Grape seed proanthocyanidins and metformin act by different mechanisms to promote insulin signaling in rats fed high calorie diet

  • Baskaran Yogalakshmi
  • Saravanan Bhuvaneswari
  • S. Sreeja
  • Carani Venkatraman Anuradha
Research Article

Abstract

Key pathways like insulin signaling, AMP activated kinase (AMPK) activation and inflammatory signaling are involved in the complex pathological network of hepatic insulin resistance. Our aim is to investigate whether grape seed proanthocyanidins (GSP) and metformin (MET) target any of these pathways in insulin resistant rat liver. Albino Wistar rats were rendered insulin resistant by feeding a high fat-fructose diet (HFFD). Either GSP (100 mg/kg b.w), MET(50 mg/kg b.w) or both were administered to insulin resistant rats as therapeutic options. HFFD-feeding caused hyperglycemia, hyperinsulinemia, increased gluconeogenesis, decreased tyrosine phosphorylation of insulin receptor-β(IR-β) and insulin receptor substrate-1 (IRS-1) and increased serine phosphorylation of IRS-1. The association of p85α subunit of phosphotidyl inositol 3 kinase(PI3K) with IRS-1 and subsequent Akt phosphorylation were reduced while the expression of mitogen activated protein kinases (MAPK) were increased in HFFD rats. Both MET and GSP reduced hyperglycemia and hyperinsulinemia and improved glycolysis, tyrosine phosphorylation of IR-β and IRS-1, IRS-1-PI3K association and Akt activation. However, activation of tumor necrosis factor-α, interleukin-6, leptin and suppressor of cytokine signaling-3 and reduction in adiponectin caused by chronic HFFD feeding were reversed by GSP better than by MET. Activation of AMPK by GSP was much less compared to that by MET. These findings suggest that GSP might activate PI3K pathway and promote insulin action by reducing serine kinase activation and cytokine signaling and MET by targeting AMPK. The beneficial effects were enhanced during combination therapy. Thus, combination therapy with MET and GSP may be considered for the management of metabolic syndrome.

Keywords

High fat-fructose diet Grape seed proanthocyanidins Metformin Insulin signaling Inflammation 

