Berberis integerrima ameliorates insulin resistance in high- fructose-fed insulin-resistant rats

Document Type : Original Article


1 Department of Biochemistry, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran

2 Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran

3 Student Research Committee, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran


Objective(s): This study was aimed to investigate the effect of Berberis integerrima (B. integerrima) extract on insulin sensitivity in high-fructose-fed insulin-resistant rats.
Materials and Methods: Experimental rats were randomly divided into two groups: the control group was fed a regular chow diet while other group fed with a high-fructose diet for 8 weeks. After the first six weeks, the animals were treated with B. integerrima extract or pioglitazone for two weeks. Insulin and adiponectin levels were measured by ELISA. Additionally, Insulin resistance was calculated using a Homeostasis Model Assessment of Insulin resistance (HOMA-IR). The plasma free fatty acid (FFA) profile was obtained by gas chromatography. PPARγ and GLUT4 gene expression were assessed by real-time polymerase chain reaction (PCR) and western-blotting.
Results: Comparing the B. integerrima treated group with the control group, weight gain (P=0.009) and levels of insulin (P=0.001), blood glucose (P<0.0001), and HOMA-IR (P<0.0001) were significantly reduced. Additionally, the adiponectin concentration was significantly increased (P<0.0001). Among the FFA fractions, the mean concentration of palmitoleic acid and stearic acid in the B. integerrima group were significantly higher than the control group (P<0.0001 and P=0.005, respectively). However, there was no significant difference at the mRNA and protein level of GLUT4 and PPAR-γ between B. integerrima treated group and control group.
Conclusion: The study findings revealed that B. integerrima might be a protective candidate against Type 2 diabetes/insulin resistance through direct insulin-like effect and an increase in adiponectin levels. However, the mechanism of B. integerrima was independent of GLUT4 and PPARγ.


