Pdx1 expression in Irs2-deficient mouse beta-cells is regulated in a strain-dependent manner.

Suzuki R, Tobe K, Terauchi Y, Komeda K, Kubota N, Eto K, Yamauchi T, Azuma K, Kaneto H, Taguchi T, Koga T, German MS, Watada H, Kawamori R, Wright CV, Kajimoto Y, Kimura S, Nagai R, Kadowaki T
J Biol Chem. 2003 278 (44): 43691-8

PMID: 12869553 · DOI:10.1074/jbc.M307004200

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.

MeSH Terms (25)

Animal Feed Animals Blotting, Western Down-Regulation Female Gene Expression Regulation Glucose Homeodomain Proteins Hypoglycemia Immunohistochemistry Insulin Insulin Receptor Substrate Proteins Insulin Secretion Intracellular Signaling Peptides and Proteins Islets of Langerhans Male Mice Mice, Inbred C57BL Mice, Transgenic Phosphoproteins Reverse Transcriptase Polymerase Chain Reaction RNA Species Specificity Time Factors Trans-Activators

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