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

Tohru Uchida; Takehiro Nakamura; Naoko Hashimoto; Tomokazu Matsuda; Ko Kotani; Hiroshi Sakaue; Yoshiaki Kido; Yoshitake Hayashi; Keiichi I. Nakayama; Morris F. White; Masato Kasuga

doi:10.1038/nm1187

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

Tohru Uchida, Takehiro Nakamura, Naoko Hashimoto, Tomokazu Matsuda, Ko Kotani, Hiroshi Sakaue, Yoshiaki Kido, Yoshitake Hayashi, Keiichi I. Nakayama, Morris F. White, Masato Kasuga

Department of Molecular and Cellular Biology

Research output: Contribution to journal › Article › peer-review

178 Citations (Scopus)

Abstract

The protein p27Kip1 regulates cell cycle progression in mammals by inhibiting the activity of cyclin-dependent kinases (CDKs). Here we show that p27^Kip1 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 p27^Kip1 (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, p27^Kip1 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.

Original language	English
Pages (from-to)	175-182
Number of pages	8
Journal	Nature medicine
Volume	11
Issue number	2
DOIs	https://doi.org/10.1038/nm1187
Publication status	Published - Feb 2005

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Biochemistry, Genetics and Molecular Biology(all)

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title = "Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice",

abstract = "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.",

author = "Tohru Uchida and Takehiro Nakamura and Naoko Hashimoto and Tomokazu Matsuda and Ko Kotani and Hiroshi Sakaue and Yoshiaki Kido and Yoshitake Hayashi and Nakayama, {Keiichi I.} and White, {Morris F.} and Masato Kasuga",

note = "Funding Information: We thank M. Kawasaki, K. Satomura, M. Nagano and K. Kakinoki for technical assistance. This work was supported by grants for the Intellectual Cluster Formation Project and the 21st Century Center of Excellence Program “Center of Excellence for Signal Transduction Disease: Diabetes Mellitus as a Model” from the Ministry of Education, Culture, Sports, Science and Technology of Japan to M.K.",

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doi = "10.1038/nm1187",

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T1 - Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice

AU - Uchida, Tohru

AU - Nakamura, Takehiro

AU - Hashimoto, Naoko

AU - Matsuda, Tomokazu

AU - Kotani, Ko

AU - Sakaue, Hiroshi

AU - Kido, Yoshiaki

AU - Hayashi, Yoshitake

AU - Nakayama, Keiichi I.

AU - White, Morris F.

AU - Kasuga, Masato

N1 - Funding Information: We thank M. Kawasaki, K. Satomura, M. Nagano and K. Kakinoki for technical assistance. This work was supported by grants for the Intellectual Cluster Formation Project and the 21st Century Center of Excellence Program “Center of Excellence for Signal Transduction Disease: Diabetes Mellitus as a Model” from the Ministry of Education, Culture, Sports, Science and Technology of Japan to M.K.

PY - 2005/2

Y1 - 2005/2

N2 - 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.

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

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