, Schwenger V (2008) Rage expression in the human peritoneal membrane. Nephrology, Dialysis, Transplantation 23:3302–3306

    CAS  Article  PubMed  Google Scholar 

  22. Lander HM, Tauras JM, Ogiste JS, Hori O, Moss RA, Schmidt AM (1997) Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. Journal of Biological Chemistry 272:17810–17814

    CAS  Article  PubMed  Google Scholar 

  23. Lee BH, Hsu WH, Chang YY, Kuo HF, Hsu YW, Pan TM (2012) Ankaflavin: A natural novel ppargamma agonist upregulates nrf2 to attenuate methylglyoxal-induced diabetes in vivo. Free Radical Biology and Medicine 53:2008–2016

    CAS  Article  PubMed  Google Scholar 

  24. Lv L, Shao X, Chen H, Ho CT, Sang S (2011) Genistein inhibits advanced glycation end product formation by trapping methylglyoxal. Chemical Research in Toxicology 24:579–586

    CAS  Article  PubMed  Google Scholar 

  25. Miele C, Riboulet A, Maitan MA, Oriente F, Romano C, Formisano P, Giudicelli J, Beguinot F, Van Obberghen E (2003) Human glycated albumin affects glucose metabolism in L6 skeletal muscle cells by impairing insulin-induced insulin receptor substrate (irs) signaling through a protein kinase c alpha-mediated mechanism. Journal of Biological Chemistry 278:47376–47387

    CAS  Article  PubMed  Google Scholar 

  26. Mothe I, Van Obberghen E (1996) Phosphorylation of insulin receptor substrate-1 on multiple serine residues, 612, 632, 662, and 731, modulates insulin action. Journal of Biological Chemistry 271:11222–11227

    CAS  Article  PubMed  Google Scholar 

  27. O’brien J, Morrissey PA (1989) Nutritional and toxicological aspects of the Maillard browning reaction in foods. Critical Reviews in Food Science and Nutrition 28:211–248

    Article  PubMed  Google Scholar 

  28. Riboulet-Chavey A, Pierron A, Durand I, Murdaca J, Giudicelli J, Van Obberghen E (2006) Methylglyoxal impairs the insulin signaling pathways independently of the formation of intracellular reactive oxygen species. Diabetes 55:1289–1299

    CAS  Article  PubMed  Google Scholar 

  29. Rowland AF, Fazakerley DJ, James DE (2011) Mapping insulin/glut4 circuitry. Traffic 12:672–681

    CAS  Article  PubMed  Google Scholar 

  30. Schmidt AM, Yan SD, Wautier JL, Stern D (1999) Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circulation Research 84:489–497

    CAS  Article  PubMed  Google Scholar 

  31. Seo K, Ki SH, Shin SM (2014) Methylglyoxal induces mitochondrial dysfunction and cell death in liver. Toxicology Research 30:193–198

    CAS  Article  Google Scholar 

  32. Shinohara M, Thornalley PJ, Giardino I, Beisswenger P, Thorpe SR, Onorato J, Brownlee M (1998) Overexpression of glyoxalase-i in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycemia-induced increases in macromolecular endocytosis. Journal of Clinical Investigation 101:1142–1147

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  33. Suji G, Sivakami S (2006) Dna damage by free radical production by aminoguanidine. Annals of the New York Academy of Sciences 1067:191–199

    CAS  Article  PubMed  Google Scholar 

  34. Sultan KR, Henkel B, Terlou M, Haagsman HP (2006) Quantification of hormone-induced atrophy of large myotubes from c2c12 and l6 cells: Atrophy-inducible and atrophy-resistant C2C12 myotubes. American Journal of Physiology Cell Physiology 290:C650–659

    CAS  Article  PubMed  Google Scholar 

  35. Taniguchi N, Takahashi M, Sakiyama H, Park YS, Asahi M, Misonou Y, Miyamoto Y (2005) A common pathway for intracellular reactive oxygen species production by glycoxidative and nitroxidative stress in vascular endothelial cells and smooth muscle cells. Annals of the New York Academy of Sciences 1043:521–528

