The effect of betulinic acid on leptin, adiponectin, hepatic enzyme levels and lipid profiles in streptozotocin–nicotinamide-induced diabetic mice

Akram Ahangarpour, Razieh Shabani, Yaghoob Farbood


Diabetes mellitus is developed by lack of insulin secretion or reduction of tissues sensitivity to insulin, which lead to serious complications. The aim of this study is to evaluate antihyperlipidemic effect of betulinic acid (BA) on streptozotocin-nicotinamide (STZ-NA) induced diabetic mice. In this experimental study, seventy adult male NMRI mice (20-25 g) were divided randomly into seven groups (n = 10) of control, sham, diabetes, diabetes + BA (10, 20 and 40 mg/kg), and diabetes + metformin (200 mg/kg). Diabetes was induced by intraperitoneal (i.p.) injection of a single dose of STZ (50 mg/kg) 15 min after an i.p. administration of nicotinamide (NA) (120 mg/kg). BA and metformin were orally administered and after two weeks blood samples were taken. Blood levels of leptin, adiponectin, lipid profile and liver enzyme were then measured. One day after the last drug administration, liver was removed to evaluate the histological changes. A significant increase (P < 0.05) in the plasma levels of leptin, alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), alkaline phosphatase (ALP), low density lipoprotein cholesterol (LDL-C), cholesterol, and a significant decrease in adiponectin and high density lipoprotein cholesterol (HDL-C) were observed in diabetic mice. The groups treated with BA indicated a significant decrease in leptin, AST, ALT, ALP, TG, cholesterol, LDL-C and an increases in adiponectin and HDL levels, while VLDL did not show significant changes. BA was found to have positive effects on liver injury. BA has an effective role on liver damage induced by diabetes through amelioration of leptin, adiponectin, liver enzyme levels and lipid profile. Since BA has a positive effect on lipid profile, adiponectin and leptin, it may improve metabolic syndrome.


Diabetes; Betulinic Acid; Streptozotocin; Nicotinamide; Liver

Full Text:



Mousavi SE, Shahriari A, Ahangarpour A, Vatanpour H, Jolodar A. Effects of Teucrium polium ethyl acetate extract on serum, liver and muscle triglyceride content of sucrose-induced insulin resistance in rat. Iran J Pharm Res. 2012;11: 347-355.

Beckert S, Witte M, Wicke C, Königsrainer A, Coerper S. A new wound-based severity score for diabetic foot ulcers a prospective analysis of 1,000 patients. Diabetes Care. 2006;29:988-992.

Chung HH, Moon JS, Yoon JS, Lee HW, Won KC. The relationship between metformin and cancer in patients with type 2 diabetes. Diabetes Metab J. 2013;37:125-131.

Salemi Z, Rafie E, Goodarzi MT, ali Ghaffari M. Effect of metformin, acarbose and their combination on the serum visfatin level in nicotinamide/streptozocin-induced type 2 diabetic rats. Iran Red Crescent Med J. 2016;18:1-12.

Schulze MB, Rimm EB, Shai I, Rifai N, Hu FB. Relationship between adiponectin and glycemic control, blood lipids, and inflammatory markers in men with type 2 diabetes. Diabetes Care. 2004;27:1680–1687.

Cnop M, Havel PJ, Utzschneider KM, Carr DB, Sinha MK, Boyko EJ, et al. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia. 2003;46:459–469.

Xu R, Fazio GC, Matsuda SP. On the origins of triterpenoid skeletal diversity. Phytochemistry. 2004;65:261-291.

Singab ANB, El-Beshbishy HA, Yonekawa M, Nomura T, Fukai T. Hypoglycemic effect of Egyptian Morus alba root bark extract: effect on diabetes and lipid peroxidation of streptozotocin-induced diabetic rats. J Ethnopharmacol. 2005;100:333-338.

Pierre W, Gildas AJH, Ulrich MC, Modeste W-N, azTélesphore Benoît N, Albert K. Hypoglycemic and hypolipidemic effects of Bersama engleriana leaves in nicotinamide/streptozotocin-induced type 2 diabetic rats. BMC Complement Altern Med. 2012;12:264.

Yogeeswari P, Sriram D. Betulinic acid and its derivatives: a review on their biological properties. Curr Med Chem. 2005;12:657–666

Ahangarpour A, Oroojan AA, Khorsandi L, Shabani R, Mojaddami S. Preventive effects of betulinic acid on streptozotocin-nicotinamide induced diabetic nephropathy in male mouse. J Nephropathol. 2016;5(4):128-133.

Lee J, Yee S-T, Kim J-J, Choi M-S, Kwon E-Y, Seo K-I, et al. Ursolic acid ameliorates thymic atrophy and hyperglycemia in streptozotocin–nicotinamide-induced diabetic mice. Chem Biol Interact. 2010;188:635-642.