1. Soares FL, de Oliveira Matoso R, Teixeira LG, Menezes Z, Pereira SS, Alves AC, et al. Gluten-free diet reduces adiposity, inflammation and insulin resistance associated with the induction of PPAR-alpha and PPAR-gamma expression. J Nutr Biochem 2013; 24:1105–1111.
2. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology 2007; 132:2169–2180.
3. Araújo TG, de Oliveira AG, Vecina JF, Marin RM, Franco ES, Abdalla Saad MJ, et al. Parkinsonia aculeata (Caesalpineaceae) improves high-fat diet-induced insulin resistance in mice through the enhancement of insulin signaling and mitochondrial biogenesis. J Ethnopharmacol 2016; 183:95–102.
4. Joo H, Kim CT, Kim IH, Kim Y. Anti-obesity effects of hot water extract and high hydrostatic pressure extract of garlic in rats fed a high-fat diet. Food Chem Toxicol 2013; 55:100–105.
5. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112:1821–1830.
6. Koo SH, Satoh H, Herzig S, Lee CH, Hedrick S, Kulkarni R, et al. PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3. Nat Med 2004; 10:530–534.
7. Kahn BB, Flier JS. On diabetes : insulin resistance Obesity and insulin resistance. J Clin Invest 2000; 106:473–481.
8. Maury E, Brichard SM. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol 2010; 314:1–16.
9. Jung UJ, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci 2014; 15:6184–6223.
10. Goossens GH. The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav 2008; 94:206–218.
11. Kalupahana NS, Moustaid-Moussa N, Claycombe KJ. Immunity as a link between obesity and insulin resistance. Mol Aspects Med 2012; 33:26–34.
12. Esfahani M, Movahedian A, Baranchi M, Goodarzi MT. Adiponectin: an adipokine with protective features against metabolic syndrome. Iran J Basic Med Sci 2015; 18:430–442.
13. Caselli C. Role of adiponectin system in insulin resistance. Mol Genet Metab 2014; 113:155–160.
14. Li L, Wu L, Wang C, Liu L, Zhao Y. Adiponectin modulates carnitine palmitoyltransferase-1 through AMPK signaling cascade in rat cardiomyocytes. Regul Pept 2007; 139:72–79.
15. Dupont J, Chabrolle C, Ramé C, Tosca L, Coyral-Castel S. Role of the peroxisome proliferator-activated receptors, adenosine monophosphate-activated kinase, and adiponectin in the ovary. PPAR Res 2008; 2008:176275.
16. Maebuchi M, Machidori M, Urade R, Ogawa T, Moriyama T. Low resistin levels in adipose tissues and serum in high-fat fed mice and genetically obese mice: Development of an ELISA system for quantification of resistin. Arch Biochem Biophys 2003; 416:164–170.
17. Boden G. Obesity, insulin resistance and free fatty acids. Curr Opin Endocrinol Diabetes Obes 2011; 18:139–143.
18. Capurso C, Capurso A. From excess adiposity to insulin resistance: The role of free fatty acids. Vasc Pharmacol 2012; 57:91–97.
19. Cusi K, Kashyap S, Gastaldelli A, Bajaj M, Cersosimo E. Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes. Am J Physiol Endocrinol Metab 2007; 292:E1775–1781.
20. Hotamisligil GS. Inflammation and metabolic disorders 1. Nature 2006; 444:860–867.
21. Mohammadi A, Gholamhoseinian A, Fallah H. Zataria multiflora increases insulin sensitivity and PPARγ gene expression in high fructose fed insulin resistant rats. Iran J Basic Med Sci 2014; 17:263–270.
22. Meshkani R, Adeli K. Hepatic insulin resistance, metabolic syndrome and cardiovascular disease. Clin Biochem 2009; 42:1331–1346.
23. Leguisamo NM, Lehnen AM, Machado UF, Okamoto MM, Markoski MM, Pinto GH, et al. GLUT4 content decreases along with insulin resistance and high levels of inflammatory markers in rats with metabolic syndrome. Cardiovasc Diabetol 2012; 11:100.
24. Butler M, McKay RA, Popoff IJ, Gaarde WA, Witchell D, Murray SF, et al. Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice. Diabetes 2002; 51:1028–1034.
25. Westerblad H, Bruton JD, Katz A. Skeletal muscle: Energy metabolism, fiber types, fatigue and adaptability. Exp Cell Res 2010; 316:3093–3099.
26. Kajiya T, Ho C, Wang J, Vilardi R, Kurtz TW. Molecular and cellular effects of azilsartan: a new generation angiotensin II receptor blocker. J Hypertens 2011; 29:2476–2483.
27. Lee JY, Hashizaki H, Goto T, Sakamoto T, Takahashi N, Kawada T. Activation of peroxisome proliferator-activated receptor-alpha enhances fatty acid oxidation in human adipocytes 3332. Biochem Biophys Res Commun 2011; 407:818–822.
28. Papaetis GS, Orphanidou D, Panagiotou TN. Thiazolidinediones and type 2 diabetes: from cellular targets to cardiovascular benefit. Curr Drug Targets 2011; 12:1498–512.
29. Taylor C, Hobbs FDR. Type 2 diabetes, thiazolidinediones, and cardiovascular risk. Br J Gen Pract 2009; 59:520–524.
30. Papaetis GS, Orphanidou D, Panagiotou TN. Thiazolidinediones and type 2 diabetes: from cellular targets to cardiovascular benefit 2553. Curr Drug Targets 2011; 12:1498–1512.
31. Seymour EM, Tanone II, Urcuyo-Llanes DE, Lewis SK, Kirakosyan A, Kondoleon MG, et al. Blueberry ikntake alters keletal muscle and adipose tissue peroxisome proliferator-activated receptor activity and reduces insulin resistance in obese rats. J Med Food 2011; 14:1511–1518.
