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Article
Nature Medicine  11, 175 - 182 (2005)
Published online: 30 January 2005; | doi:10.1038/nm1187

Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice

Tohru Uchida1, 5, Takehiro Nakamura1, 5, Naoko Hashimoto1, Tomokazu Matsuda1, Ko Kotani1, Hiroshi Sakaue1, Yoshiaki Kido1, Yoshitake Hayashi2, Keiichi I Nakayama3, Morris F White4 & Masato Kasuga1

1  Division of Diabetes and Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.

2  Division of Molecular Medicine and Medical Genetics, International Center for Medical Research, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.

3  Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.

4  Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

5  These authors contributed equally to this work.

Correspondence should be addressed to Masato Kasuga kasuga@med.kobe-u.ac.jp
The protein p27Kip1 regulates cell cycle progression in mammals by inhibiting the activity of cyclin-dependent kinases (CDKs). Here we show that p27Kip1 progressively accumulates in the nucleus of pancreatic beta cells in mice that lack either insulin receptor substrate 2 (Irs2-/-) or the long form of the leptin receptor (Lepr-/- or db/db). Deletion of the gene encoding p27Kip1 (Cdkn1b) ameliorated hyperglycemia in these animal models of type 2 diabetes mellitus by increasing islet mass and maintaining compensatory hyperinsulinemia, effects that were attributable predominantly to stimulation of pancreatic beta-cell proliferation. Thus, p27Kip1 contributes to beta-cell failure during the development of type 2 diabetes in Irs2-/- and Lepr-/- mice and represents a potential new target for the treatment of this condition.

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Nature Medicine
ISSN: 1078-8956
EISSN: 1546-170X
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