Skip to main content

Dried leaf extract of Olea europaea ameliorates islet-directed autoimmunity in mice

  • Tamara Cvjetićanin (a1), Djordje Miljković (a1), Ivana Stojanović (a1), Dragana Dekanski (a2) and Stanislava Stošić-Grujičić (a1)...

The health-promoting effects of various constituents of the olive tree (Olea europaea) are mainly associated with hypoglycaemic and insulin-sensitising activities and have been widely demonstrated in the metabolic syndrome and type 2 diabetes. However, their biological activity in autoimmune type 1 diabetes (T1D) is poorly characterised. Therefore, the influence of O. europaea-derived components present in dry olive leaf extract (DOLE) was examined in two established preclinical models of human T1D, which differ in some aspects of diabetogenesis: multiple low-dose streptozotocin-induced diabetes in susceptible C57BL/6 and CBA/H mouse strains; cyclophosphamide-accelerated diabetes in non-obese diabetic mice. In both T1D models, in vivo administration of DOLE significantly reduced clinical signs of diabetes (hyperglycaemia and body weight loss) and led to complete suppression of histopathological changes in pancreatic islets. In line with these, insulin expression and release were restored in DOLE-treated mice. Interestingly, inducible NO synthase expression and NO production were significantly elevated in peripheral tissues but were down-regulated within the local environment of the endocrine pancreas. This interference was reflected in NO-mediated suppression of T lymphocyte proliferation and lower production of the proinflammatory cytokines interferon-γ, IL-17 and TNF-α in the spleen, with subsequent blockade of β-cell destruction. The results suggest that DOLE interferes with development of autoimmune diabetes by down-regulating production of proinflammatory and cytotoxic mediators. Therefore, the potential use of a DOLE-enriched diet for prophylaxis/treatment of human T1D, and possibly other autoimmune diseases, is worthy of further investigation.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Dried leaf extract of Olea europaea ameliorates islet-directed autoimmunity in mice
      Available formats
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Dried leaf extract of Olea europaea ameliorates islet-directed autoimmunity in mice
      Available formats
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Dried leaf extract of Olea europaea ameliorates islet-directed autoimmunity in mice
      Available formats
Corresponding author
*Corresponding author: Stanislava Stošić-Grujičić, fax +381 11 2761 433, email
Hide All
1 Gianni, C, Mohn, A & Chiarelli, F (2009) Technology and the issue cost/benefit in diabetes. Diabetes Metab Res Rev 25, Suppl. 1, S34S44.
2 Craig, ME, Hattersley, A, Donaghue, TC, et al. (2009) ISPAD clinical practice consensus guidelines 2009 compendium. Definition, epidemiology and classification of diabetes in children and adolescents. Pediatr Diabetes 10, Suppl. 12, 312.
3 Tisch, R & McDevitt, H (1996) Insulin-dependent diabetes mellitus. Cell 85, 291297.
4 Daaboul, J & Schatz, D (2003) Overview of prevention and intervention trials for type 1 diabetes. Rev Endocr Metab Dis 4, 317323.
5 Watson, S & Miller, K (2004) Encyclopedia of the Human Body: The Endocrine System. Westport, CT: Greenwood Publishing.
6 Mastrandrea, L, Yu, J, Behrens, T, et al. (2009) Etanercept treatment in children with new-onset type 1 diabetes. Pilot randomized, placebo-controlled, double-blind study. Diabetes Care 32, 12441249.
7 Staeva-Vieira, T, Peakman, M & von Herrath, M (2007) Translational mini-review series on type 1 diabetes: immune-based therapeutic approaches for type 1 diabetes. Clin Exp Immunol 148, 1731.
8 Kawano, Y, Irie, J, Nakatani, H, et al. (2009) Pioglitazone might prevent the progression of slowly progressive type 1 diabetes. Inter Med 48, 10371039.
9 Rother, KJ, Brown, RJ, Morales, MM, et al. (2009) Effect of ingested interferon-α on β-cell function in children with new onset type 1 diabetes. Diabetes Care 32, 12501255.
10 Shoda, LK, Young, DL, Ramanujan, S, et al. (2005) A comprehensive review of interventions in the NOD mouse and implications for translation. Immunity 23, 115126.
11 Stosic-Grujicic, S, Cvetkovic, I, Mangano, K, et al. (2007) A potent immunomodulatory compound (S, R)-3-phenyl-4, 5-dihydro-5-isoxasole acetic acid, prevents spontaneous and accelerated forms of autoimmune diabetes in NOD mice and inhibits the immunoinflammatory diabetes induced by multiple low doses of streptozotocin in CBA/H mice. J Pharmacol Exp Ther 320, 10381049.
12 Stosić-Grujicić, S, Cvjetićanin, T & Stojanović, I (2009) Retinoids differentially regulate the progression of autoimmune diabetes in three preclinical models in mice. Mol Immunol 47, 7986.