References

  1. Aguirre V, Uchida T, Yenush L, Davis R, White MF (2000) The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307. J Biol Chem 275:9047–9054PubMedCrossRefGoogle Scholar
  2. Anithanandhini AT, Balakrishnan SD, Anuradha CV (2002) Taurine modulates antioxidant potential and controls lipid peroxidation in the aorta of high fructose-fed rats. J Biochem Mol Biol Biophys 6:129–133CrossRefGoogle Scholar
  3. Bailey CJ, Day C (2004) Avandamet: combined metformin-rosiglitazone treatment for insulin resistance in type 2 diabetes. Int J Clin Pract 58:867–876PubMedCrossRefGoogle Scholar
  4. Bjorbak C, Lavery HJ, Bates SH, Olson RK, Davis SM, Flier JS, Myers MG Jr (2000) SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J Biol Chem 275:40649–40657PubMedCrossRefGoogle Scholar
  5. Coate KC, Scott M, Farmer B, Moore MC, Smith M, Roop J, Neal DW, Williams P, Cherrington AD (2010) Chronic consumption of a high-fat/high-fructose diet renders the liver incapable of net hepatic glucose uptake. Am J Physiol Endocrinol Metab 299:887–898CrossRefGoogle Scholar
  6. Greenberg AS, Obin MS (2006) Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 83:461S–465SPubMedGoogle Scholar
  7. Hokayem M, Blond E, Vidal H, Lambert K, Meugnier E, Feillet-Coudray C, Coudray C, Pesenti S, Luyton C, Lambert-Porcheron S, Sauvinet V, Fedou C, Brun JF, Rieusset J, Bisbal C, Sultan A, Mercier J, Goudable J, Dupuy AM, Cristol JP, Laville M, Avignon A (2013) Grape polyphenols prevent fructose-induced oxidative stress and insulin resistance in first-degree relatives of type 2 diabetic patients. Diabetes Care 36:1454–1461PubMedCrossRefGoogle Scholar
  8. Johnston AM, Pirola L, Van Obberghen E (2003) Molecular mechanisms of insulin receptor substrate protein-mediated modulation of insulin signaling. FEBS Lett 546:32–36PubMedCrossRefGoogle Scholar
  9. Kaur M, Singh RP, Gu M, Agarwal R, Agarwal C (2006) Grape seed extract inhibits in vitro and in vivo growth of human colorectal carcinoma cells. Clin Cancer Res 12:6194–6202PubMedCrossRefGoogle Scholar
  10. Kershaw EE, Flier JS (2004) Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 89:2548–2556PubMedCrossRefGoogle Scholar
  11. Li XM, Li Y, Zhang NN, Xie YH, Shi YQ (2011) Combination therapy with metformin and fenofibrate for insulin resistance in obesity. J Int Med Res 39:1876–1882PubMedCrossRefGoogle Scholar
  12. Lowry OH, Rosebrough N, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–725PubMedGoogle Scholar
  13. Medina EA, Afsari RR, Ravid T, Castillo SS, Erickson KL, Goldkorn T (2005) Tumor necrosis factor-{alpha} decreases Akt protein levels in 3T3-L1 adipocytes via the caspase-dependent ubiquitination of Akt. Endocrinology 146:2726–2735PubMedCrossRefGoogle Scholar
  14. Miller BS, Shankavaram UT, Horney MJ, Gore ACS, Kurtz DT, Rosenzweig SA (1996) Activation of cJun NH2-terminal kinase/stress-activated protein kinase by insulin. Biochemistry 35:8769–8775PubMedCrossRefGoogle Scholar
  15. Montagut G, Onnockx S, Vaqué M, Bladé C, Blay M, Fernández-Larrea J, Pujadas G, Salvadó MJ, Arola L, Pirson I, Ardévol A, Pinent M (2010) Oligomers of grape-seed procyanidin extract activate the insulin receptor and key targets of the insulin signaling pathway differently from insulin. J Nutr Biochem 21:476–481PubMedCrossRefGoogle Scholar
  16. Otero M, Lago R, Lago F, Casanueva FF, Dieguez C, Gómez-Reino JJ, Gualillo O (2005) Leptin, from fat to inflammation: old questions and new insights. FEBS Lett 579:295–301PubMedCrossRefGoogle Scholar
  17. Phillips L, Prins J (2008) The link between abdominal obesity and the metabolic syndrome. Curr Hypertens Rep 10:156–164PubMedCrossRefGoogle Scholar
  18. Rabe K, Lehrke M, Parhofer KG, Broedl UC (2008) Adipokines and insulin resistance. Mol Med 14:741–751PubMedCentralPubMedCrossRefGoogle Scholar
  19. Sarraf P, Frederich RC, Turner EM, Ma G, Jaskowiak NT, Rivet DJ 3rd, Flier JS, Lowell BB, Fraker DL, Alexander HR (1997) Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. J Exp Med 185:171–175PubMedCentralPubMedCrossRefGoogle Scholar
  20. Strowig SM, Raskin P (2005) Combination therapy using metformin or thiazolidinediones and insulin in the treatment of diabetes mellitus. Diabetes Obes Metab 7:633–641PubMedCrossRefGoogle Scholar
  21. Suwannaphet W, Meeprom A, Yibchok-Anun S, Adisakwattanna S (2010) Preventive effect of grape seed extract against high-fructose diet-induced insulin resistance and oxidative stress in rats. Food Chem Toxicol 48:1853–1857PubMedCrossRefGoogle Scholar
  22. Taniguchi CM, Brice E, Kahn CR (2006) Critical nodes in signaling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7:85–96PubMedCrossRefGoogle Scholar
  23. Terra X, Montagut G, Bustos M, Llopiz N, Ardèvol A, Bladé C, Fernández-Larrea J, Pujadas G, Salvadó J, Arola L, Blay M (2009) Grape-seed procyanidins prevent low-GSPde inflammation by modulating cytokine expression in rats fed a high-fat diet. J Nutr Biochem 20:210–218PubMedCrossRefGoogle Scholar
  24. Ueki K, Kondo T, Kahn CR (2004) Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 24:5434–5446PubMedCentralPubMedCrossRefGoogle Scholar
  25. Werner ED, Lee J, Hansen L, Yuan M, Shoelson SE (2004) Insulin resistance due to phosphorylation of insulin receptor substrate-1 at serine 302. J Biol Chem 279:35298–35305PubMedCrossRefGoogle Scholar
  26. Whitehead JP, Richards AA, Hickman IJ, Macdonald GA, Prins JB (2006) Adiponectin—a key adipokine in the metabolic syndrome. Diabetes Obes Metab 8:264–280PubMedCrossRefGoogle Scholar
  27. Winder WW, Hardie DG (1999) The AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol 277:E1–E10PubMedGoogle Scholar
  28. Yousef MI, Saad AA, El-Shennawy LK (2009) Protective effect of grape seed proanthocyanidin extract against oxidative stress induced by cisplatin in rats. Food Chem Toxicol 47:1176–1183PubMedCrossRefGoogle Scholar
  29. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© The International CCN Society 2013

Authors and Affiliations

  • Baskaran Yogalakshmi
    • 1
  • Saravanan Bhuvaneswari
    • 1
  • S. Sreeja
    • 1
  • Carani Venkatraman Anuradha
    • 1
  1. 1.Department of Biochemistry and BiotechnologyAnnamalai UniversityAnnamalai NagarIndia

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