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1 !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! II I II II Drug discovery for treatment against diabetes by using hyperglycemic silkworms Yasuhiko Matsumoto and Kazuhisa Sekimizu Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, The University of Tokyo,, Hongo, Bunkyo-ku, Tokyo, Japan pp.

2 R Replacement Reduction Refinement Relative Replacement Caenorhabditis elegans Drosophila melanogaster A Silkmate S B C D E F B

3 A B C D E F A c AGEs advanced glycation end products AGEs A AGEs A D E I Akt

4 A B CD Akt AAkt in vitro Akt B Akt PIphosphoinositide -kinase PI Kwortmannin B PI AMP adenosine -monophosphate-activated protein kinase AMPK AICAR -aminoimidazole- -carboxamide ribonucleotideamp AICAR C AICAR AMPK D AICAR AMPK AICAR E G AICAR H AMPK

5 A AGEs AGEs B CDE AGEs in vivo

6 AMPK A B Akt PI K C AICAR D AICAR AMPK E AICAR FGH AICAR AICAR

Zimmet, P., Alberti, K.G., Shaw, J.Nature,,. Carver, C.Diabetes Educ.,,. Russell, W.M.S. Burch, R.L.The Principles of Humane Experimental Technique, Methuen, London. O Reilly, L.P., Luke, C.J., Perlmutter, D.

7 Zimmet, P., Alberti, K.G., Shaw, J.Nature,,. Carver, C.Diabetes Educ.,,. Russell, W.M.S. Burch, R.L.The Principles of Humane Experimental Technique, Methuen, London. O Reilly, L.P., Luke, C.J., Perlmutter, D.H., Silverman, G.A., Pak, S.C.Adv. Drug Deliv. Rev., C,. Labuschagne, C.F. Brenkman, A.B.Ageing Res. Rev.,,. Tipping, M. Perrimon, N.J. Cell Physiol.,,. Musselman, L.P., Fink, J.L., Narzinski, K., Ramachandran, P. V., Hathiramani, S.S., Cagan, R.L., Baranski, T.J. Dis. Model Mech.,,. Rudrapatna, V.A., Cagan, R.L., Das, T.K.Dev. Dyn.,,. Hirabayashi, S., Baranski, T.J., Cagan, R.L.Cell,,. Kurokawa, K., Kaito, C., Sekimizu, K.Methods Enzymol.,,. Kaito, C., Akimitsu, N., Watanabe, H., Sekimizu, K. Microb. Pathog.,,. Hamamoto, H., Kurokawa, K., Kaito, C., Kamura, K., Razanajatovo, I.M., Kusuhara, H., Santa, T., Sekimizu, K. Antimicrob. Agents Chemother.,,. Matsumoto, Y., Miyazaki, S., Fukunaga, D.H., Shimizu, K., Kawamoto, S., Sekimizu, K.J. Appl. Microbiol.,,. Orihara, Y., Hamamoto, H., Kasuga, H., Shimada, T., Kawaguchi, Y., Sekimizu, K.J. Gen. Virol.,,. Hamamoto, H., Tonoike, A., Narushima, K., Horie, R., Sekimizu, K. Comp. Biochem. Physiol. C Toxicol. Pharmacol.,,. Satake, S., Kawabe, Y., Mizoguchi, A.Arch. Insect Biochem. Physiol.,,. Horie, Y.Nature,,. Yamashita, O., Sumida, M., Hasegawa, K.J. Insect Physiol.,,. Matsumoto, Y., Sumiya, E., Sugita, T., Sekimizu, K. PLoS ONE,, e. Ohkubo, Y., Kishikawa, H., Araki, E., Miyata, T., Isami, S., Motoyoshi, S., Kojima, Y., Furuyoshi, N., Shichiri, M. Diabetes Res. Clin. Pract.,,. Miura, J., Yamagishi, S., Uchigata, Y., Takeuchi, M., Yamamoto, H., Makita, Z., Iwamoto, Y.J. Diabetes Complications,,. Coughlan, M.T., Mibus, A.L., Forbes, J.M.Ann. N. Y. Acad. Sci.,,. Yamamoto, Y., Kato, I., Doi, T., Yonekura, H., Ohashi, S., Takeuchi, M., Watanabe, T., Yamagishi, S., Sakurai, S., Takasawa, S., Okamoto, H., Yamamoto, H.J. Clin. Invest.,,. Stadler, K., Jenei, V., Somogyi, A., Jakus, J.Diabetes Metab. Res. Rev.,,. Soulis, T., Cooper, M.E., Sastra, S., Thallas, V., Panagiotopoulos, S., Bjerrum, O.J., Jerums, G.Diabetologia,,. Nagata, S., Hakuno, F., Takahashi, S., Nagasawa, H. Comp. Biochem. Physiol. B Biochem. Mol. Biol.,,. Summers SA, Yin VP, Whiteman EL, Garza LA, Cho H, Tuttle, R.L., Birnbaum, M.J.Ann. N.Y. Acad. Sci.,,. Merrill, G.F., Kurth, E.J., Hardie, D.G., Winder, W.W. Am. J. Physiol.,, E E. http: bisei

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2007050781......_.L.O...z.W a s d f g a s d f g h j k l 0 in vitro in vivo in vitro in vivo in vivo in vivo in vitro Metabolism Metabolism Endocr Endocr Endocrinol Ann NYA cad Sci J clin Endocr Metab