13 Perona, JS, Cabello-Moruno, R & Ruiz-Gutierrez, V (2006) The role of virgin olive oil components in the modulation of endothelial function. J Nutr Biochem 17, 429445.
14 Dekanski, D, Janicijevic-Hudomal, S, Tadic, V, et al. (2009) Phytochemical analysis and gastroprotective activity of an olive leaf extract. J Serb Chem Soc 74, 367377.
15 Ramírez-Tortosa, MC, Suárez, A, Gómez, MC, et al. (1999) Effect of extra-virgin olive oil and fish-oil supplementation on plasma lipids and susceptibility of low-density lipoprotein to oxidative alteration in free-living Spanish male patients with peripheral vascular disease. Clin Nutr 18, 167174.
16 Vissers, MN, Zock, PL & Katan, MB (2004) Bioavailability and antioxidant effects of olive oil phenols in humans: a review. Eur J Clin Nutr 58, 955965.
17 Esposito, K, Ciotola, M & Giugliano, D (2007) Mediterranean diet and the metabolic syndrome. Mol Nutr Food Res 51, 12681274.
18 Fitó, M, de la Torre, R, Farré-Albaladejo, M, et al. (2007) Bioavailability and antioxidant effects of olive oil phenolic compounds in humans: a review. Ann Ist Super Sanita 43, 375381.
19 Panagiotakos, DB & Polychronopoulos, E (2005) The role of Mediterranean diet in the epidemiology of metabolic syndrome; converting epidemiology to clinical practice. Lipids Health Dis 4, 7.
20 Visioli, F, Bellosta, S & Galli, C (1998) Oleuropein, the bitter principle of olives, enhances nitric oxide production by mouse macrophages. Life Sci 62, 541546.
21 Carluccio, MA, Siculella, L, Ancora, MA, et al. (2003) Olive oil and red wine antioxidant polyphenols inhibit endothelial activation: antiatherogenic properties of Mediterranean diet phytochemicals. Arterioscler Thromb Vasc Biol 23, 622629.
22 Bitler, CM, Viale, TM, Damaj, B, et al. (2005) Hydrolyzed olive vegetation water in mice has anti-inflammatory activity. J Nutr 135, 14751479.
23 Al-Azzawie, HF & Alhamdani, MS (2006) Hypoglycemic and antioxidant effects of oleuropein in alloxan-diabetic rabbits. Life Sci 78, 13711377.
24 Sato, H, Genet, C, Strehle, A, et al. (2007) Anti-hyperglycemic activity of TGR5 agonist isolated from Olea europaea. Biochem Biophys Res Commun 362, 793798.
25 Said, O, Fulder, S, Khalil, K, et al. (2008) Maintaining a physiological blood glucose level with ‘glucolevel’, a combination of four anti-diabetes plants used in the traditional Arab herbal medicine. Evid Based Complement Alternat Med 5, 421428.
26 Eidi, A, Eidi, M & Darzi, R (2009) Antidiabetic effect of Olea europea L. in normal and diabetic rats. Phytother Res 23, 347350.
27 Miljkovic, DJ, Dekanski, D, Miljkovic, Z, et al. (2009) Dry olive leaf extract ameliorates experimental autoimmune encephalomyelitis. Clin Nutr 28, 346350.
28 Brode, S, Raine, T, Zaccone, P, et al. (2006) Cyclophosphamide-induced type-1 diabetes in the NOD mouse is accelerated with a reduction of CD4+CD25+Foxp3+ regulatory T cells. J Immunol 177, 66036612.
29 Like, AA & Rossini, AA (1976) Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus. Science 193, 415417.
30 Bach, JF (1995) Insulin-dependent diabetes mellitus as a beta-cell targeted disease of immunoregulation. J Autoimmun 8, 439463.
31 Cvetkovic, I, Al-Abed, Y, Miljkovic, D, et al. (2005) Critical role of macrophage migration inhibitory factor activity in experimental autoimmune diabetes. Endocrinology 146, 29422951.
32 Perrinjaquet-Moccetti, T, Busjahn, A, Schmidlin, C, et al. (2008) Food supplementation with an olive (Olea europaea L.) leaf extract reduces blood pressure in borderline hypertensive monozygotic twins. Phytother Res 22, 12391242.
33 Rucker, RB (2007) Allometric scaling, metabolic body size and interspecies comparisons of basal nutritional requirements. J Anim Physiol Anim Nutr (Berl) 91, 148156.
34 Gonzalez, M, Zarzuelo, A, Gamez, MJ, et al. (1992) Hypoglycemic activity of olive leaf. Planta Med 58, 513515.
35 Briante, R, Patumi, M, Terenziani, S, et al. (2002) Olea europea L. leaf extract and derivatives: antioxidant properties. J Agric Food Chem 50, 49344940.
36 Visioli, F, Poli, A & Galli, C (2002) Antioxidant and other biological activities of phenols from olives and olive oil. Med Res Rev 22, 6575.
