Skip to main content
SpringerLink
Log in

A role for atorvastatin and insulin combination in protecting from liver injury in a model of type 2 diabetes with hyperlipidemia

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a major complication linked with the metabolic syndrome associated with dyslipidemia, inflammation, and oxidative stress. Impact of type 2 diabetes with hyperlipidemia in NAFLD has to be established, as well as the utility of commonly prescribed anti-diabetic and lipid-lowering agents in improving liver injury markers. Genetic type 2 diabetic Goto–Kakizaki rats were fed with a high-fat diet to test hepatic effects of type 2 diabetes with hyperlipidemia and the effect of atorvastatin and insulin, individually and in combination, in systemic and hepatic inflammatory and oxidative stress markers. High-fat diet aggravated fasting glycemia, systemic and liver lipids, and inflammatory and oxidative stress markers. Individual treatments improved glycemic and lipid profiles, but failed to improve inflammatory markers, whereas insulin was able to reduce liver oxidative stress parameters. Combination of insulin and atorvastatin further improved glycemic and lipid profiles and decreased circulating C-reactive protein levels and liver inflammatory and oxidative stress markers. Insulin and atorvastatin combination leads to better glycaemic and lipid profiles and to better protection against liver inflammation and oxidative stress, giving a superior level of liver protection in type 2 diabetic with hyperlipidemia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

NAFLD:

Non-alcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

CRP:

C-reactive protein

TNF-α:

Tumour necrosis factor α

IL-6:

Interleukin-6

References

  • Aas A, Seljeflot I, Torjesen P, Diep L, Thorsby P, Birkeland K (2006) Blood glucose lowering by lifestyle intervention has different effects on adipokines as compared with insulin treatment in subjects with type 2 diabetes. Diabetologia 49:872–880

    Article  PubMed  CAS  Google Scholar 

  • Athyros V, Mikhailidis D, Didangelos T, Giouleme O, Liberopoulos E, Karagiannis A et al (2006) Effect of multifactorial treatment on non-alcoholic fatty liver disease in metabolic syndrome: a randomised study. Curr Med Res Opin 22:873–883

    Article  PubMed  CAS  Google Scholar 

  • Bayés B, Granada ML, Lauzurica R, Pastor MC, Navarro M, Bonet J, Llopis MA, Romero R (2005) Effect of low doses of atorvastatin on adiponectin, glucose homeostasis, and clinical inflammatory markers in kidney transplant recipients. Transplant Proc 37:3808–3812

    Article  PubMed  Google Scholar 

  • Bisgaier C, Essenburg A, Auerbach B, Pape M, Sekerke C, Gee A, Wölle S, Newton R (1997) Attenuation of plasma low density lipoprotein cholesterol by select 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in mice devoid of low density lipoprotein receptors. J Lipid Res 38:2502–2525

    PubMed  CAS  Google Scholar 

  • Bradbury M (2006) Lipid metabolism and liver inflammation. Am J Physiol Gastrointest Liver Physiol 290:G194–G198

    Article  PubMed  CAS  Google Scholar 

  • Brownlee M (2005) The pathobiology of diabetic complications. Diabetes 54:1615–25

    Article  PubMed  CAS  Google Scholar 

  • Bugianesi E, Gastaldelli A, Gambino R, Cassader M, Baldi S, Ponti V, Pagano G, Ferrannini E, Rizzetto M (2005a) Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 48:634–642

    Article  PubMed  CAS  Google Scholar 

  • Bugianesi E, McCullough A, Marchesini G (2005b) Insulin resistance. Hepatology 42:987–1000

    Article  PubMed  CAS  Google Scholar 

  • Cave M, Deaciuc I, Mendez C, Song Z, Joshi-Barve S, Barve S, McClain C (2007) Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition. J Nutr Biochem 18:184–195

