To investigate the role of insulin receptor substrate (IRS)-2 in vivo, we generated IRS-2-deficient mice by gene targeting. Although homozygous IRS-2-deficient mice (IRS-2-/- mice) had a body weight similar to wild-type mice, they progressively developed type 2 diabetes at 10 weeks. IRS-2-/- mice showed insulin resistance and a defect in the insulin-stimulated signaling pathway in liver but not in skeletal muscle. Despite insulin resistance, the amount of beta-cells was reduced to 83% of that in wild-type mice, which was in marked contrast to the 85% increase in the amount of beta-cells in IRS-1-deficient mice (IRS-1-/- mice) to compensate for insulin resistance. Thus, IRS-2 plays a crucial role in the regulation of beta-cell mass. On the other hand, insulin secretion by the same number of cells in response to glucose measured ex vivo was significantly increased in IRS-2-/- mice compared with wild-type mice but was decreased in IRS-1-/- mice. These results suggest that IRS-1 and IRS-2 may play different roles in the regulation of beta-cell mass and the function of individual beta-cells.
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Abstract|
November 01 2000
Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia.
N Kubota;
N Kubota
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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K Tobe;
K Tobe
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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Y Terauchi;
Y Terauchi
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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K Eto;
K Eto
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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T Yamauchi;
T Yamauchi
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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R Suzuki;
R Suzuki
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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Y Tsubamoto;
Y Tsubamoto
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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K Komeda;
K Komeda
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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R Nakano;
R Nakano
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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H Miki;
H Miki
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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S Satoh;
S Satoh
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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H Sekihara;
H Sekihara
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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S Sciacchitano;
S Sciacchitano
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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M Lesniak;
M Lesniak
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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S Aizawa;
S Aizawa
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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R Nagai;
R Nagai
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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S Kimura;
S Kimura
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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Y Akanuma;
Y Akanuma
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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S I Taylor;
S I Taylor
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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T Kadowaki
T Kadowaki
Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
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Citation
N Kubota, K Tobe, Y Terauchi, K Eto, T Yamauchi, R Suzuki, Y Tsubamoto, K Komeda, R Nakano, H Miki, S Satoh, H Sekihara, S Sciacchitano, M Lesniak, S Aizawa, R Nagai, S Kimura, Y Akanuma, S I Taylor, T Kadowaki; Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia.. Diabetes 1 November 2000; 49 (11): 1880–1889. https://doi.org/10.2337/diabetes.49.11.1880
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