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Ultrastructural Analysis of In Vivo Hypoglycemiant Effect of Two Polyoxometalates in Rats with Streptozotocin-Induced Diabetes

  • Ştefana Bâlici (a1) (a2), Modeste Wankeu-Nya (a1) (a3), Dan Rusu (a4), Gheorghe Z. Nicula (a1), Mariana Rusu (a2), Adrian Florea (a1) and Horea Matei (a1)...


Two polyoxometalates (POMs), synthesized through a self-assembling method, were used in the treatment of streptozotocin (STZ)-induced diabetic rats. One of these nanocompounds [tris(vanadyl)-substituted tungsto-antimonate(III)-anions—POM1] was previously described in the literature, whereas the second [tris-butyltin-21-tungsto-9-antimonate(III)-anions—POM2], was prepared by us based on our original formula. In rats with STZ-induced diabetes treated with POMs (up to a cumulative dose of 4 mg/kg bodyweight at the end of the treatments), statistically significant reduced levels of blood glucose were measured after 3 weeks, as compared with the diabetic control groups (DCGs). Ultrastructural analysis of pancreatic β-cells (including the mean diameter of secretory vesicles and of their insulin granules) in the treated diabetic rats proved the POMs contribute to limitation of cellular degeneration triggered by STZ, as well as to the presence of increased amounts of insulin-containing vesicles as compared with the DCG. The two POMs also showed hepatoprotective properties when ultrastructural aspects of hepatocytes in the experimental groups of rats were studied. Based on our in vivo studies, we concluded that the two POMs tested achieved hypoglycemiant effects by preventing STZ-triggered apoptosis of pancreatic β-cells and stimulation of insulin synthesis.


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Abeeleh, M.A., Ismail, Z.B., Alzaben, K.R., Abu-Halaweh, S.A., Al-Essa, M.K., Abuabeeleh, J. & Alsmady, M.M. (2009). Induction of diabetes mellitus in rats using intraperitoneal streptozotocin: A comparison between 2 strains of rats. Eur J Sci Res 32, 398402.
Altirriba, J., Barbera, A., Del Zotto, H., Nadal, B., Piquer, S., Sanchez-Pla, A., Gagliardino, J.J. & Gomis, R. (2009). Molecular mechanisms of tungstate-induced pancreatic plasticity: A transcriptomics approach. BMC Genomics 10, 406.
Arora, S., Ojha, S.K. & Vohora, D. (2009). Characterisation of streptozotocin induced diabetes mellitus in Swiss Albino mice. Global J Pharm 3, 8184.
Badmaev, V., Prakash, S. & Majeed, M. (1999). Vanadium: A review of its potential role in the fight against diabetes. J Altern Complement Med 5, 273291.
Barg, S., Ma, X., Eliasson, L., Galvanovskis, J., Göpel, S.O., Obermüller, S., Platzer, J., Renström, E., Turs, M., Atlas, D., Striessnig, J. & Rorsman, P. (2001). Fast exocytosis with few Ca2+ channels in insulin-secreting mouse pancreatic β-cells. Biophys J 81, 33083323.
Barrio, D.A., Williams, P.A.M., Cortizo, A.M. & Etcheverry, S.B. (2003). Synthesis of a new vanadyl(IV) complex with trehalose (TreVO): Insulin-mimetic activities in osteoblast-like cells in culture. J Biol Inorg Chem 8, 459468.
Cam, M.C., Brownsey, R.W. & McNeill, J.H. (2000). Mechanisms of vanadium action: Insulin-mimetic or insulin-enhancing agent? Can J Physiol Pharmacol 78, 829847.
Cibert, C. & Jasmin, C. (1982). Determination of the intracellular localization of a polyoxotungstate (HPA-23) by Raman laser and X-fluorescence spectroscopies. Biochem Biophys Res Commun 108, 14241433.
Clark, T.A., Heyliger, C.E., Kopilas, M., Edel, A.L., Junaid, A., Aguilar, F., Smyth, D.D., Thliveris, J.A., Merchant, M., Kim, H.K. & Pierce, G.N. (2012). A tea/vanadate decoction delivered orally over 14 months to diabetic rats induces long-term glycemic stability without organ toxicity. Metab Clin Experim 61, 742753.
Cros, G.H., Cam, M.C., Serrano, J.J., Ribes, G. & McNeill, J.H. (1995). Long-term antidiabetic activity of vanadyl after treatment withdrawal: Restoration of insulin secretion? Mol Cell Biochem 153, 191195.
Dean, P.M. (1973). Ultrastructural morphometry of the pancreatic β-cell. Diabetologia 9, 115119.