    Article  PubMed  CAS  Google Scholar 

  • Chen H, Sullivan G, Quon MJ (2005) Assessing the predictive accuracy of QUICKI as a surrogate index for insulin sensitivity using a calibration model. Diabetes 54:1914–1925

    Article  PubMed  CAS  Google Scholar 

  • Chrysohoou C, Pitsavos C, Skoumas J, Masoura C (2006) The emerging anti-inflammatory role of HDL-cholesterol, illustrated in cardiovascular disease free population, the ATTICA Study. Int J Cardiol 122:29–33

    Article  PubMed  Google Scholar 

  • Comar K, Sterling R (2006) Review article: drug therapy for non-alcoholic fatty liver disease. Aliment Pharmacol Ther 23:207–215

    Article  PubMed  CAS  Google Scholar 

  • Davidson M (2005) Reducing residual risk for patients on statin therapy: the potential role of combination therapy. Am J Cardiol 96:3K–13K

    Article  PubMed  CAS  Google Scholar 

  • Ekstedt M, Franzén L, Mathiesen U, Holmqvist M, Bodemar G, Kechagias S (2007) Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study. J Hepatol 47:135–141

    Article  PubMed  CAS  Google Scholar 

  • Federico A, Trappoliere C, Loguercio C (2006) Treatment of patients with non-alcoholic fatty liver disease: current views and perspectives. Dig Liver Dis 38:789–801

    Article  PubMed  CAS  Google Scholar 

  • Forst T, Pfützner A, Lübben G, Weber M, Marx N, Karagiannis E et al (2007) Effect of simvastatin and/or pioglitazone on insulin resistance, insulin secretion, adiponectin, and pro-insulin levels in nondiabetic patients at cardiovascular risk—the PIOSTAT Study. Metabolism 56:491–496

    Article  PubMed  CAS  Google Scholar 

  • Fujita H, Fujishima H, Koshimura J, Hosoba M, Yoshioka T, Shimotomai T et al (2005) Effects of antidiabetic treatment with metformin and insulin on serum and adipose tissue adiponectin levels in db/db mice. Endoc J 52:427–433

    Article  CAS  Google Scholar 

  • Georgescu E, Georgescu M (2007) Therapeutic options in non-alcoholic steatohepatitis (NASH). Are all agents alike? Results of a preliminary study. J Gastrointest Liver Dis 16:39–46

    Article  Google Scholar 

  • Gómez-Domínguez E, Gisbert JP, Moreno-Monteagudo JA, García-Buey L, Moreno-Otero R (2006) A pilot study of atorvastatin treatment in dyslipemic, non-alcoholic fatty liver patients. Aliment Pharmacol Ther 23:1643–1647

    Article  PubMed  Google Scholar 

  • Grimsrud P, Picklo M, Griffin T, Bernlohr D (2007) Carbonylation of adipose proteins in obesity and insulin resistance: identification of adipocyte fatty acid-binding protein as a cellular target of 4-hydroxynonenal. Mol Cell Proteomics 6:624–37

    Article  PubMed  CAS  Google Scholar 

  • Hanley A, Williams K, Festa A, Wagenknecht L, D’Agostino R, Haffner S (2005) Liver markers and development of the metabolic syndrome. Diabetes 54:3140–3147

    Article  PubMed  CAS  Google Scholar 

  • Hernandez T, Capell W, Wolfe P, Gerard L, Eckel R (2006) Time course of C-reactive protein reduction with simvastatin therapy in patients with type 2 diabetes mellitus. Am J Cardiol 98:1656–1659

    Article  PubMed  CAS  Google Scholar 

  • Kaneto H, Matsuoka T, Nakatani Y, Kawamori D, Miyatsuka T, Matsuhisa M, Yamasaki Y (2005) Oxidative stress, ER stress and the JNK pathway in type 2 diabetes. J Mol Med 83:429–439

