Comparison of the efficacy of sitagliptin with pioglitazone on dexamethasone-induced hepatic steatosis, dyslipidemia, and hyperglycemia in albino rats

Paul Mathai, Nagendra Nayak, Mamtha Rao, G. M. Nitasha Bhat, K. Vinodraj, N. Chandralekha, D. Rajesh, T. K. Chethan

Abstract


Background: Sitagliptin is a dipeptidyl peptidase type 4 inhibitor. This study was done to assess the insulin-sensitizing effect of sitagliptin on Wistar albino rats by means of surrogate measures.

Methods: There were four groups of six rats each. First group received dexamethasone alone in a dose of 8 mg/kg intraperitoneally for 6 days to induce metabolic changes and considered as dexamethasone control. Second group received sitagliptin 100 mg/kg orally 6 days before dexamethasone and 6 days during dexamethasone administration. Third group received pioglitazone 45 mg/kg orally 6 days before dexamethasone and 6 days during dexamethasone administration. Fourth group did not receive any medication and was considered as normal control. Fasting blood sugar, lipid profile, blood sugar 2 hrs after glucose load (postprandial blood sugar), liver weight, liver volume, and histopathological analysis were done.

Results: The effects of sitagliptin were compared with that of pioglitazone. Dexamethasone caused hepatomegaly, dyslipidemia, and hyperglycemia. Both pioglitazone and sitagliptin significantly reduced hepatomegaly, dyslipidemia, and hyperglycemia (p<0.01). Reduction of blood sugar levels after glucose load was significant with pioglitazone in comparison to sitagliptin (p<0.01).

Conclusions: Sitagliptin has comparable efficacy to pioglitazone in dexamethasone-induced hepatomegaly, dyslipidemia, and fasting hyperglycemia.


Keywords


Sitagliptin, Pioglitazone, Dexamethasone, Hepatomegaly, Dyslipidemia, Hyperglycemia

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References


Bagley A, Malabu UH. Diabetes epidemic in the Asia Pacific region: has hemoglobin A1C finally earned its place as a diagnostic tool? Asian Pac J Trop Biomed. 2014;4(2):85-9.

Ginter E, Simko V. Type 2 diabetes mellitus, pandemic in 21st century. Adv Exp Med Biol. 2012;771:42-50.

Buckingham JC. Glucocorticoids: Exemplars of multi-tasking. Br J Pharmacol. 2006;147 Suppl 1:S258-68.

Chapman K, Holmes M, Seckl J. 11ß-hydroxysteroid dehydrogenases: Intracellular gate-keepers of tissue glucocorticoid action. Physiol Rev. 2013;93(3):1139-206.

Nyirenda MJ, Carter R, Tang JI, de Vries A, Schlumbohm C, Hillier SG, et al. Prenatal programming of metabolic syndrome in the common marmoset is associated with increased expression of 11beta-hydroxysteroid dehydrogenase type 1. Diabetes. 2009;58(12):2873-9.

Terzolo M, Reimondo G, Bovio S, Angeli A. Subclinical Cushing’s syndrome. Pituitary. 2004;7(4):217-23.

Hwang JL, Weiss RE. Steroid-induced diabetes: A clinical and molecular approach to understanding and treatment. Diabetes Metab Res Rev. 2014;30(2):96-102.

Giby VG, Ajith TA. Role of adipokines and peroxisome proliferator-activated receptors in nonalcoholic fatty liver disease. World J Hepatol. 2014;6(8):570-9.

Dekker MJ, Su Q, Baker C, Rutledge AC, Adeli K. Fructose: A highly lipogenic nutrient implicated in insulin resistance, hepatic steatosis, and the metabolic syndrome. Am J Physiol Endocrinol Metab. 2010;299(5):E685-94.

Xu J, Kulkarni SR, Donepudi AC, More VR, Slitt AL. Enhanced Nrf2 activity worsens insulin resistance, impairs lipid accumulation in adipose tissue, and increases hepatic steatosis in leptin-deficient mice. Diabetes. 2012;61(12):3208-18.

Ahmed A, Rabbitt E, Brady T, Brown C, Guest P, Bujalska IJ, et al. A switch in hepatic cortisol metabolism across the spectrum of non alcoholic fatty liver disease. PLoS One. 2012;7(2):e29531.

Patel R, Patel M, Tsai R, Lin V, Bookout AL, Zhang Y, et al. LXRß is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice. J Clin Invest. 2011;121(1):431-41.

Macfarlane DP, Forbes S, Walker BR. Glucocorticoids and fatty acid metabolism in humans: Fuelling fat redistribution in the metabolic syndrome. J Endocrinol. 2008;197(2):189-204.

Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, Diehl AM. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med. 2000;6(9):998-1003.

Kita Y, Takamura T, Misu H, Ota T, Kurita S, Takeshita Y, et al. Metformin prevents and reverses inflammation in a non-diabetic mouse model of nonalcoholic steatohepatitis. PLoS One. 2012;7(9):e43056.

Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet. 2001;358(9285):893-4.

Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005;100(5):1082-90.

Haukeland JW, Konopski Z, Eggesbø HB, von Volkmann HL, Raschpichler G, Bjøro K, et al. Metformin in patients with non-alcoholic fatty liver disease: A randomized, controlled trial. Scand J Gastroenterol. 2009;44(7):853-60.

Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis of randomised trials. Diabetologia. 2012;55(4):885-904.

Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6):2005-23.

Ding X, Saxena NK, Lin S, Gupta NA, Anania FA. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology. 2006;43(1):173-81.

Armstrong MJ, Houlihan DD, Rowe IA, Clausen WH, Elbrønd B, Gough SC, et al. Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: Individual patient data meta-analysis of the LEAD program. Aliment Pharmacol Ther. 2013;37(2):234-42.

Akaslan SB, Degertekin CK, Yilmaz G, Cakir N, Arslan M, Toruner FB. Effects of sitagliptin on nonalcoholic fatty liver disease in diet-induced obese rats. Metab Syndr Relat Disord. 2013;11(4):243-50.

Shirakawa J, Fujii H, Ohnuma K, Sato K, Ito Y, Kaji M, et al. Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice. Diabetes. 2011;60(4):1246-57.

Arab JP, Candia R, Zapata R, Muñoz C, Arancibia JP, Poniachik J, et al. Management of nonalcoholic fatty liver disease: An evidence-based clinical practice review. World J Gastroenterol. 2014;20(34):12182-201.

Hanefeld M, Pfützner A, Forst T, Kleine I, Fuchs W. Double-blind, randomized, multicentre, and active comparator controlled investigation of the effect of pioglitazone, metformin, and the combination of both on cardiovascular risk in patients with type 2 diabetes receiving stable basal insulin therapy: The PIOCOMB study. Cardiovasc Diabetol. 2011;10:65.

Miyazaki Y, Matsuda M, DeFronzo RA. Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes. Diabetes Care. 2002;25(3):517-23.

Ahlkvist L, Brown K, Ahrén B. Upregulated insulin secretion in insulin-resistant mice: evidence of increased islet GLP1 receptor levels and GPR119-activated GLP1 secretion. Endocr Connect. 2013;2(2):69-78.