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Cardiovascular Drugs and Therapy

, Volume 26, Issue 5, pp 375–382 | Cite as

Rosuvastatin may Modulate Insulin Signaling and Inhibit Atherogenesis Beyond its Plasma Cholesterol-Lowering Effect in Insulin-Resistant Mice

  • Hangyuan Guo
  • Haitao Lv
  • Weiliang Tang
  • Jufang Chi
  • Longbin Liu
  • Fukang Xu
  • Zheng Ji
  • Xiaoya Zhai
  • Fang Peng
Article

Abstract

Objectives

To provide evidence that rosuvastatin may improve insulin-resistance and inhibit atherogenesis by modulating insulin signaling, and whether this effect occurs beyond its plasma cholesterol-lowering effect.

Methods

Thirty-two 6-week-old low-density lipoprotein receptor deficient mice were randomized into 4 groups (n = 8 in each group): Normal control group (NC); High fat and high fructose diet group (HFF); HFF plus rosuvastatin group (HFFR); HFFR plus mevalonic acid group (HFFRMA). After 12 weeks, we measured fasting blood sugar, fasting insulin and cholesterol levels; the morphological concentrations of the aorta and aortic sinus; the expression of insulin receptor substrate 2, phosphorylated insulin receptor substrate 2, protein kinase B, phosphorylated protein kinase B and the glucose transporter 4 in the liver.

Results

Compared with other groups, fasting blood sugar and fasting insulin increased significantly in HFF group. Furthermore, HFF group had an increase in the morphological concentrations of the aorta and aortic sinus, but there was a significant decrease in the HFFRMA group and the HFFR group. Moreover, there was a high expression of insulin receptor substrate 2, phosphorylated insulin receptor substrate 2, protein kinase B, phosphorylated protein kinase B and the glucose transporter 4 in the HFFRMA and HFFR groups, but a low expression in the HFF group. No significant differences regarding each afore-mentioned index was observed in the HFFR and HFFRMA groups.

Conclusions

Our data show that rosuvastatin may improve insulin-resistance and inhibit atherogenesis in HFF-fed mice by partially reversing the decrease in the insulin stimulated insulin receptor substrate 2/Phosphatidylinositol 3-kinase/protein kinase B/glucose transporter 4 pathway in the liver, and that this effect is independent of its cholesterol-lowering effect.

Key words

Rosuvastatin Atherogenesis Insulin signaling Insulin resistance 

Abbreviations

LDL

Low-density lipoprotein

LDLR−/−

Low-density lipoprotein receptor deficient

NC

Normal control group

HFF

High fat and high fructose diet group

HFFR

HFF plus rosuvastatin group

HFFRMA

HFFR plus mevalonic acid group

HMG-CoA

3-hydroxy-3-methylglutaryl coenzyme A

FBS

Fasting blood sugar

TG

Triglycerides

TC

Total cholesterol

LDL-C

Low-density lipoprotein cholesterol

HDL-C

High-density lipoprotein cholesterol

FINS

Fasting insulin

IR

Insulin resistance

IRS-2

Insulin receptor substrate 2

P-IRS-2

Phosphorylated insulin receptor substrate 2

AKT

Protein kinase B

P-AKT

Phosphorylated protein kinase B

GLUT4

Glucose transporter 4

PI3-K

Phosphatidylinositol 3-kinase

IGF

Insulin-like growth factors

Notes

Acknowledgments

This study was supported by medical health science and technology plan projects of Zhejiang province, China (Grant No. 2010KYA179); natural science foundation of Zhejiang province, China. (Grant No.Y2100535); shaoxing municipal science and technology plan projects (Grant No. 2010A23010).

