Therapeutic Effect of Sitagliptin and Berberine Interaction on Fatty Liver and Hepatic GLUT4 Gene Expression in Diabetic Male Rats

Subject Areas : Journal of Animal Biology

Soraya Mehrdoost ¹ , Parichehreh Yaghmaei ² , Hanieh Jafari ³ , Azadeh Ebrahim-Habibi ⁴

1 - Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
2 - Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
3 - Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
4 - Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences

Received: 2023-04-15 Accepted : 2023-06-18 Published : 2024-06-01

Keywords: Sitagliptin, DDP-4, GLUT4Glucose transporter type 4, Berberine, Non-alcoholic fatty liver, disease,

Abstract :

Fatty liver disease causes accumulation of excess fat in liver cells. Berberine has antioxidant and anti-inflammatory activities, and Sitagliptin is a DPP-4 inhibitor that increases the function of incretin hormones. In this study biological activities of Berberine and Sitagliptin for the treatment of fatty liver in diabetic Sprague-Dawley rats were investigated. The therapeutic effects of Sitagliptin and Berberine on fatty liver in diabetic rats by Alloxan injection with a single dose of 100 mg/kg were done with the following groups. Groups include 1: control (physiology serum as Alloxan solvent); 2: model (fatty liver + Alloxan); 3: Sitagliptin (fatty liver + Alloxan and Sitagliptin 10 mg/kg); 4: Berberine (fatty liver + Alloxan and Berberine 150mg/kg); 5: Berberine/Sitagliptin (fatty liver + Alloxan and Sitagliptin 5 mg/kg and Berberine 75 mg/kg). After the treatment, the liver tissue separated and weighed. Levels of Liver triglyceride, cholesterol and GLUT4 gene expression in liver tissue measured by real-time PCR method. The level of GLUT4 gene expression levels increased in the treatment groups compared to the model group, but a significant difference was seen only in the co-administration group with the model group (p < 0.05). There was a significant decrease in the amount of liver cholesterol in the treatment groups compared to the model group (p < 0.01). Hepatic triglyceride decreased in the treatment groups, but only in the co-administration group, a significant difference was seen with the model group (p < 0.05). Berberine and Sitagliptin, especially when prescribed together with the increased expression of GLUT4 and the reduction of liver cholesterol and triglycerides, have a favorable effect on lipid metabolism and can be considered as an effective treatment for hyperlipidemia and fatty liver.

 

References:

