title: Pdx1 expression in Irs2-deficient mouse beta-cells is regulated in a strain-dependent manner.
abstract: We previously demonstrated that Irs2-/- mice develop diabetes due to beta-cell growth failure and insulin resistance; however, glucose-induced insulin secretion was increased in islets isolated from Irs2-/- mice. Pdx-1, a transcription factor important for maintenance of the beta-cell function, was recently reported to be severely reduced in Irs2-/- murine beta-cells. We report herein that Pdx-1 expression, including the amount of Pdx-1 localized in the nucleus, is not down-regulated in our Irs2-/- murine beta-cells with a C57BL/6 background. We have also demonstrated the expression of upstream genes of Pdx-1, such as HNF3beta and HNF1alpha, as well as its downstream genes, including insulin, Glut2, and Nkx6.1, to be well preserved. We have further demonstrated Pdx-1 expression to also be preserved in beta-cells of 30-week-old diabetic Irs2-/- mice. In addition, surprisingly, even in Irs2-/- mice on a high fat diet with markedly elevated blood glucose, exceeding 400 mg/dl, Pdx-1 expression was not reduced. Furthermore, we found Pdx-1 to be markedly decreased in certain severely diabetic Irs2-/- mice with a mixed C57BL/6J x 129Sv background. We conclude that 1) Pdx-1 expression in Irs2-/- mice is regulated in a strain-dependent manner, 2) Irs2-/- mice develop diabetes associated with beta-cell growth failure even when Pdx1 expression is preserved, and 3) Pdx-1 expression is preserved in severely hyperglycemic Irs2-/- mice with a C57BL/6 background on a high fat diet.
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Kajuro
authors.initials: K
authors.lastname: Komeda
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Eto
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Kousuke
authors.initials: K
authors.lastname: Azuma
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kaneto
authors.forename: Takashi
authors.initials: T
authors.lastname: Taguchi
authors.forename: Teiichiro
authors.initials: T
authors.lastname: Koga
authors.forename: Michael S
authors.initials: MS
authors.lastname: German
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Watada
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Kawamori
authors.forename: Christopher V E
authors.initials: CV
authors.lastname: Wright
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kajimoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kimura
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000821:Animal Feed; D000818:Animals; D015153:Blotting, Western; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D007003:Hypoglycemia / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D000078790:Insulin Secretion; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D013997:Time Factors; D015534:Trans-Activators / Q000096:biosynthesis* / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; C491328:Nkx6-1 protein, mouse; D010750:Phosphoproteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D012313:RNA; D005947:Glucose