References

  1. 1.
    Bloomgarden ZT. IR concepts. Diabetes Care. 2007;30:1320–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Hsueh WA, Law RE. Cardiovascular risk continuum: implications of insulin resistance and diabetes. Am J Med. 1998;105:4S–14S.PubMedCrossRefGoogle Scholar
  3. 3.
    Kostapanos MS, Liamis GL, Milionis HJ, Elisaf MS. Do statins beneficially or adversely affect glucose homeostasis? Curr Vasc Pharmacol. 2010;8:612–31.PubMedCrossRefGoogle Scholar
  4. 4.
    Bełtowski J, Atanassova P, Chaldakov GN, Jamroz-Wiśniewska A, Kula W, Rusek M. Opposite effects of pravastatin and atorvastatin on insulin sensitivity in the rat: role of vitamin D metabolites. Atherosclerosis. 2011;219:526–31.PubMedCrossRefGoogle Scholar
  5. 5.
    Koh KK, Sakuma I, Quon MJ. Differential metabolic effects of distinct statins. Atherosclerosis. 2011;215:1–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Altunbas H, Balci MK, Karayalcin U. No effect of simvastain treatment on insulin sensitivity in patients with parimary hypercholesrolemia. Endocr Res. 2003;29:265–75.PubMedCrossRefGoogle Scholar
  7. 7.
    Suzuki M, Kakuta H, Takahashi A, Shimano H, Tada-Iida K, Yokoo T, et al. Effects of atorvastatin on glucose metabolism and insulin resistance in KK/Ay mice. J Atheroscler Thromb. 2005;12:77–84.PubMedCrossRefGoogle Scholar
  8. 8.
    Naples M, Federico LM, Xu E, Nelken J, Adeli K. Effect of rosuvastatin on insulin sensitivity in an animal model of insulin resistance: evidence for statin-induced hepatic insulin sensitization. Atherosclerosis. 2008;198:94–103.PubMedCrossRefGoogle Scholar
  9. 9.
    Furuya DT, Poletto AC, Favaro RR, Martins JO, Zorn TM, Machado UF. Anti-inflammatory effect of atorvastatin ameliorates insulin resistance in monosodium glutamate-treated obese mice. Metabolism. 2010;59:395–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Kendrach MG, Kelly-Freeman M. Approximate equivalent rosuvastatin doses for temporary statin interchange programs. Ann Pharmacother. 2004;38:1286–92.PubMedCrossRefGoogle Scholar
  11. 11.
    Rosenson RS. Rosuvastatin: a new inhibitor of HMG-coA reductase for the treatment of dyslipidemia. Expert Rev Cardiovasc Ther. 2003;1:495–505.PubMedCrossRefGoogle Scholar
  12. 12.
    Istvan ES. Bacterial and mammalian HMG-CoA reductases:related enzymes with distinct architectures. Curr Opin Struct Biol. 2001;11:746–51.PubMedCrossRefGoogle Scholar
  13. 13.
    McTaggart F. Comparative pharmacology of rosuvastatin. Atheroscler Suppl. 2003;4:9–14.PubMedCrossRefGoogle Scholar
  14. 14.
    White MF, Maron R, Kahn CR. Insulin rapidly stimulates tyrosine phosphorylation of a Mr-185,000 protein in intact cells. Nature. 1985;318:183–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, et al. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature. 1991;352:73–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Sun XJ, Wang LM, Zhang Y, Yenush L, Myers Jr MG, Glasheen E, et al. Role of IRS-2 in insulin and cytokine signalling. Nature. 1995;377:173–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Lavan BE, Lane WS, Lienhard GE. The 60-kDa phosphotyrosine protein in insulin-treated adipocytes is a new member of the insulin receptor substrate family. J Biol Chem. 1997;272:11439–43.PubMedCrossRefGoogle Scholar
  18. 18.
    Lavan BE, Fantin VR, Chang ET, Lane WS, Keller SR, Lienhard GE. A novel 160-kDa phosphotyrosine protein in insulin-treated embryonic kidney cells is a new member of the insulin receptor substrate family. J Biol Chem. 1997;272:21403–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Kulkarni RN, Winnay JN, Daniels M, Brüning JC, Flier SN, Hanahan D, et al. Altered function of insulin receptor substrate-1-deficient mouse islets and cultured b-cell lines. J Clin Invest. 1999;104:R69–75.PubMedCrossRefGoogle Scholar
  20. 20.
    Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature. 1998;391:900–4.PubMedCrossRefGoogle Scholar
  21. 21.
    Withers DJ, Burks DJ, Towery HH, Altamuro SL, Flint CL, White MF. Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Nat Genet. 1999;23:32–40.PubMedGoogle Scholar
  22. 22.
    Kido Y, Burks DJ, Withers D, Bruning JC, Kahn CR, White MF, et al. Tissue-specific insulin resistance in mice with combined mutations of Insulin Receptor, IRS-1 and IRS-2. J Clin Invest. 2000;105:199–205.PubMedCrossRefGoogle Scholar
  23. 23.
    Rother KI, Imai Y, Caruso M, Beguinot F, Formisano P, Accili D. Evidence that IRS-2 phosphorylation is required for insulin action in hepatocytes. J Biol Chem. 1998;273:17491–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, et al. Insulin resistance differentially affects PI 3-K and MAP kinase-mediated signalling in human muscle. J Clin Invest. 2000;105:311–20.PubMedCrossRefGoogle Scholar