1. Abud M.A., Nardello A.L., Torti J.F. 2017. Hypoglycemic effect due to insulin stimulation with Plantago major in wistar rats. Medicinal and Aromatic Plants, 6(3): 292-303.
2. Akaslan S.B., Degertekin C.K., Yilmaz G., Cakir N., Arslan M., Toruner F.B. 2013. Effects of Sitagliptin on nonalcoholic fatty liver disease in diet-induced obese rats. Metabolic Syndrome and Related Disorders, 11(4):243-250
3. Balakrishnan B.B, Banu B., Krishnasamy K., Choi C. 2018. 'Moringa concanensis Nimmo ameliorates hyperglycemia in 3T3-L1 adipocytes by upregulating PPAR-γ, C/EBP-α via Akt signaling pathway and STZ-induced diabetic rats. Biomedicine and Pharmacotherapy, 103:719-728.
4. Bogan J.S., Hendon N., McKee A.E., Tsao T.S., Lodish H.F. 2003. Functional cloning of TUG as a regulator of GLUT4 glucose transporter trafficking, Nature, 425:727-33.
5. Bugianesi E., McCullough A.J., Marchesini G. 2005. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology, 42:987-1000.
6. Bugianesi E ,.Moscatiello S., Ciaravella M.F., Marchesini G. 2010. 'Insulin resistance in nonalcoholic fatty liver disease. Current Pharmaceutical Design, 16:1941-1951.
7. Burri L., Thoresen G.H., Berge R. K. 2010. The role of PPARα activation in liver and muscle. PPAR Research, 2010:542351-11.
8. Byrne C.D., Targher G. 2015. NAFLD: a multisystem disease. Journal of Hepatology, 62:S47-S64.
9. Chen L.N., Lyu J., Yang X.F., Ji W.J., Yuan B.X., Chen M.X., Ma X., Wang B. 2013. Liraglutide ameliorates glycometabolism and insulin resistance through the upregulation of GLUT4 in diabetic KKAy mice. International Journal of Molecular Medicine, 32:892-900.
10. Day E.A., Ford R. J., Steinberg G.R. 2017. AMPK as a Therapeutic Target for treating metabolic diseases. Trends in Endocrinology and Metabolism, 28:545-60.
11. DeAngelis R.A., Markiewski M.M., Taub R., Lambris J. D. 2005. A high-fat diet impairs liver regeneration in C57BL/6 mice through overexpression of the NF-kappaB inhibitor, IkappaBalpha. Hepatology, 42:1148-1157.
12. Deng Y., Tang K., Chen R., Nie H., Liang S. J., Zhang Y., Yang Q. 2019. Berberine attenuates hepatic oxidative stress in rats with non-alcoholic fatty liver disease via the Nrf2/ARE signalling pathway, Experimental and Therapeutic Medicine , 17:2091-2098.
13. Ding X., Saxena N.K., Lin S., Gupta N.A., Anania F.A. 2006. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology, 43:173-181.
14. Fon T.K., Rozman D. 2011. Nonalcoholic fatty liver disease: focus on lipoprotein and lipid deregulation. Journal of Lipids, 2011:783976.
15. Jiao Y., Wang X., Jiang X., Kong F., Wang S., Yan C. 2017. Antidiabetic effects of morus alba fruit polysaccharides on high-fat diet- and streptozotocin-induced type 2 diabetes in rats. Journal of Ethnopharmacology, 199:119-127.
16. Kong W.J., Zhang H., Song D.Q., Xue R., Zhao W., Wei J., Wang Y.M., Shan N., Zhou Z.X., Yang P., You X.F., Li Z.R., Si S.Y., Zhao L.X., Pan H.N., Jiang J.D. 2009. Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression. Metabolism, 58(1):109-119.
17. McCullough A.J. 2006. Pathophysiology of nonalcoholic steatohepatitis. Journal of Clinical Gastroenterology, 40(1):S17-29.
18. Mu J., Woods J., Zhou Y.P., Roy R.S., Li Z., Zycband E., Feng Y., Zhu L., Li C., Howard A.D., Moller D.E., Thornberry N.A., Zhang B.B. 2006. Chronic inhibition of dipeptidyl peptidase-4 with a Sitagliptin analog preserves pancreatic β-cell mass and function in a rodent model of type 2 diabetes. Diabetes, 55(6):1695-1704.
19. Pang B., Zhao L.H., Zhou Q., Zhao T..., Wang H., Gu C.J., Tong X.L. 2015. Application of Berberine on treating type 2 diabetes mellitus. International Journal of Endocrinology, 2015:905749.
20. Perry R.J., Rachel J., Varman T. S., Petersen K.F., Gerald I.S. 2014. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes, Nature, 510: 84-91.
21. Pettinelli, P., Obregón A.M., Videla L. A. 2011. Molecular mechanisms of steatosis in nonalcoholic fatty liver disease. Nutricion Hospitalaria, 26:441-450.
22. Shen T., Xu B., Lei T., Chen L., Zhang C., Ni Z. 2018. Sitagliptin reduces insulin resistance and improves rat liver steatosis via the SIRT1/AMPKα pathway. Experimental and Therapeutic Medicine, 16(4):3121-3128
23. Suji G., Sivakami S. 2003. Approaches to the treatement of diabetes mellitus. Cellular and Molecular Biology, 49:635-639.
24. Takaki A., Daisuke K., Kazuhide Y. 2014. Molecular mechanisms and new treatment strategies for non-alcoholic steatohepatitis (NASH). International Journal of Molecular Sciences, 15:7352-7379.
25. Taniguchi C.M., Emanuelli B., Kahn C.R.. 2006. Critical nodes in signalling pathways: insights into insulin action, Nature Reviews Molecular Cell Biology, 7(2):85-96.
26. Wang Y., Yi X., Ghanam K., Zhang S., Zhao T., Zhu X. 2014. Berberine decreases cholesterol levels in rats through multiple mechanisms, including inhibition of cholesterol absorption. Metabolism, 63:1167-77.
27. Xu B., Shen T., Chen L., Xia J., Zhang C., Wang H., Yu M., Lei T. 2017. The Effect of Sitagliptin on Lipid Metabolism of Fatty Liver Mice and Related Mechanisms. Medical science Monitor :International Medical Journal of Experimental and Clinical Research, 23:1363-1370.
28. Xu G., Huang K., Zhou J. 2018. Hepatic AMP Kinase as a Potential Target for Treating Nonalcoholic Fatty Liver Disease.: Evidence from Studies of Natural Products. Current Medicinal Chemistry, 25:889-907.
29. Yu H., Li C., Yang J., Zhang T., Zhou Q. 2016. Berberine is a potent agonist of peroxisome proliferator activated receptor alpha. Frontiers in Bioscience-Landmark, 21:1052-1060.
30. Zhang Q., Lu L.G. 2015. Nonalcoholic Fatty Liver Disease: Dyslipidemia, Risk for Cardiovascular Complications, and Treatment Strategy. Journal of Clinical and Translational Hepatology, 3:78-84.
31. Zou Y., Li J., Lu C., Wang J., Ge J., Huang Y., Zhang L., Wang Y. 2006. High-fat emulsion-induced rat model of nonalcoholic steatohepatitis. Life Science, 79(11):1100-1107.