Hostname: page-component-cd9895bd7-fscjk Total loading time: 0 Render date: 2024-12-27T21:51:44.427Z Has data issue: false hasContentIssue false

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

Published online by Cambridge University Press:  07 September 2015

Ştefana Bâlici
Affiliation:
Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, 6 Louis Pasteur St., 400349 Cluj-Napoca, România Department of Inorganic Chemistry, Faculty of Chemistry and Chemical Engineering, “Babeş-Bolyai” University, 11 Arany Janos St., 400028 Cluj-Napoca, România
Modeste Wankeu-Nya
Affiliation:
Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, 6 Louis Pasteur St., 400349 Cluj-Napoca, România Laboratory of Animal Biology and Physiology, Department of Animal Organism Biology, Faculty of Science, University of Douala, PO Box 24157, Douala, Cameroon
Dan Rusu
Affiliation:
Department of Physical-Chemistry, Faculty of Pharmacy, “Iuliu Haţieganu” University of Medicine and Pharmacy, 6 Louis Pasteur St., 400349 Cluj-Napoca, România
Gheorghe Z. Nicula
Affiliation:
Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, 6 Louis Pasteur St., 400349 Cluj-Napoca, România
Mariana Rusu
Affiliation:
Department of Inorganic Chemistry, Faculty of Chemistry and Chemical Engineering, “Babeş-Bolyai” University, 11 Arany Janos St., 400028 Cluj-Napoca, România
Adrian Florea*
Affiliation:
Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, 6 Louis Pasteur St., 400349 Cluj-Napoca, România
Horea Matei
Affiliation:
Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, 6 Louis Pasteur St., 400349 Cluj-Napoca, România
*
*Corresponding author. aflorea@umfcluj.ro
Get access

Abstract

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.

Type
Biological Applications
Copyright
© Microscopy Society of America 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

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.Google Scholar
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.Google Scholar
Arora, S., Ojha, S.K. & Vohora, D. (2009). Characterisation of streptozotocin induced diabetes mellitus in Swiss Albino mice. Global J Pharm 3, 8184.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
Dean, P.M. (1973). Ultrastructural morphometry of the pancreatic β-cell. Diabetologia 9, 115119.Google Scholar
Desgraz, R., Bonal, C. & Herrera, P.L. (2011). β-cell regeneration: The pancreatic intrinsic faculty. Trends Endocrinol Metab 22, 3443.CrossRefGoogle ScholarPubMed
Domingo, J.L. (2002). Vanadium and tungsten derivatives as antidiabetic agents. A review of their toxic effects. Biol Trace Elem Res 88, 97112.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.Google Scholar
Goc, A. (2006). Biological activity of vanadium compounds. Cent Eur J Biol (CEJB) 1, 314332.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
Harland, B.F. & Harden-Williams, B.A. (1994). Is vanadium of human nutritional importance yet? J Am Diet Assoc 94, 891894.Google Scholar
Hasenknopf, B. (2005). Polyoxometalates: Introduction to a class of inorganic compounds and their biomedical applications. Front Biosci 10, 275287.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
Kahn, S.E., Hull, R.L. & Utzschneider, K.M. (2006). Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840846.Google Scholar
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.Google Scholar
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.Google Scholar
Lamanna, G., Battigelli, A., Ménard-Moyon, C. & Bianco, A. (2012). Multifunctionalized carbon nanotubes as advanced multimodal nanomaterials for biomedical applications. Nanotechnol Rev 1, 1729.Google Scholar
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.CrossRefGoogle Scholar
Lenzen, S. (2008 a). The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 51, 216226.Google Scholar
Lenzen, S. (2008 b). Oxidative stress: The vulnerable β-cell. Biochem Soc Trans 36, 343347.Google Scholar
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.Google Scholar
MacDonald, P.E., Joseph, J.W. & Rorsman, P. (2005). Glucose-sensing mechanisms in pancreatic β-cells. Philos Trans R Soc B 360, 22112225.Google Scholar
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.Google Scholar
Makinen, M.W. & Salehitazangi, M. (2014). The structural basis of action of vanadyl (VO2+) chelates in cells. Coord Chem Rev 279, 122.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google ScholarPubMed
Orci, L., Malaisse-Lagae, F., Ravazzola, M., Amherdt, M. & Renold, A.E. (1973). Exocytosis-endocytosis coupling in the pancreatic beta cell. Science 181, 561562.Google Scholar
Orza, A., Casciano, D. & Biriş, A. (2014). Nanomaterials for targeted drug delivery to cancer stem cells. Drug Metab Rev 46, 191206.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
Pope, M.T. & Müller, A. (1991). Polyoxometalate chemistry: An old field with new dimensions in several disciplines. Angew Chem Int Ed 30, 3448.Google Scholar
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.Google Scholar
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.Google Scholar
Ragbetli, C. & Ceylan, E. (2010). Effect of streptozotocin on biochemical parameters in rats. Asian J Chem 22, 23752378.Google Scholar
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.Google Scholar
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.Google Scholar
Rhule, J.T., Hill, C.L., Judd, D.A. & Schinazi, R.F. (1998). Polyoxometalate in medicine. Chem Rev 98, 327357.Google Scholar
Richardson, S.J., Morgan, N.G. & Foulis, A.K. (2014). Pancreatic pathology in type 1 diabetes mellitus. Endocr Pathol 25, 8092.Google Scholar
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.Google Scholar
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.Google Scholar
Rorsman, P. & Renström, E. (2003). Insulin granule dynamics in pancreatic beta cells. Diabetologia 46, 10291045.Google Scholar
Rusu, D. & Bâlici, S. (2013). Polioxometalaţii. Aplicaţii Biomedicale. Cluj-Napoca, România: Casa Cărţii de Stiinţă.Google Scholar
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.Google Scholar
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.Google Scholar
Srivastava, A.K. (2000). Anti-diabetic and toxic effects of vanadium compounds. Mol Cell Biochem 206, 177182.Google Scholar
Strigul, N. (2010). Does speciation matter for tungsten ecotoxicology? Ecotoxicol Environ Saf 73, 10991113.CrossRefGoogle ScholarPubMed
Tanikawa, K. (1968). Ultrastructural Aspects of the Liver and Its Disorders. Berlin-Tokyo, Japan: Springer-Verlag Igaku-Shoin Ltd.Google Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
Thompson, K.H. & Orvig, C. (2006). Vanadium in diabetes: 100 years from phase 0 to phase I. J Inorg Biochem 100, 19251935.Google Scholar
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.Google Scholar
Vardatsikos, G., Pandey, N.R. & Srivastava, A.K. (2013). Insulin-mimetic and anti-diabetic effects of zinc. J Inorg Biochem 120, 817.Google Scholar
Vaulont, S., Vasseur-Cognet, M. & Kahn, A. (2000). Glucose regulation of gene transcription. J Biol Chem 275, 3155531558.Google Scholar
Vetere, A., Choudhary, A., Burns, S.M. & Wagner, B.K. (2014). Targeting the pancreatic β-cell to treat diabetes. Nature 13, 278289.Google Scholar
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.Google Scholar
Weiss, R.B. (1982). Streptozocin: A review of its pharmacology, efficacy, and toxicity. Cancer Treat Rep 66, 427438.Google ScholarPubMed
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.Google Scholar
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.Google Scholar
World Health Organization, Diabetes Programme (2014). Available at http://www.who.int/diabetes/en (retrieved November 10, 2014).Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
Yoon, J.W. & Hee-Sook Jun, H.S. (2005). Autoimmune destruction of pancreatic β-cells. Am J Therapeut 12, 580591.Google Scholar