37 Jemai, H, Bouaziz, M, Fki, I, et al. (2008) Hypolipidimic and antioxidant activities of oleuropein and its hydrolysis derivative-rich extracts from Chemlali olive leaves. Chem Biol Interact 176, 8898.
38 Bennani-Kabchi, N, Fdhil, H, Cherrah, Y, et al. (2000) Therapeutic effect of Olea europea var. oleaster leaves on carbohydrate and lipid metabolism in obese and prediabetic sand rats (Psammomys obesus). Ann Pharm Fr 58, 271277.
39 Coskun, O, Kanter, M, Korkmaz, A, et al. (2005) Quercetin, a flavonoid antioxidant, prevents and protects streptozotocin-induced oxidative stress and β-cell damage in rat pancreas. Pharmacol Res 51, 117123.
40 Albina, JE, Abate, JA & Henry, WL Jr (1991) Nitric oxide production is required for murine resident peritoneal macrophages to suppress mitogen-stimulated T cell proliferation. Role of IFN-gamma in the induction of the nitric oxide-synthesizing pathway. J Immunol 147, 144148.
41 Bogdan, C (2001) Nitric oxide and the immune response. Nat Immunol 2, 907916.
42 Lemaire, G, Guittet, O, Vesin, MF, et al. (2009) Glutathione depletion reveals impairment of antigen processing and inhibition of cathepsin activity by nitric oxide in antigen-presenting cells. Mol Immunol 46, 11001108.
43 Stassi, G, De Maria, R, Trucco, G, et al. (1997) Nitric oxide primes pancreatic beta cells for Fas-mediated destruction in insulin-dependent diabetes mellitus. J Exp Med 186, 11931200.
44 Pearl-Yafe, M, Kaminitz, A, Yolcu, ES, et al. (2007) Pancreatic islets under attack: cellular and molecular effectors. Curr Pharm Des 13, 749760.
45 Ischiropoulos, H, Zhu, L, Chen, J, et al. (1992) Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase. Arch Biochem Biophys 298, 431437.
46 Emamaullee, JA, Davis, J, Merani, S, et al. (2009) Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice. Diabetes 58, 13021311.
47 Martin-Orozco, N, Chung, Y, Chang, SH, et al. (2009) Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur J Immunol 39, 216224.
48 Miljkovic, D, Cvetkovic, I, Momcilovic, M, et al. (2005) Interleukin-17 stimulates inducible nitric oxide synthase-dependent toxicity in mouse beta cells. Cell Mol Life Sci 62, 26582668.
49 Tesmer, LA, Lundy, SK, Sarkar, S, et al. (2008) Th17 cells in human disease. Immunol Rev 223, 87113.
50 Hartupee, J, Liu, C, Novotny, M, et al. (2009) IL-17 signaling for mRNA stabilization does not require TNF receptor-associated factor 6. J Immunol 182, 16601666.
51 Blonska, M, Czuba, ZP & Krol, W (2003) Effect of flavone derivatives on interleukin-1 beta (IL-1 beta) mRNA expression and IL-1 beta protein synthesis in stimulated RAW 264.7 macrophages. Scand J Immunol 57, 162166.
52 Miles, EA, Zoubouli, P & Calder, PC (2005) Differential anti-inflammatory effects of phenolic compounds from extra virgin olive oil identified in human whole blood cultures. Nutrition 21, 389394.
53 Zunino, SJ, Storms, DH & Stephensen, CB (2007) Diets rich in polyphenols and vitamin A inhibit the development of type 1 autoimmune diabetes in nonobese diabetic mice. J Nutr 137, 12161221.
54 Sanchez-Avila, N, Priego-Capote, F, Ruiz-Jimenez, J, et al. (2009) Fast and selective determination of triterpenoic compounds in olive leaves by liquid chromatography–tandem mass spectrometry with multiple reaction monitoring after microwave-assisted extraction. Talanta 78, 4048.
55 Jang, S-M, Yee, S-T, Choi, J, et al. (2009) Ursolic acid enhances the cellular immune system and pancreatic beta-cell function in streptozotocin-induced diabetic mice fed a high-fat diet. Int Immunopharmacol 9, 113119.
56 Liu, J, Sun, H, Duan, W, et al. (2007) Maslinic acid reduces blood glucose in KK-Ay mice. Biol Pharm Bull 30, 20752078.
57 Lory, D, Incani, A, Deiana, M, et al. (2009) Protective effect of hydroxytyrosol and tyrosol against oxidative stress in kidney cells. Toxic Ind Health 25, 301310.
58 Andrikopoulos, NK, Kaliora, AC, Assimopoulou, AN, et al. (2002) Inhibitory activity of minor polyphenolic and nonpolyphenolic constituents of olive oil against in vitro low-density lipoprotein oxidation. J Med Food 5, 17.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

British Journal of Nutrition
  • ISSN: 0007-1145
  • EISSN: 1475-2662
  • URL: /core/journals/british-journal-of-nutrition
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed