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

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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.

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Figure 1: Accumulation of p27 in beta cells of diabetic mice.
Figure 2: Induction of diabetes by overexpression of p27 in mouse beta cells.
Figure 3: Improvement in glucose metabolism induced by Cdkn1b disruption in Irs2−/− and Lepr−/− mice.
Figure 4: Effects of Cdkn1b deletion on islet characteristics.
Figure 5: IGF-1 and leptin signaling promote nuclear exclusion of p27 in beta cells.

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Acknowledgements

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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Correspondence to Masato Kasuga.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Expression of p21Cip1 in islets of Irs2−/− and Lepr−/− mice. (PDF 162 kb)

Supplementary Fig. 2

Detection of phosphorylated p27. (PDF 79 kb)

Supplementary Fig. 3

Decreased Pcna-positive β cells in RIP-p27 mice. (PDF 580 kb)

Supplementary Fig. 4

The effect of p27 deletion on apoptosis in the islets of Lepr−/− mice. (PDF 735 kb)

Supplementary Fig. 5

The effect of p27 on apoptosis in Min6 insulinoma cells. (PDF 203 kb)

Supplementary Fig. 6

Deletion of p27 increases Pcna-positive β cells in Irs2−/− mice. (PDF 673 kb)

Supplementary Fig. 7

Igf-1 and leptin each induce Akt activation in Min6 cells. (PDF 123 kb)

Supplementary Fig. 8

p27 mRNA is not increased in the islets of diabetic mice. (PDF 33 kb)

Supplementary Fig. 9

Deletion of p27 does not affect insulin resistance in Irs2−/− mice (PDF 122 kb)

Supplementary Fig. 10

Abundance of p27 in various tissues of Lepr−/− or Lepr+/− mice. (PDF 319 kb)

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