Desgraz, R., Bonal, C. & Herrera, P.L. (2011). β-cell regeneration: The pancreatic intrinsic faculty. Trends Endocrinol Metab 22, 3443.
Domingo, J.L. (2002). Vanadium and tungsten derivatives as antidiabetic agents. A review of their toxic effects. Biol Trace Elem Res 88, 97112.
Eidi, A. & Eidi, M. (2009). Antidiabetic effects of sage (Salvia officinalis L.) leaves in normal and streptozotocin-induced diabetic rats. Diabetes Metab Syndr: Clin Res Rev 3, 4044.
Erlandensen, S.L., Parsons, J.A., Burke, J.P., Redick, J.A. & Van Orden, L.S. (1975). A modification of the unlabeled antibody enzyme method using heterologous antisera for the light microscopic and ultrastructural localization of insulin, glucagon and growth hormone. J Histochem Cytochem 23, 666677.
Fernandez-Alvarez, J., Barbera, A., Nadal, B., Barcelo-Batllori, S., Piquer, S., Claret, M., Guinovart, J.J. & Gomis, R. (2004). Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate. Diabetologia 47, 470477.
Ferrannini, E., Lanfranchi, A., Rohner-Jeanrenaud, F., Manfredini, G. & Van de Werve, G. (1990). Influence of long-term diabetes on liver glycogen metabolism in the rat. Metabolism 39, 10821088.
Fierabracci, V., De Tata, V., Pocai, A., Novelli, M., Barberà, A. & Masiello, P. (2002). Oral tungstate treatment improves only transiently alteration of glucose metabolism in a new rat model of type 2 diabetes. Endocrine 19, 177184.
Florea, A. & Crăciun, C. (2013). Bee venom induced in vivo ultrastructural reactions of cells involved in the bone marrow erythropoiesis and of circulating red blood cells. Microsc Microanal 19, 393405.
Fouad Shalaby, M.A., El Latif, H.A.A. & El Sayed, M.E. (2013). Interaction of insulin with prokinetic drugs in STZ-induced diabetic mice. World J Gastrointest Pharmacol Ther 4, 2838.
Gezginci-Oktayoglu, S., Sacan, O., Bolkent, S., Ipci, Y., Kabasakal, L., Sener, G. & Yanardag, R. (2014). Chard (Βeta vulgaris L. var. cicla) extract ameliorates hyperglycemia by increasing GLUT2 through Akt2 and antioxidant defense in the liver of rats. Acta Histochem 116, 3239.
Goc, A. (2006). Biological activity of vanadium compounds. Cent Eur J Biol (CEJB) 1, 314332.
Gouzerh, P. & Che, M. (2006). From Scheele and Berzelius to Müller. Polyoxometalates (POMs) revisited and the “missing link” between the bottom up and top down approaches. L’Actualité Chimique 298, 114.
Graham, M.L., Janecek, J.L., Kittredge, J.A., Hering, B.J. & Schuurman, H.J. (2011). The streptozotocin-induced diabetic nude mouse model: Differences between animals from different sources. Comp Med 61, 356360.
Guyton, A.C. & Hall, J.E. (2006). Insulin, glucagon, and diabetes mellitus. In Textbook of Medical Physiology, Guyton, A.C. & Hall, J.E. (Eds.), pp. 961977). Philadelphia, USA: Elsevier-Saunders.
Harland, B.F. & Harden-Williams, B.A. (1994). Is vanadium of human nutritional importance yet? J Am Diet Assoc 94, 891894.
Hasenknopf, B. (2005). Polyoxometalates: Introduction to a class of inorganic compounds and their biomedical applications. Front Biosci 10, 275287.
Hoppa, M.B., Jones, E., Karanauskaite, J., Ramracheya, R., Braun, M., Collins, S.C., Zhang, Q., Clark, A., Eliasson, L., Genoud, C., MacDonald, P.E., Monteith, A.G., Barg, S., Galvanovskis, J. & Rorsman, P. (2012). Multivesicular exocytosis in rat pancreatic beta cells. Diabetologia 55, 10011012.
Ilyas, Z., Shah, H.S., Al-Oweini, R., Kortz, U. & Iqbal, J. (2014). Antidiabetic potential of polyoxotungstates: In vitro and in vivo studies. Metallomics 6, 15211526.
Kahn, S.E., Hull, R.L. & Utzschneider, K.M. (2006). Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840846.
