بررسی اثرات تعاملی بربرین و سیتاگلیپتین بر پروفایل لیپیدی، میزان گلوکز و انسولین در موش‌های نر دیابتی مبتلا به کبد چرب

محورهای موضوعی : فصلنامه زیست شناسی جانوری

ثریا مهردوست ¹ , پریچهره یغمایی ² , هانیه جعفری ³ , آزاده ابراهیم حبیبی ⁴

1 - گروه زیست شناسی، واحد علوم و تحقیقات، دانشگاه آزاد اسلامی، تهران، ایران
2 - گروه زیست شناسی، واحد علوم و تحقیقات، دانشگاه آزاد اسلامی، تهران، ایران
3 - گروه زیست شناسی، واحد علوم و تحقیقات، دانشگاه آزاد اسلامی، تهران، ایران
4 - پژوهشکده علوم بالینی غدد و متابولیسم، مرکز تحقیقات غدد و متابولیسم، دانشگاه علوم پزشکی تهران، ایران

تاریخ دریافت : 1402/02/09 تاریخ پذیرش : 1402/03/20 تاریخ انتشار : 1402/12/01

کلید واژه: کبد چرب, دیابت نوع 2, مقاومت به انسولین, بربرین, سیتاگلیپتین,

چکیده مقاله :

مقاومت انسولینی کبدی به شدت با NAFLD ارتباط داشته و فاکتور اصلی در بیماریزایی دیابت نوع 2 و سندرم متابولیک است. مقاومت به انسولین سبب لیپولیز در بافت چربی شده و اختلال در تنظیم متابولیسم لیپیدی سبب انباشته شدن چربی در کبد می‌شود. در این مطالعه اثرات بربرین و سیتاگلیپتین برای بهبود مقاومت به انسولین و پروفایل لیپیدی در موش‌های اسپراگ-داولی مبتلا به دیابت نوع 2 بررسی شده است. گروه‌ها شامل: 1- کنترل (سرم فیزیولوژی به عنوان حلال آلوکسان)؛ 2- مدل (کبد چرب + آلوکسان)؛ 3- سیتاگلیپتین (کبد چرب + آلوکسان و 10 میلی گرم/کیلوگرم سیتاگلیپتین)؛ 4- بربرین (کبدچرب + آلوکسان و 150 میلی گرم/کیلوگرم بربرین)؛ 5- بربرین/سیتاگلیپتین (کبد چرب + آلوکسان و 5 میلی گرم/کیلوگرم سیتاگلیپتین و 75 میلی گرم/کیلوگرم بربرین). پس از اتمام دوره تیمار در شرایط بیهوشی خونگیری از قلب انجام گرفت و میزان پروفایل لیپیدی، گلوکز، انسولین سنجش شد. میزان تری‌گلیسرید (01/0 p <)، کلسترول (05/0 p <)، LDL(01/0 p <)، اسید چرب آزاد (05/0 p <)، گلوکز ناشتا (05/0 p <) و انسولین (01/0 p <) در گروه تیمار توام نسبت به گروه مدل کاهش و HDL افزایش یافت که این افزایش معنی‌دار نبود. بربرین و سیتاگلیپتین بویژه در تجویز توام اثر مطلوبی در متابولیسم لیپیدها و مقاومت به انسولین دارند و می‌توانند به عنوان یک رژیم درمانی مؤثر برای هایپرلیپیدمی و کبد چرب در نظر گرفته شوند.