    Article  PubMed  CAS  Google Scholar 

  • Lam H, Chu C, Wei M, Keng H, Lu C, Sun C et al (2006) The effects of different doses of atorvastatin on plasma endothelin-1 levels in type 2 diabetic patients with dyslipidemia. Exp Biol Med 231:1010–1015

    Article  CAS  Google Scholar 

  • Ludwig S, Dharmalingam S, Erickson-Nesmith S, Ren S, Zhu F, Ma G et al (2005) Impact of simvastatin on homeostatic and fibrinolytic regulators in type 2 diabetes mellitus. Diabetes Res Clin Pract 70:110–118

    Article  PubMed  CAS  Google Scholar 

  • Maeda K, Cao H, Kono K, Gorgun C, Furuhashi M, Uysal K et al (2005) Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell Metab 1:107–119

    Article  PubMed  CAS  Google Scholar 

  • Makowski L, Hotamisligil G (2005) The role of fatty acid binding protein in metabolic syndrome and atherosclerosis. Curr Opin Lipidol 16:543–548

    Article  PubMed  CAS  Google Scholar 

  • Maseri A (1995) In: Maseri A (ed) Ischemic heart disease. Churchill Livingstone, New York, p 713

    Google Scholar 

  • Mäuser W, Perwitz N, Meier B, Fasshauer M, Klein J (2007) Direct adipotropic actions of atorvastatin: differentiation state-dependent induction of apoptosis, modulation of endocrine function and inhibition of glucose uptake. Eur J Pharm 564:37–46

    Article  Google Scholar 

  • Meier U, Gressner A (2004) Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin and resistin. Clin Chem 50:1511–1525

    Article  PubMed  CAS  Google Scholar 

  • Neuschwander-Tetri B (2005) Nonalcoholic steatohepatitis and the metabolic syndrome. Am J Med Sci 330:326–335

    Article  PubMed  Google Scholar 

  • Nunes E, Peixoto F, Louro T, Sena CM, Santos MS, Matafome P, Moreira PI, Seiça R (2007) Soybean oil treatment impairs glucose-stimulated insulin secretion and changes fatty acid composition of normal and diabetic islets. Acta Diabetol 44:121–130

    Article  PubMed  CAS  Google Scholar 

  • Ota T, Takamura T, Kurita S, Matsuzawa N, Kita Y, Uno M et al (2007) Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis. Gastroenterology 132:282–293

    Article  PubMed  CAS  Google Scholar 

  • Paumelle R, Blanquart C, Briand O, Barbier O, Duhem C, Woerly G et al (2006) Acute anti-inflamatory properties of statins involve peroxissome proliferator-activated receptor-α via inhibition of the protein kinase C signalling pathway. Circ Res 98:361–369

    Article  PubMed  CAS  Google Scholar 

  • Pfützner A, Forst T (2006) High-sensitivity C-reactive protein as cardiovascular risk marker in patients with diabetes mellitus. Diabetes Technol Ther 8:28–36

    Article  PubMed  Google Scholar 

  • Planavila A, Juan L, Vásquez-Carrera M (2005) Atorvastatin improves peroxisome proliferator-activated receptor signaling in cardiac hypertrophy by preventing nuclear factor-kappaB activation. Biochim Biophys Acta 1687:76–83

    PubMed  CAS  Google Scholar 

  • Satoh K, Keimatsu N, Kanda M, Kasai T, Takaguri A, Sun F, Ichihara K (2005) HMG-CoA reductase inhibitors do not improve glucose intolerance in spontaneously diabetic Goto–Kakizaki rats. Biol Pharm Bull 28:2092–2095

    Article  PubMed  CAS  Google Scholar 

  • Seiça RM, Suzuki KI, Santos RM, Rosário LM (2004) Deficiência primária da secreção de insulina de ilhéus isolados de ratos Goto–Kakizaki, um modelo animal de diabetes tipo 2 não obesa. Acta Med Port 17:42–48

    PubMed  Google Scholar 

  • Sethi J, Hotamisligil G (1999) The role of TNFα in adipocyte metabolism. Sem Cell Dev Biol 10:19–29

