title: Identification of putative biomarkers for prediabetes by metabolome analysis of rat models of type 2 diabetes.
abstract: Biomarkers for the development of type 2 diabetes (T2D) are useful for prediction and intervention of the disease at earlier stages. In this study, we performed a longitudinal study of changes in metabolites using an animal model of T2D, the spontaneously diabetic Torii (SDT) rat. Fasting plasma samples of SDT and control Sprague-Dawley (SD) rats were collected from 6 to 24 weeks of age, and subjected to gas chromatography-mass spectrometry-based metabolome analysis. Fifty-nine hydrophilic metabolites were detected in plasma samples, including amino acids, carbohydrates, sugars and organic acids. At 12 weeks of age, just before the onset of diabetes in SDT rats, the amounts of nine of these metabolites (asparagine, glutamine, glycerol, kynurenine, mannose, n-alpha-acetyllysine, taurine, threonine, and tryptophan) in SDT rats were significantly different from those in SD rats. In particular, metabolites in the tryptophan metabolism pathway (tryptophan and kynurenine) were decreased in SDT rats at 12 weeks of age and later. The lower tryptophan and kynurenine levels in the prediabetic state and later were further confirmed by a replication study on SDT rats and by a longitudinal study on another animal model of T2D, the Otsuka Long-Evans Tokushima Fatty rat. Our data indicate that tryptophan and its metabolites are potential biomarkers for prediabetes and that tryptophan metabolism may be a potential target of intervention for treatment of the disease.
authors.affiliation: Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan.
authors.forename: Norihide
authors.initials: N
authors.lastname: Yokoi
authors.affiliation: Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan ; Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, 650-0017 Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Beppu
authors.affiliation: Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, 650-0017 Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Yoshida
authors.affiliation: Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Hoshikawa
authors.affiliation: Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan.
authors.forename: Shihomi
authors.initials: S
authors.lastname: Hidaka
authors.affiliation: Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan ; Life Science Research Center, Technology Research Laboratory, Shimadzu Corporation, Kyoto, 619-0237 Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Matsubara
authors.affiliation: Tokyo Animal and Diet Department, CLEA Japan, Inc., Meguro-ku, Tokyo, 153-8533 Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, 650-0017 Japan ; Division of Evidenced-based Laboratory Medicine, Kobe University Graduate School of Medicine, Kobe, 650-0017 Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Irino
authors.affiliation: The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, 650-0017 Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Hatano
authors.affiliation: Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan ; Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, 650-0017 Japan ; The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, 650-0017 Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
keywords: Longitudinal study; Metabolomics; Plasma biomarkers; Rat models; Tryptophan; Type 2 diabetes