Kalailingam, P., Balasubramanian, K., Kannaian, B., Mohammed, A.K.N., Meenakshisundram, K., Tamilmani, E. & Kaliaperumala, R. (2013). Isolation and quantification of flavonoids from ethanol extract of Costus igneus rhizome (CiREE) and impact of CiREE on hypoglycaemic, electron microscopic studies of pancreas in streptozotocin (STZ)-induced diabetic rats. Biomed Prev Nutr 3, 285297.
Kiersztan, A., Winiarska, K., Drozak, J., Przedlacka, M., Wegrzynowicz, M., Fraczyk, T. & Bryla, J. (2004). Differential effects of vanadium, tungsten and molybdenum on inhibition of glucose formation in renal tubules and hepatocytes of control and diabetic rabbits: Beneficial action of melatonin and N-acetylcysteine. Mol Cell Biochem 261, 921.
Lamanna, G., Battigelli, A., Ménard-Moyon, C. & Bianco, A. (2012). Multifunctionalized carbon nanotubes as advanced multimodal nanomaterials for biomedical applications. Nanotechnol Rev 1, 1729.
Lemaire, K., Ravier, M.A., Schraenen, A., Creemers, J.W., Van de Plas, R., Granvik, M., Van Lommel, L., Waelkens, E., Chimienti, F., Rutter, G.A., Gilon, P., Veld, P.A. & Schuit, F.C. (2009). Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice. Proc Natl Acad Sci USA 106, 1487214877.
Lenzen, S. (2008 a). The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 51, 216226.
Lenzen, S. (2008 b). Oxidative stress: The vulnerable β-cell. Biochem Soc Trans 36, 343347.
Liu, F., Xie, M., Chen, D., Li, J. & Ding, W. (2013). Effect of VIVO(dipic-Cl)(H2O)2 on lipid metabolism disorders in the liver of STZ-induced diabetic rats. J Diab Res 2, 110.
MacDonald, P.E., Joseph, J.W. & Rorsman, P. (2005). Glucose-sensing mechanisms in pancreatic β-cells. Philos Trans R Soc B 360, 22112225.
Maedler, K., Schumann, D.M., Sauter, N., Ellingsgaard, H., Bosco, D., Baertschiger, R., Iwakura, Y., Oberholzer, J., Wollheim, C.B., Gauthier, B.R. & Donath, M.Y. (2006). Low concentration of interleukin-1β induces FLICE-inhibitory protein-mediated β-cell proliferation in human pancreatic islets. Diabetes 55, 27132722.
Makinen, M.W. & Salehitazangi, M. (2014). The structural basis of action of vanadyl (VO2+) chelates in cells. Coord Chem Rev 279, 122.
Matsumoto, S., Koshiishi, I., Inoguchi, T., Nawata, H. & Utsumi, H. (2003). Confirmation of superoxide generation via xanthine oxidase in streptozotocin-induced diabetic mice. Free Radic Res 37, 767772.
Mohanasundaram, D., Drogemuller, C., Brealey, J., Jessup, C.F., Milner, C., Murgia, C., Lang, C.J., Milton, A., Zalewski, P.D., Russ, G.R. & Coates, P.T. (2011). Ultrastructural analysis, zinc transporters, glucose transporters and hormones expression in new world primate (Callithrix jacchus) and human pancreatic islets. Gen Comp Endocrinol 174, 7179.
Morini, S., Braun, M., Onori, P., Cicalese, L., Elias, G., Gaudio, E. & Rastellini, C. (2006). Morphological changes of isolated rat pancreatic islets: A structural, ultrastructural and morphometric study. J Anat 209, 381392.
Munoz, M.C., Barbera, A., Dominguez, J., Fernandez-Alvarez, J., Gomis, R. & Guinovart, J.J. (2001). Effects of tungstate, a new potential oral antidiabetic agent, in Zucker diabetic fatty rats. Diabetes 50, 131138.
Nagamatsu, S., Nakamichi, Y., Yamamura, C., Matsushima, S., Watanabe, T., Ozawa, S., Furukawa, H. & Ishida, H. (1999). Decreased expression of t-SNARE, Syntaxin 1, and SNAP-25 in pancreatic beta-cells is involved in impaired insulin secretion from diabetic GK rat islets: Restoration of decreased t-SNARE proteins improves impaired insulin secretion. Diabetes 48, 23672373.
Ni, L., Greenspan, P., Gutman, R., Kelloes, C., Farmer, M.A. & Boudinot, F.D. (1996). Cellular localization of antiviral polyoxometalates in J774 macrophages. Antiviral Res 32, 141148.