  25. 25.
    Montagnani M, Golovchenko I, Kim I, Koh GY, Goalstone ML, Mundhekar AN, et al. Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. J Biol Chem. 2002;277:1794–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Wang CC, Loalstone ML, Draznin B. Molecular mechanism of insulin resistance that impact cardiovascular biology. Diabetes. 2004;53:2735–40.PubMedCrossRefGoogle Scholar
  27. 27.
    Yenush L, White MF. The IRS-signaling system during insulin and cytokine action. BioEssays. 1997;19:491–500.PubMedCrossRefGoogle Scholar
  28. 28.
    Alessi DR, Cohen P. Mechanism of activation and function of protein kinase B. Curr Opin Genet Dev. 1998;8:55–62.PubMedCrossRefGoogle Scholar
  29. 29.
    Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. AKT promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor [in process citation]. Cell. 1999;96:857–68.PubMedCrossRefGoogle Scholar
  30. 30.
    Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74.PubMedCrossRefGoogle Scholar
  31. 31.
    Huang J, Manning BD. A complex interplay between Akt, TSC2, and the two mTOR complexes. Biochem Soc Trans. 2009;37:217–22.PubMedCrossRefGoogle Scholar
  32. 32.
    Asano T, Ogihara T, Katagiri H, Sakoda H, Ono H, Fujishiro M, et al. Glucose transporter and Na+/glucose cotransporter as molecular targets of anti-diabetic drugs. Curr Med Chem. 2004;11:2717–24.PubMedCrossRefGoogle Scholar
  33. 33.
    Leturque A, Brot-Laroche E, Le Gall M, Stolarczyk E, Tobin V. The role of GLUT2 in dietary sugar handling. J Physiol Biochem. 2005;61:529–37.PubMedCrossRefGoogle Scholar
  34. 34.
    Zhao FQ, Keating AF. Functional properties andgenomics of glucose transporters. Curr Genomics. 2007;8:113–28.PubMedCrossRefGoogle Scholar
  35. 35.
    Benomar Y, Naour N, Aubourg A, Bailleux V, Gertler A, Djiane J, et al. Insulin and leptin induce Glut4 plasma membrane translocation and glucose uptake in a human neuronal cell line by a phosphatidylinositol 3-kinase-dependent mechanism. Endocrinology. 2006;147:2550–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Leney SE, Tavare JM. The molecular basis of insulin-stimulated glucose uptake: signalling, trafficking and potential drug targets. J Endocrinol. 2009;203:1–18.PubMedCrossRefGoogle Scholar
  37. 37.
    Brüning JC, Michael MD, Winnay JN, Hayashi T, Hörsch D, Accili D, et al. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell. 1998;2:559–69.PubMedCrossRefGoogle Scholar
  38. 38.
    Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR. Tissue-specific knockout of the insulin receptor in pancreatic b cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell. 1999;96:329–39.PubMedCrossRefGoogle Scholar
  39. 39.
    Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature. 1994;372:182–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Patti ME, Sun XJ, Bruening JC, Araki E, Lipes MA, White MF, et al. 4PS/IRS-2 is the alternative substrate of the insulin receptor in IRS-1 deficient mice. J Biol Chem. 1995;270:24670–3.PubMedCrossRefGoogle Scholar
  41. 41.
    Yamauchi T, Tobe K, Tamemoto H, Ueki K, Kaburagi Y, Yamamoto-Honda R, et al. Insulin signaling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice. Mol Cell Biol. 1996;16:3074–84.PubMedGoogle Scholar
  42. 42.
    Contreras JL, Smyth CA, Bilbao G, Young CJ, Thompson JA, Eckhoff DE. Simvastatin induces activation of the serine-threonine protein kinase AKT and increases survival of isolated human pancreatic islets. Transplantation. 2002;74:1063–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase AKT and promotes angiogenesis in normocholesterolemic animals. Nat Med. 2000;6:1004–10.PubMedCrossRefGoogle Scholar
  44. 44.
    Alberts AW. Discovery biochemistry and biology of lovastatin. Am J Cardiol. 1988;62:10J–5J.PubMedCrossRefGoogle Scholar
  45. 45.
    Yokote K, Shimano H, Urashima M, Teramoto T. Efficacy and safety of pitavastatin in Japanese patients with hypercholesterolemia: LIVES study and subanalysis. Expert Rev Cardiovasc Ther. 2011;9:555–62.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Hangyuan Guo
    • 1
  • Haitao Lv
    • 1
    • 2
  • Weiliang Tang
    • 1
  • Jufang Chi
    • 1
  • Longbin Liu
    • 1
  • Fukang Xu
    • 1
  • Zheng Ji
    • 1
    • 2
  • Xiaoya Zhai
    • 1
    • 2
  • Fang Peng
    • 1
  1. 1.Department of Cardiology, Shaoxing People’s HospitalShaoxing Hospital of Zhejiang UniversityShaoxing CityChina
  2. 2.Wenzhou Medical CollegeWenzhou CityChina

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