1Associate Professor, Department ofClinical Biochemistry, AfzalipourSchool of Medicine & Physiology Research Center ,Kerman University of Medical Sciences,Kerman,Iran
2General Physician, Kerman Hygiene Center,KermanUniversity of Medical Sciences,Kerman,Iran
3Assistant Professor, Department of Clinical Biochemistry, AfzalipourSchool of Medicine & Physiology Research Center,KermanUniversity of Medical Sciences,Kerman,Ira
4Department of Clinical Biochemistry, AfzalipourSchool of Medicine,KermanUniversity of Medical Sciences,Kerman,Iran
Backgrounds: Insulin resistance is a pathological condition associated with metabolic syndrome. In this condition, insulin action in liver, muscles, and adipocytes decreases which leads to hyperglycemia, hyperinsulinemia, and dyslipidemia. Thiazolidinediones (Pioglitazone) have been used to enhance insulin sensitivity but due to dyslipidemia associated with insulin resistance, adult treatment panel III (ATPIII) have suggested statin therapy for ameliorating dyslipidemia in metabolic syndrome. Method: In this study, 40 rats were randomly divided into 5 groups (8 rats per group). The first group was considered as the healthy control group and fed with regular chow. In other groups, insulin resistance was induced by feeding a high-fructose diet for 6 weeks. Then, the 2nd, 3rd and 4th groups respectively received Pioglitazone, Simvastatin and Simvastatin+Pioglitazone through gavage for 2 weeks and the 5th group (control group) did not receive any drug. At the end of the treatment period, serum samples were collected in fasting condition. The levels of glucose, triglycerides, insulin, and adiponectin were measured by ELISA method, and HOMA-IR was calculated. Animals were anesthetized to remove liver for measuring PPAR.γ expression. Results: Blood glucose in Pioglitazone group (129.1±5.8 mg/dl) and Simvastatin+Pioglitazone group (137.1±9.9 mg/dl), triglyceride in Simvastatin group (123.6±16.6 mg/dl) and Simvastatin+Pioglitazone group (101.5±7.5 mg/dl), insulin in Pioglitazone group (40.27±2.75 pmol/L), Simvastatin group (70.07±10.35 pmol/L), and Simvastatin+Pioglitazone group (47.62±2.80 pmol/L) and adiponectin in Pioglitazone group (5.90±0.29 μg/ml) and Simvastatin+Pioglitazone group (5.89±0.41 μg/ml) showed significant differences with the corresponding values in the control group [blood glucose (187.5±15.9 mg/dl), triglyceride (217.6±18.5 mg/dl), adiponectin (3.86±0.14 μg/ml), insulin (137.65±34.22 pmol/L) and HOMA-IR (9.7±2.13)]. Pioglitazone significantly increased PPAR.γ expression, but Simvastatin suppressed the effect of Pioglitazone on PPAR.γ expression. Conclusion: The results show that Simvastatin has beneficial effects on insulin resistance in rats fed with high-fructose diet, but it has no synergistic or antagonistic effect with Pioglitazone.
Sathya Bhama C.V, Balaji S, Sithalakshemi A. Analysis of the degree of insulin resistance in post menopausal women by using skin temperature measurements and fasting insulin and fasting glucose levels: a case control study. J Clin Diagn Res 2012; 6 (10):1644-7.
de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett 2008; 582 (1):97-105.
Ding Y, Li S, Ma RL, Guo H, Zhang J, Zhang M, et al. Association of homeostasis model assessment of insulin resistance, adiponectin, and low-grade inflammation with the course of the metabolic syndrome. Clin Biochem 2015; 48 (7-8):503-7.
Schaalan MF. Effects of pioglitazone and/or simvastatin on circulating TNFalpha and adiponectin levels in insulin resistance. J Immunotoxicol. 2012; 9(2): 201-9.
He W, Barak Y, Hevener A, Olson P, Liao D, Le J, et al. Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. PNAS 2003; 100 (26):15712-7.
Zhang Y, Zhan RX, Chen JQ, Gao Y, Chen L, Kong Y, et al. Pharmacological activation of PPAR gamma ameliorates vascular endothelial insulin resistance via a non-canonical PPAR gamma-dependent nuclear factor-kappa B trans-repression pathway. Europ J Pharmacol 2015; 754: 41-51.
Chong T, Naples M, Federico L, Taylor D, Smith GJ, Cheung RC, et al. Effect of rosuvastatin on hepatic production of apolipoprotein B-containing lipoproteins in an animal model of insulin resistance and metabolic dyslipidemia. Atherosclerosis 2006; 185 (1):21-31.
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 (1):94-103.
Shih CC, Lin CH, Lin WL, Wu JB. Momordica charantia extract on insulin resistance and the skeletal muscle GLUT4 protein in fructose-fed rats. J Ethnopharmacol 2009; 123 (1):82-90.
Yadav H, Jain S, Yadavb M, Sinha PR, Prasad GBKS, Marotta F. Epigenomic derangement of hepatic glucose metabolism by feeding of high fructose diet and its prevention by Rosiglitazone in rats. Digestive and Liver Disease 2009; 41: 500-8.