Nomiya, K., Torii, H., Hasegawa, T., Nemoto, Y., Nomura, K., Hashino, K., Uchida, M., Kato, Y., Shimizu, K. & Oda, M. (2001). Insulin mimetic effect of a tungstate cluster. Effect of oral administration of homo-polyoxotungstates and vanadium-substituted polyoxotungstates on blood glucose level of STZ mice. J Inorg Biochem 86, 657667.
Norlund, R., Norlund, L., Bloom, G.D. & Täljedal, I.B. (1984). Influence of fixation and staining techniques on the ultrastructure of the insulin secretory granule. Med Biol 62, 2733.
Orci, L., Malaisse-Lagae, F., Ravazzola, M., Amherdt, M. & Renold, A.E. (1973). Exocytosis-endocytosis coupling in the pancreatic beta cell. Science 181, 561562.
Orza, A., Casciano, D. & Biriş, A. (2014). Nanomaterials for targeted drug delivery to cancer stem cells. Drug Metab Rev 46, 191206.
Orza, A., Soriţău, O., Olenic, L., Diudea, M., Florea, A., Rus Ciucă, D., Mihu, C., Casciano, D. & Biriş, A.S. (2011). Electrically conductive gold-coated collagen nanofibers for placental-derived mesenchymal stem cells enhanced differentiation and proliferation. ACS Nano 5, 44904503.
Palsamy, P. & Subramanian, S. (2009). Modulatory effects of resveratrol on attenuating the key enzymes activities of carbohydrate metabolism in streptozotocin–nicotinamide-induced diabetic rats. Chem Biol Interact 179, 356362.
Pillai, S.I., Subramanian, S.P. & Kandaswamy, M. (2013). Evaluation of antioxidant efficacy of vanadium-3-hydroxyflavone complex in streptozotocin-diabetic rats. Chem Biol Interact 204, 6774.
Plentz, R.R., Palagani, V., Wiedemann, A., Diekmann, U., Glage, S., Naujok, O., Jörns, A. & Müller, T. (2012). Islet microarchitecture and glucose transporter expression of the pancreas of the marmoset monkey display similarities to the human. Islets 4, 123129.
Pope, M.T. & Müller, A. (1991). Polyoxometalate chemistry: An old field with new dimensions in several disciplines. Angew Chem Int Ed 30, 3448.
Potara, M., Boca, S., Licarete, E., Damert, A., Alupei, M.C., Chiriac, M.T., Popescu, O., Schmidt, U. & Astilean, S. (2013). Chitosan-coated triangular silver nanoparticles as a novel class of biocompatible, highly sensitive plasmonic platforms for intracellular SERS sensing and imaging. Nanoscale 5, 60136022.
Qiao, W., Zhao, C., Qin, N., Zhai, H.Y. & Duan, H.Q. (2011). Identification of trans-tiliroside as active principle with anti-hyperglycemic, anti-hyperlipidemic and antioxidant effects from Potentilla chinesis . J Ethnopharmacol 135, 515521.
Ragbetli, C. & Ceylan, E. (2010). Effect of streptozotocin on biochemical parameters in rats. Asian J Chem 22, 23752378.
Rajagopala, A., Kulkarnia, S., Lewisa, K.T., Chena, X., Maarouf, A., Kelly, C.V., Taatjes, D.J. & Jena, B.P. (2015). Proteome of the insulin-secreting Min6 cell porosome complex: Involvement of Hsp90 in its assembly and function. J Proteomics 114, 8392.
Reul, B.A., Amin, S.S., Buchet, J.P., Ongemba, L.N., Crans, D.C. & Brichard, S.M. (1999). Effects of vanadium complexes with organic ligands on glucose metabolism: A comparison study in diabetic rats. Br J Pharmacol 126, 467477.
Rhule, J.T., Hill, C.L., Judd, D.A. & Schinazi, R.F. (1998). Polyoxometalate in medicine. Chem Rev 98, 327357.
Richardson, S.J., Morgan, N.G. & Foulis, A.K. (2014). Pancreatic pathology in type 1 diabetes mellitus. Endocr Pathol 25, 8092.
Rodrigues, B., Poucheret, P., Battell, M. & McNeill, J.H. (1999). Streptozotocin-induced diabetes: Induction, mechanism(s) and dose-dependency. In Experimental Models of Diabetes, McNeill, J.H. (Ed.), pp. 339). Boca Raton, USA: CRC Press.
Roglic, G., Unwin, N., Bennett, P.H., Mathers, C., Tuomilehto, J., Nag, S., Connolly, V. & King, H. (2005). The burden of mortality attributable to diabetes. Diabetes Care 28, 21302135.
Rorsman, P. & Renström, E. (2003). Insulin granule dynamics in pancreatic beta cells. Diabetologia 46, 10291045.