Brusotti G, Montanari R, Capelli D, Cattaneo G, Laghezza A, Tortorella P, Loiodice F, Peiretti F, Bonardo B, Paiardini A, Calleri E. Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis. Scientific Reports. 2017;7:5777.

Ahangarpour A, Akbari FRA, Moghadam HF. Effect of c-peptide alone or in combination with nicotinamide on glucose and insulin levels in streptozotocin-nicotinamide-induced type 2 diabetic mice. Malays J Med. 2014;21:12-17.

Ahangarpour A, Teymuri Zamaneh H, Jabari A, Malekshahi Nia H, Heidari H. Antidiabetic and hypolipidemic effects of Dorema aucheri hydroalcoholic leave extract in streptozotocin-nicotinamide induced type 2 diabetes in male rats. Iran J Basic Med Sci. 2014;17(10):808-814.

Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 2006;116:1784-1792.

Ananda PK, Kumarappan C, Christudas S, Kalaichelvan V. Effect of Biophytum sensitivum on streptozotocin and nicotinamide-induced diabetic rats. Asian Pac J Trop Biomed. 2012;2:31-35.

Saravanan R, Pari L. Effect of a novel insulinotropic agent, succinic acid monoethyl ester, on lipids and lipoproteins levels in rats with streptozotocin-nicotinamide-induced type 2 diabetes. J Bio sci. 2006;31:581-587.

Ahmadi SA, Boroumand MA, Gohari-Moghaddam K, Tajik P, Dibaj SM. The impact of low serum triglyceride on LDL-cholesterol estimation. Arch Iran Med. 2008;11:318-321.

Rafieian-kopaei M, Shahinfard N, Rouhi-Boroujeni H, Gharipour M, Darvishzadeh-Boroujeni P. Effects of Ferulago angulata extract on serum lipids and lipid peroxidation. Evid Based Complement Alternat Med. 2014;2014:680856.

Orazizadeh M, Fakhredini F, Mansouri E, Khorsandi L. Effect of glycyrrhizic acid on titanium dioxide nanoparticles-induced hepatotoxicity in rats. Chem Biol Interact. 2014;220:214-221.

Ahangarpour A, Oroojan AA, Heidari H, Ehsan G, Nooshabadi R, Reza M. Effects of hydro-alcoholic extract of Rhus coriaria (Sumac) seeds on reproductive complications of nicotinamide-streptozotocin induced type-2 diabetes in male mice. World J Mens Health. 2014;32(3):151-158.

Singh SK, Kesari AN, Gupta RK, Jaiswal D, Watal G. Assessment of antidiabetic potential of Cynodon dactylon extract in streptozotocin diabetic rats. J Ethnopharmacol. 2007;114(2):174-179.

Jung DY, Park JB, Joo SY, Joh JW, Kwon CH, Kwon GY, et al. Effect of nicotinamide on early graft failure following intraportal islet transplantation. Exp Mol Med. 2009:30;41:782-792.

Alenzi FQ. Effect of nicotinamide on experimental induced diabetes. Iran J Allergy Asthma Immunol. 2009;8:11-18.

26. Castro AJG, Frederico MJS, Cazarolli LH, Bretanha LC, de Carvalho Tavares L, da Silva Buss Z, et al. Betulinic acid and 1, 25 (OH) 2 vitamin D 3 share intracellular signal transduction in glucose homeostasis in soleus muscle. Int J Biochem Cell Biol. 2014;48:18-27.

Ko BS, Kang S, Moon BR, Ryuk JA, Park S. A 70% ethanol extract of mistletoe rich in betulin, betulinic acid, and oleanolic acid potentiated β-cell function and mass and enhanced hepatic insulin sensitivity. Evid Based Complement Alternat Med. 2016;2016:7836823.

Yi J, Xia W, Wu J, Yuan L, Wu J, Tu D, et al. Betulinic acid prevents alcohol-induced liver damage by improving the antioxidant system in mice. J Vet Sci. 2014;15:141-148.

de Melo CL, Queiroz MG, Arruda Filho AC, Rodrigues AM, de Sousa DF, Almeida JG, et al. Betulinic acid, a natural pentacyclic triterpenoid, prevents abdominal fat accumulation in mice fed a high-fat diet. J Agr Gr Food Chem. 2009;57:8776-8781.

Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000;49:2063-2069.

Zilaei Bouri S, Peeri M, Azarbayjani MA, Ahangarpour A. The effect of physical activity on adiponectin and osteocalcin in overweight young females. Int Med J. 2015;22:43-46.


  • There are currently no refbacks.

Creative Commons Attribution-NonCommercial 3.0

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.