    CAS  Article  PubMed  Google Scholar 

  36. Tsuchiya Y, Hatakeyama H, Emoto N, Wagatsuma F, Matsushita S, Kanzaki M (2010) Palmitate-Induced down-regulation of sortilin and impaired glut4 trafficking in C2C12 myotubes. Journal of Biological Chemistry 285:34371–34381

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  37. Ulrich P, Cerami A (2001) Protein glycation, diabetes, and aging. Recent Progress in Hormone Research 56:1–21

    CAS  Article  PubMed  Google Scholar 

  38. Uribarri J, Cai W, Ramdas M, Goodman S, Pyzik R, Chen X, Zhu L, Striker GE, Vlassara H (2011) Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of ager1 and sirt1. Diabetes Care 34:1610–1616

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  39. Vlassara H (2001) The age-receptor in the pathogenesis of diabetic complications. Diabetes/Metabolism Research and Reviews 17:436–443

    CAS  Article  PubMed  Google Scholar 

  40. Wang X, Jia X, Chang T, Desai K, Wu L (2008) Attenuation of hypertension development by scavenging methylglyoxal in fructose-treated rats. Journal of Hypertension 26:765–772

    CAS  Article  PubMed  Google Scholar 

  41. Waraich RS, Weigert C, Kalbacher H, Hennige AM, Lutz SZ, Haring HU, Schleicher ED, Voelter W, Lehmann R (2008a) Phosphorylation of ser357 of rat insulin receptor substrate-1 mediates adverse effects of protein kinase c-delta on insulin action in skeletal muscle cells. Journal of Biological Chemistry 283:11226–11233

    CAS  Article  PubMed  Google Scholar 

  42. Waraich RS, Zaidi N, Moeschel K, Beck A, Weigert C, Voelter W, Kalbacher H, Lehmann R (2008b) Development and precise characterization of phospho-site-specific antibody of ser(357) of irs-1: Elimination of cross reactivity with adjacent ser(358). Biochemical and Biophysical Research Communications 376:26–31

    CAS  Article  PubMed  Google Scholar 

  43. Yamamoto N, Sato T, Kawasaki K, Murosaki S, Yamamoto Y (2006) A nonradioisotope, enzymatic assay for 2-deoxyglucose uptake in l6 skeletal muscle cells cultured in a 96-well microplate. Analytical Biochemistry 351:139–145

    CAS  Article  PubMed  Google Scholar 

  44. Yan SF, Ramasamy R, Schmidt AM (2008) Mechanisms of disease: Advanced glycation end-products and their receptor in inflammation and diabetes complications. Nature Clinical Practice Endocrinology & Metabolism 4:285–293

    CAS  Article  Google Scholar 

  45. Yoon YW, Kang TS, Lee BK, Chang W, Hwang KC, Rhee JH, Min PK, Hong BK, Rim SJ, Kwon HM (2008) Pathobiological role of advanced glycation endproducts via mitogen-activated protein kinase dependent pathway in the diabetic vasculopathy. Experimental & Molecular Medicine 40:398–406

    CAS  Article  Google Scholar 

  46. Yoon SJ, Yoon YW, Lee BK, Kwon HM, Hwang KC, Kim M, Chang W, Hong BK, Lee YH, Park SJ, Min PK, Rim SJ (2009) Potential role of HMG CoA reductase inhibitor on oxidative stress induced by advanced glycation endproducts in vascular smooth muscle cells of diabetic vasculopathy. Experimental & Molecular Medicine 41:802–811

    CAS  Article  Google Scholar 

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Acknowledgments

We thank Rahat M. Khan for his technical assistance. This work was supported by grants (HEC Grant No: 20-1141 and No. 20-1910) from the Higher Education Commission of Pakistan to Dr. Rizwana S. Waraich and Dr. Khalid M. Khan, respectively.

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Correspondence to Rizwana Sanaullah Waraich.

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Aftab, M.F., Afridi, S.K., Ghaffar, S. et al. A bis-Schiff base of isatin improves methylglyoxal mediated insulin resistance in skeletal muscle cells. Arch. Pharm. Res. (2015). https://doi.org/10.1007/s12272-015-0670-z

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Keywords

  • Insulin signal transduction
  • Insulin receptor substrate 1
  • Insulin resistance
  • Protein kinase
  • Advanced glycation end products
  • Bis-Schiff bases of istain
  • Diabetes