QIN YW, YE P, HE JQ, Seng L, Wang LY, Du J. Simvastatin inhibited cardiac hypertrophy and fibrosis in apolipoprotein E-deficient mice fed a "Western-style diet" by increasing PPAR α and γ expression and reducing TC, MMP-9, and Cat S levels. Acta Pharmacol Sin 2010; 31 (10):1350-8.
DeFronzo RA, Tripathy D. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 2009; 32 Suppl 2: S157-63.
Quinn CE, Hamilton PK, Lockhart CJ, McVeigh GE. Thiazolidinediones: effects on insulin resistance and the cardiovascular system. Br J Pharmacol 2008; 153 (4):636-45.
Hanefeld M, Marx N, Pfutzner A, Baurecht W, Lubben G, Karagiannis E, et al. Anti-inflammatory effects of pioglitazone and/or simvastatin in high cardiovascular risk patients with elevated high sensitivity C-reactive protein: the PIOSTAT Study. J Am Coll Cardiol 2007; 49 (3): 290-7.
Ding YS, Guo SX, Ma RL, Li SG, Guo H, Zhang JY, et al. Association of Metabolic Syndrome with the Adiponectin to Homeostasis Model Assessment of Insulin Resistance Ratio. Mediators Inflam 2015; 607364.
Bulcão C, Ribeiro-Filho FF, Sañudo A, Roberta Ferreira SG. Effects of simvastatin and metformin on inflammation and insulin resistance in individuals with mild metabolic syndrome. Am J Cardiovasc Drugs2007; 7 (3): 219-24.
Ding PY-A, Hsu P-F, Lu T-M. Statin Therapy on Insulin Resistance and Plasma Level of Adiponectin in Non-Diabetic, Hypercholesterolemic Patients. Acta Cardiol Sin 2009; 25: 183 9.
Forst T, Pfutzner A, Lubben G, Weber M, Marx N, Karagiannis E, et al. Effect of simvastatin and/or pioglitazone on insulin resistance, insulin secretion, adiponectin, and proinsulin levels in nondiabetic patients at cardiovascular risk-the PIOSTAT Study. Metabolism 2007; 56 (4): 491- 6.
Wang L, Duan G, Lu Y, Pang S, Huang X, Jiang Q, et al. The Effect of Simvastatin on Glucose Homeostasis in Streptozotocin Induced Type 2 Diabetic Rats. Journal of Diabetes Research 2013; 1:1-5.
Paolisso G, Barbagallo M, Petrella G, Ragno E, Barbieri M, Giordano M, et al. Effects of simvastatin and atorvastatin administration on insulin resistance and respiratory quotient in aged dyslipidemic non-insulin dependent diabetic patients. Atherosclerosis 2000; 150 (1):121-7.
Lalli CA, Pauli JR, Prada PO, Cintra DE, Ropelle ER, Velloso LA, et al. Statin modulates insulin signaling and insulin resistance in liver and muscle of rats fed a high-fat diet. Metabolism 2008; 57 (1): 57-65.
Shen Y, Wu H, Wang C, Shao H, Huang H, Jing H, et al. Simvastatin attenuates cardiopulmonary bypass-induced myocardial inflammatory injury in rats by activating peroxisome proliferator-activated receptor gamma. Eur J Pharmacol 2010; 649 (1-3): 255-62.
Patterson AD, Peters JM. PPAR action in insulin resistance unraveled by metabolomics: potential clinical implications. Genome Med 2011; 3 (8): 54.
Leonhardt W, Pfutzner A, Muller J, Pietzsch J, Forst T, Karagiannis E, et al. Effects of pioglitazone and/or simvastatin on low density lipoprotein subfractions in non-diabetic patients with high cardiovascular risk: A sub-analysis from the PIOSTAT study. Atherosclerosis 2008; 201:155-62.
Kim SH, Hur HJ, Yang HJ, Kim HJ, Kim MJ, Park JH, et al. Citrus junos Tanaka Peel Extract Exerts Antidiabetic Effects via AMPK and PPAR-gamma both In Vitro and In Vivo in Mice Fed a High-Fat Diet. Evidence-based Complementary and Alternative Medicine: eCAM. 2013; 1-8.
Collino M, Aragno M, Castiglia S, Miglio G, Tomasinelli C, Boccuzzi G, et al. Pioglitazone improves lipid and insulin levels in overweight rats on a high cholesterol and fructose diet by decreasing hepatic inflammation. Br ـ Pharmacol 2010; 160 (8):1892-902.
Iwata M, Haruta T, Usui I, Takata Y, Takano A, Uno T, et al. Pioglitazone ameliorates tumor necrosis factor-alpha-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferator--activated receptor-gamma. Diabetes 2001; 50 (5):1083-92.
Hayashi AA, Webb J, Choi J, Baker C, Lino M, Trigatti B, et al. Intestinal SR-BI is upregulated in insulin-resistant states and is associated with overproduction of intestinal apoB48-containing lipoproteins. Am j physiol Gastrointest liver physiol 2011; 301(2): 326-37.