چکیده انگلیسی:

Hepatic insulin resistance is associated with NAFLD and it is a major factor in the pathogenesis of type 2 diabetes and metabolic syndrome. Insulin resistance causes lipolysis in adipose tissue and disturbance in the regulation of lipid metabolism causes fat accumulation in the liver. In this study, the biological activities of Berberine and Sitagliptin to improve insulin resistance and lipid profile in Sprague-Dawley rats with type 2 diabetes was investigated. groups include 1: control (physiological serum as an 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). At the end of the treatment period, under anesthesia, Blood sampling done from the heart and lipid profile, glucose and insulin measured. The amount of triglyceride (p < 0.01), cholesterol (p < 0.05), LDL (p < 0.01), FFA (p < 0.05), fasting glucose (p < 0.05) and insulin (p < 0.01) in the coadministration group decreased compared to the model group and HDL increased, which was not significant. Berberine and Sitagliptin, especially when administered together, have a favorable effect on lipid metabolism and insulin resistance and can be considered as an effective treatment regimen for hyperlipidemia and fatty liver.  

منابع و مأخذ:

1. Abidi P., Zhou Y., Jiang J.D., Liu J. 2005. Extracellular signal-regulated kinase-dependent stabilization of hepatic low-density lipoprotein receptor mRNA by herbal medicine berberine. Arteriosclerosis, Thrombosis, and Vascular Biology, 25(10):2170-2176.


2. 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).


3. 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.


4. Alam S., Mustafa G., Alam M., Ahmad N. 2016. Insulin resistance in development and progression of nonalcoholic fatty liver disease. World Journal of Gastrointestinal Pathophysiology, 7(2):211-217.


5. Bai M., Y. Liu, F. Zhou, Y. Zhang, Q. Zhu, L. Zhang, Q. Zhang, S. Wang, K. Zhu, X. Wang and L. Zhou 2018. Berberine inhibits glucose oxidation and insulin secretion in rat islets. Endocrinology Journal, 65(4):469-477.


6. Cameron J., Ranheim T., Kulseth M.A., Leren T.P., Berge K.E. 2008. Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis, 201(2):266-273.


7. Chen L., Teng H., Cao H. 2019. Chlorogenic acid and caffeic acid from Sonchus oleraceus Linn synergistically attenuate insulin resistance and modulate glucose uptake in HepG2 cells. Food Chemistry and Toxicology, 127:182-187.


8. Fan M., Li Y., Zhang S. 2016. Effects of sitagliptin on lipid profiles in patients with type 2 diabetes mellitus: A meta-analysis of randomized clinical trials. Medicine, 95(2):e2386-e2386.


9. Gomez-Peralta F., Abreu C., Gomez-Rodriguez S., Barranco R.J., Umpierrez G.E. 2018. Safety and Efficacy of DPP4 Inhibitor and Basal Insulin in Type 2 Diabetes: An Updated Review and Challenging Clinical Scenarios. Diabetes Therapy, 9(5):1775-1789.


10. Goossens G.H. 2008. The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav , 94(2): 206-218.


11. Hsieh J., Longuet C., Baker C.L., Qin B., Federico L.M., Drucker D.J., K. Adeli 2010. The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice. Diabetologia, 53(3):552-561.


12. Hussain M., Atif M.A., Ghafoor M.B. 2016. Beneficial effects of sitagliptin and metformin in non-diabetic hypertensive and dyslipidemic patients. Pakistan Journal of Pharmaceutical Sciences, 29(6):2385-2389.


13. Ju J., J. Li, Q. Lin and H. Xu 2018. Efficacy and safety of berberine for dyslipidaemias: A systematic review and meta-analysis of randomized clinical trials. Phytomedicine, 50:25-34.


14. Kong W., Wei J., Abidi P., Lin M., Inaba S., Li C., Wang Y., Wang Z., Si S., Pan H., Wang S., Wu J., Wang Y., Li Z., Liu J., Jiang J.D. 2004. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nature Medicine, 10(12):1344-1351.


15. 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.


16. Kutoh E., Wada A., Hayashi J. 2018. Regulation of free fatty acid by sitagliptin monotherapy in drug-naive subjects with type 2 diabetes. Endocrine Practice, 24(12):1063-1072.


17. Lewis G.F., A. Carpentier, K. Adeli and A. Giacca 2002. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocrine Reviews, 23(2):201-229.