Rusu, D. & Bâlici, S. (2013). Polioxometalaţii. Aplicaţii Biomedicale. Cluj-Napoca, România: Casa Cărţii de Stiinţă.
Soleimanpour, S.A. & Stoffers, D.A. (2013). The pancreatic β-cell and type 1 diabetes: Innocent bystander or active participant? Trends Endocrinol Metab 24, 324331.
Soveid, M., Dehghani, G.A. & Omrani, G.R. (2013). Long-term efficacy and safety of vanadium in the treatment of type 1 diabetes. Arch Iran Med 16, 408411.
Srivastava, A.K. (2000). Anti-diabetic and toxic effects of vanadium compounds. Mol Cell Biochem 206, 177182.
Strigul, N. (2010). Does speciation matter for tungsten ecotoxicology? Ecotoxicol Environ Saf 73, 10991113.
Tanikawa, K. (1968). Ultrastructural Aspects of the Liver and Its Disorders. Berlin-Tokyo, Japan: Springer-Verlag Igaku-Shoin Ltd.
Terao, K., Murat, G., Okonogi, A., Fuke, A., Okitsu, T., Tada, T., Suzuki, T., Nagamatsu, S., Washizu, M. & Kotera, H. (2014). Subcellular glucose exposure biases the spatial distribution of insulin granules in single pancreatic beta cells. Sci Rep 4, 41234128.
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (2003). Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 26, 31603167.
Thompson, K.H. & Orvig, C. (2006). Vanadium in diabetes: 100 years from phase 0 to phase I. J Inorg Biochem 100, 19251935.
van de Waterbeemd, H., Smith, D.A., Beaumont, K. & Walker, D.K. (2001). Property-based design: Optimization of drug absorption and pharmacokinetics. J Med Chem 44, 13131333.
Vardatsikos, G., Pandey, N.R. & Srivastava, A.K. (2013). Insulin-mimetic and anti-diabetic effects of zinc. J Inorg Biochem 120, 817.
Vaulont, S., Vasseur-Cognet, M. & Kahn, A. (2000). Glucose regulation of gene transcription. J Biol Chem 275, 3155531558.
Vetere, A., Choudhary, A., Burns, S.M. & Wagner, B.K. (2014). Targeting the pancreatic β-cell to treat diabetes. Nature 13, 278289.
Wankeu-Nya, M., Florea, A., Bâlici, S., Watcho, P., Matei, H. & Kamanyi, A. (2013). Dracaena arborea alleviates ultra-structural spermatogenic alterations in streptozotocin-induced diabetic rats. BMC Complement Altern Med 13, 71.
Weiss, R.B. (1982). Streptozocin: A review of its pharmacology, efficacy, and toxicity. Cancer Treat Rep 66, 427438.
Willsky, G.R., Chi, L.H., Godzala, M. 3rd, Kostyniak, P.J., Smee, J.J., Trujillo, A.M., Alfano, J.A., Ding, W., Hu, Z. & Crans, D.C. (2011). Anti-diabetic effects of a series of vanadium dipicolinate complexes in rats with streptozotocin-induced diabetes. Coord Chem Rev 255, 22582269.
Wiser, O., Trus, M., Hernández, A., Renström, E., Barg, S., Rorsmnan, P. & Atlas, D. (1999). The voltage sensitive Lc-type Ca2+ channel is functionally coupled to the exocytotic machinery. Proc Natl Acad Sci USA 96, 248253.
World Health Organization, Diabetes Programme (2014). Available at (retrieved November 10, 2014).
Yaghmaei, P., Parivar, K., Niksereshet, F., Amini, S., Masoudi, A. & Amini, E. (2008). Pancreatic protective effects of sodium tungstate in streptozotocin-induced diabetic rats. Diab Metab Syndr Clin Res Rev 2, 259265.
Yamase, T., Botar, B., Ishikawa, E. & Fukaya, K. (2001). Chemical structure and intramolecular spin-exchange interaction of [(VO)3(SbW9O33)2]12- . Chem Lett 1, 5657.
Yasuda, H., Zhenzi Jin, Z., Nakayama, M., Yamada, K., Kishi, M., Okumachi, Y., Arai, T., Moriyama, H., Yokono, K. & Nagata, M. (2009). NO-mediated cytotoxicity contributes to multiple low-dose streptozotocin-induced diabetes but not to NOD diabetes. Diab Res Clin Prac 83, 200207.
Yoon, J.W. & Hee-Sook Jun, H.S. (2005). Autoimmune destruction of pancreatic β-cells. Am J Therapeut 12, 580591.



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