Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory β-cell hyperplasia

Naoto Kubota, Kazuyuki Tobe, Yasuo Terauchi, Kazuhiro Eto, Toshimasa Yamauchi, Ryo Suzuki, Yoshiharu Tsubamoto, Kajuro Komeda, Ryosuke Nakano, Hiroshi Miki, Shinobu Satoh, Hisahiko Sekihara, Salvatore Sciacchitano, Maxine Lesniak, Shinichi Aizawa, Ryozo Nagai, Satoshi Kimura, Yasuo Akanuma, Simeon I. Taylor, Takashi Kadowaki*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

451 Scopus citations

Abstract

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 β-cells was reduced to 83% of that in wild-type mice, which was in marked contrast to the 85% increase in the amount of β-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 β-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 β-cell mass and the function of individual β-cells.

Original languageEnglish
Pages (from-to)1880-1889
Number of pages10
JournalDiabetes
Volume49
Issue number11
DOIs
StatePublished - 2000

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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