18. Li S., Chen H., Wang J., Wang X., Hu B., Lv F. 2015. Involvement of the PI3K/Akt signal pathway in the hypoglycemic effects of tea polysaccharides on diabetic mice. International Journal of Biological Macromolecules, 81:967-974.


19. Lin C.H., Lin C.C. 2016. Sitagliptin attenuates inflammatory responses in lipopolysaccharide-stimulated cardiomyocytes via nuclear factor-κB pathway inhibition. Experimental and Therapeutic Medicine, 11(6):2609-2615.


20. Liu D., Zhang Y., Liu Y., Hou L., Li S., Tian H., Zhao T. 2018. Berberine modulates gut microbiota and reduces insulin resistance via the TLR4 signaling pathway. Experimental and Clinical Endocrinology and Diabetes, 126(8):513-520.


21. Maiztegui B., Borelli M.I., Madrid V.G., Del Zotto H., Raschia M.A., Francini F., Massa M.L., Flores L.E., Rebolledo O.R., Gagliardino J.J. 2011. Sitagliptin prevents the development of metabolic and hormonal disturbances, increased β-cell apoptosis and liver steatosis induced by a fructose-rich diet in normal rats. Clinical Sciences, 120(2):73-80.


22. McCullough A.J. 2006. Pathophysiology of nonalcoholic steatohepatitis. Journal of Clinical Gastroenterology, 40(1):S17-29.


23. 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.


24. Rhodes C.J. 2005. Type 2 diabetes-a matter of beta-cell life and death? Science, 307(5708): 380-384.


25. Sanyal A.J. 2005. Mechanisms of Disease: pathogenesis of nonalcoholic fatty liver disease. Nat Clin Pract Gastroenterol Hepatol, 2(1):46-53.


26. 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.


27. Shirakawa J., Fujii H., Ohnuma K., Sato K., Ito Y., Kaji M., Sakamoto E., Koganei M., Sasaki H., Nagashima Y., Amo K., Aoki K., Morimoto C., Takeda E., Terauchi Y. 2011. Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice. Diabetes, 60(4):1246-1257.


28. 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.


29. Van Bloemendaal L., Ten Kulve J.S., la Fleur S.E., Ijzerman R.G., Diamant M. 2014. Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS. Journal of Endocrinology, 221(1):T1-16.


30. Vuddanda P.R., Chakraborty S., Singh S. 2010. Berberine: a potential phytochemical with multispectrum therapeutic activities. Expert Opinion on Investigational Drugs, 19(10):1297-1307.


31. Wang Y., Yan A., Li S., Liu B., Li H., Yan Y. 2019. Efficacy and safety of berberine in the treatment of type 2 diabetes with insulin resistance: Protocol for a systematic review. Medicine, 98(35): e16947-e16947.


32. Wu Q.M., Ni H.X., Lu X. 2016. Changes of adipocytokine expression after diabetic rats received sitagliptin and the molecular mechanism. Asian Pacific Journal of Tropical Medicine, 9(9):893-897.


33. 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.


34. 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(8):889-907.


35. Zhang H., Wei J., Xue R., Wu J.D., Zhao W., Wang Z.Z., Wang S.K., Zhou Z.X., Song D.Q., Wang Y.M., Pan H.N., Kong W.J., Jiang J.D. 2010. Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism, 59(2):285-292.


36. Zhang N., Liu X., Zhuang L., Liu X., Zhao H., Shan Y., Liu Z., Li F., Wang Y., Fang J. 2020. Berberine decreases insulin resistance in a PCOS rats by improving GLUT4: Dual regulation of the PI3K/AKT and MAPK pathways. Regulatory Toxicology and Pharmacology, 110:104544.


37. Zhu X., Yang J., Zhu W., Yin X., Yang B., Wei Y., Guo X. 2018. Combination of berberine with resveratrol improves the lipid-lowering efficacy. International Journal of Molecular Sciences, 19(12).


38. 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.