32. Lewis JD, Ferrara A, Peng T, Hedderson M, Bilker WB, Quesenberry CP, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: Interim report of a longitudinal cohort study. Diabetes Care 2011; 34:916–922.
33. Ahvazi M, Akbarzadeh M, Khalighi Sigaroodi F, Kohandel A. Introduce some of the medicinal plants species with the most traditional usage in East Mazandaran. J Med Plants 2012; 11:164–175.
34. Alemardan A, Asadi W, Rezaei M, Tabrizi L, Mohammadi S. Cultivation of iranian seedless barberry (Berberis Integerrima “bidaneh”): A medicinal shrub. Ind Crops Prod 2013; 50:276–287.
35. Potdar D, Hirwani RR, Dhulap S. Phyto-chemical and pharmacological applications of Berberis aristata. Fitoterapia 2012; 83:817–830.
36. Ashraf H , Heidari R, Nejati V IM. Preventive effect of Berberis Integerrima on the serum levels of glucose and lipids in streptozotocin (STZ)-induced diabetes in rats. J Fasa Univ Med Sci 2012; 2:148–155.
37. Ashraf H, Zare S. Preventive effects of aqueous extract of Berberis integerrima Bge. Root on liver injury induced by diabetes Mellitus (Type 1) in rats. Iran J Pharm Res 2015; 14:335–343.
38. Chang W, Chen L, Hatch GM. Berberine as a therapy for type 2 diabetes and its complications: From mechanism of action to clinical studies. Biochem Cell Biol Biol Cell 2015; 93:479–486.
39. Mohammadi A, Gholamhosseinian A, Fallah H. Trigonella foenum-graecum water extract improves insulin sensitivity and stimulates PPAR and γ gene expression in high fructose-fed insulin-resistant rats. Adv Biomed Res 2016; 5:54.
40. Shih CC, Lin CH, Lin WL, Wu J Bin. Momordica charantia extract on insulin resistance and the skeletal muscle GLUT4 protein in fructose-fed rats. J Ethnopharmacol 2009; 123:82–90.
41. Elrashidy R, Asker M. Pioglitazone attenuates cardiac fibrosis and hypertrophy in a rat model of diabetic nephropathy. J Cardiovasc 2012; 17:324-333.
42. Gholamhoseinian A, Falah H, SHarififar F. Anti-hyperglycemic activity of four plants extracts effective against alpha glucosidase in normal and diabetic rats. J Kerman 2009; 15:35-44.
43. Kangani C, Kelley D, DeLany J. New method for GC/FID and GC-C-IRMS analysis of plasma free fatty acid concentration and isotopic enrichment. J Chromatogr B Analyt Technol Biomed Life Sci 2008; 873:95-101.
44. Abdin AA, Baalash AA, Hamooda HE. Effects of rosiglitazone and aspirin on experimental model of induced type 2 diabetes in rats: focus on insulin resistance and inflammatory markers. J Diabetes Complications 2010; 24:168–178.
45. Paradis S, Cabanac M, Marceau P, Frankham P. Body weight and satiation after duodenal switch: 2 years later. Obes Surg 2007;17:631-6.
46. Lee YS, Cha BY, Choi SS, Choi BK, Yonezawa T, Teruya T, et al. Nobiletin improves obesity and insulin resistance in high-fat diet-induced obese mice. J Nutr Biochem 2013; 24:156–162.
47. Liu X, Li G, Zhu H, Huang L, Liu Y, Ma C, et al. Beneficial effect of berberine on hepatic insulin resistance in diabetic hamsters possibly involves in SREBPs, LXRα and PPARα transcriptional programs. Endocr J 2010; 57:881–893.
48. Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes 2015; 6:456–480.
49. Bambace C, Telesca M, Zoico E, Sepe A, Olioso D, Rossi A, et al. Adiponectin gene expression and adipocyte diameter: A comparison between epicardial and subcutaneous adipose tissue in men. Cardiovasc Pathol 2011; 20:e153-156.
50. Skurk T, Alberti-Huber C, Herder C, Hauner H. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab 2007; 92:1023–1033.
51. Matsubara M, Maruoka S, Katayose S. Inverse relationship between plasma adiponectin and leptin concentrations in normal-weight and obese women. Eur J Endocrinol 2002; 147:173–180.
52. Natali A, Natali A, Ferrannini E, Ferrannini E. Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia 2006; 49:434–441.
53. Papaetis GS, Orphanidou D, Panagiotou TN. Thiazolidinediones and type 2 diabetes: from cellular targets to cardiovascular benefit. Curr Drug Targets 2011; 12:1498–1512.
54. Elmazar MM, El-Abhar HS, Schaalan MF, Farag NA. Phytol/Phytanic acid and insulin resistance: potential role of phytanic acid proven by docking simulation and modulation of biochemical alterations. PLoS One 2013; 8:e45638.
55. Sakamoto J, Kimura H, Moriyama S, Odaka H, Momose Y, Sugiyama Y, et al. Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem Biophys Res Commun 2000; 278:704–711.
56. Ye JM, Tid-Ang J, Turner N, Zeng XY, Li HY, Cooney GJ, et al. PPARδ agonists have opposing effects on insulin resistance in high fat-fed rats and mice due to different metabolic responses in muscle. Br J Pharmacol 2011; 163:556–566.
57. Derosa G, Maffioli P. Peroxisome proliferator-activated receptor- γ ( PPAR- γ ) agonists on glycemic control, lipid profile and cardiovascular risk. Curr Mol Pharmacol 2012; 272–281.
58. Olson AL. Insulin resistance: cross-talk between adipose tissue and skeletal muscle, through free fatty acids, liver X receptor, and peroxisome proliferator-activated receptor-α signaling. Horm Mol Biol Clin Investig 2013; 15:115–121.
59. Guo S. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J Endocrinol 2014; 220:T1–23.