    Article  CAS  Google Scholar 

  • Shang W, Yasuda K, Takahashi A, Hamasaki A, Takehiro M, Nabe K et al (2002) Effect of high dietary fat on insulin secretion in genetically diabetic Goto–Kakizaki rats. Pancreas 25:393–399

    Article  PubMed  Google Scholar 

  • Shetty G, Economides P, Horton E, Mantzoros C, Veves A (2004) Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes. Diabetes Care 27:2450–2457

    Article  PubMed  CAS  Google Scholar 

  • Shoelson S, Herrero L, Naaz A (2007) Obesity, inflammation, and insulin resistance. Gastroenterology 132:2169–2180

    Article  PubMed  CAS  Google Scholar 

  • Wong V, Stavar L, Szeto L, Uffelman K, Wang C, Fantus G, Lewis G (2006) Atorvastatin induces insulin sensitization in Zucker fatty rats. Atherosclerosis 184:348–355

    Article  PubMed  CAS  Google Scholar 

  • Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S et al (2003) Cloning of adiponectin receptors that mediate antidiabetic effects. Nature 423:762–769

    Article  PubMed  CAS  Google Scholar 

  • Yki-Järvinen H (2005) Fat in liver and insulin resistance. Ann Med 37:347–356

    Article  PubMed  Google Scholar 

  • Yoneda M, Iwasaki T, Fujita K, Inamori M, Nozaki Y, Maeyama S et al (2007) Hypoadiponectinemia plays a crucial role in the development of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus independent of visceral adipose tissue. Alcohol Clin Exp Res 31:15S–21S

    Article  Google Scholar 

  • Zhou H, Song X, Briggs M, Violand B, Salsgiver E, Luo Y (2005) Adiponectin represses gluconeogenesis independent of insulin in hepatocytes. Biochem Biophys Res Commun 338:793–799

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by University of Coimbra and University Hospitals of Coimbra. We tank SERVIER Portugal for financial support. We thank Prof. João Patrício and coworkers (Lurdes Silva, Carlos Silva and José Pedro Relvão) from the Animal Research Center Laboratory, University Hospitals, Coimbra for all the help in maintaining the animals. We thank Serviço de Patologia Clínica from the University Hospital of Coimbra for the technical support. We thank Mário Simões for his technical support.

Potential conflict of interests

Nothing to report.

Author information

Authors and Affiliations

  1. Institute of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    P. Matafome, E. Nunes, T. Louro, C. Amaral, J. Crisóstomo, L. Rodrigues, A. R. Moedas & R. Seiça

  2. Center of Ophthalmology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    P. Matafome

  3. Institute of Biomedical Research in Light and Image, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    P. Matafome, T. Louro, C. Amaral, J. Crisóstomo, L. Rodrigues & R. Seiça

  4. Basic Research Unit in Cardiology, Cardiology Department, Coimbra University Hospital and Medical School, Coimbra, Portugal

    P. Monteiro

  5. Serviço de Anatomia Patológica, Coimbra University Hospital, Coimbra, Portugal

    A. Cipriano

  6. Faculty of Medicine, Pole III of University of Coimbra, Subunit 1, 1st floor, Azinhaga de Santa Comba, Celas, 3000-354, Coimbra, Portugal

    P. Matafome

Authors
  1. P. Matafome
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Nunes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. Louro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Amaral
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. Crisóstomo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. R. Moedas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P. Monteiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A. Cipriano
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R. Seiça
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. Matafome.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matafome, P., Nunes, E., Louro, T. et al. A role for atorvastatin and insulin combination in protecting from liver injury in a model of type 2 diabetes with hyperlipidemia. Naunyn-Schmied Arch Pharmacol 379, 241–251 (2009). https://doi.org/10.1007/s00210-008-0363-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-008-0363-y

Keywords

Search

Navigation