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Rev Diabet Stud, 2005, 2(2):75-83 DOI 10.1900/RDS.2005.2.75

Increased Transcriptional Preproinsulin II β-Cell Activity in Neonatal Nonobese Diabetic Mice: In Situ Hybridization Analysis

Marc Throsby1, Josiane Coulaud2, Sylvie Durant3, Francoise Homo-Delarche2

1Crucell Holland B.V., Leiden 2301 CA, The Netherlands.
2CNRS UMR 7059, Paris 7 University, 75005 Paris, France.
3INSERM U530, Centre Universitaire-UFR Biomédicale, 75006 Paris, France.
Address correspondence to: Francoise Homo-Delarche, e-mail: francoise.homo-delarche@paris7.jussieu.fr.

Keywords: NOD neonates, preproinsulin II, in situ hybridization, maternal insulin treatment

Abstract

In the prediabetic nonobese diabetic (NOD) mouse, a spontaneous model of type 1 diabetes, we previously reported transient postweaning hyperinsulinemia followed by progressive islet hyperplasia. A modified in situ hybridization technique was used to determine whether these effects were accompanied by changes in insulin transcriptional activity as a function of age. We found that NOD neonates express higher levels of preproinsulin II primary transcripts than age-matched C57BL/6 mice, but this difference disappeared within the first wk of age. To manipulate insulin transcriptional activity in NOD neonates, NOD mothers were treated with insulin during the last two wk of gestation. A down-regulation of β-cell hyperactivity was observed in female NOD neonates but not in male neonates. By contrast, the same insulin treatment applied to NODscid (severe combined immunodeficiency) mothers, devoid of functional lymphocytes but showing like NOD mice postweaning hyperinsulinemia, increased transcriptional β-cell activity in both sexes of neonates. In conclusion, NOD mice exhibit successive and transient signs of β-cell hyperactivity, reflected as early as birth by high transcriptional preproinsulin II activity and later, from weaning to around 10 wk of age, by hyperinsulinemia. Of note, when thinking in terms of in utero disease programming, the NOD neonatal transcriptional β-cell hyperactivity could be modulated by environmental (maternal and/or fetal) factors.

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