title: The tuberous sclerosis complex model Eker (TSC2+/-) rat exhibits hyperglycemia and hyperketonemia due to decreased glycolysis in the liver.
abstract: Tuberous sclerosis complex (TSC) presents as benign tumors that affect the brain, kidneys, lungs and skin. The inactivation of TSC2 gene, through loss of heterozygosity is responsible for tumor development in TSC. Since TSC patients are carriers of heterozygous a TSC2; mutation, to reveal the risk factors which these patients carry prior to tumor development is important. In this experiment, Eker rat which carry a mutation in this TSC2 gene were analyzed for their metabolic changes. Wild-type (TSC2+/+) and heterozygous mutant TSC2 (TSC2+/-) Eker rats were raised for 100 days. As a result, the Eker rats were found to exhibit hyperglycemia and hyperketonemia. However the high ketone body production in the liver was observed without accompanying increased levels of plasma free fatty acids or insulin. Further, production of the ketone body β-hydroxybutyrate was inhibited due to the low NADH/NAD(+) ratio resulting from the restraint on glycolysis, which was followed by inhibition of the malate-aspartate shuttle and TCA cycle. Therefore, we conclude that glycolysis is restrained in the livers of TSC2 heterozygous mutant rats, and these defects lead to abnormal production of acetoacetate.
authors.affiliation: Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo 156-8502, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Aizawa
authors.affiliation: Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo 156-8502, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Shirai
authors.affiliation: Department of Pathology and Oncology Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Pathology and Oncology Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Okio
authors.initials: O
authors.lastname: Hino
authors.affiliation: Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo 156-8502, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Tsujii
authors.affiliation: Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo 156-8502, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo 156-8502, Japan.
authors.forename: Machiko
authors.initials: M
authors.lastname: Kazami
authors.affiliation: Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo 156-8502, Japan.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Tadokoro
authors.affiliation: Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo 156-8502, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo 156-8502, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Kobayashi
authors.affiliation: Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo 156-8502, Japan. Electronic address: yujiya@nodai.ac.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D006019:Glycolysis; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism*; D007657:Ketone Bodies / Q000096:biosynthesis; D007662:Ketosis / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D055647:Rats, Transgenic; D014402:Tuberous Sclerosis / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D007657:Ketone Bodies; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
keywords: Glycolysis; Heterozygous mutant; Malate-aspartate shuttle; Metabolic signaling; Tuberous sclerosis complex