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Insulin receptor substrate 2 plays a crucial role in β cells and the hypothalamus
Naoto Kubota, … , Takashi Kadowaki, Tetsuo Noda
Naoto Kubota, … , Takashi Kadowaki, Tetsuo Noda
Published October 1, 2004
Citation Information: J Clin Invest. 2004;114(7):917-927. https://doi.org/10.1172/JCI21484.
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Article Metabolism

Insulin receptor substrate 2 plays a crucial role in β cells and the hypothalamus

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Abstract

We previously demonstrated that insulin receptor substrate 2 (Irs2) KO mice develop diabetes associated with hepatic insulin resistance, lack of compensatory β cell hyperplasia, and leptin resistance. To more precisely determine the roles of Irs2 in β cells and the hypothalamus, we generated β cell–specific Irs2 KO and hypothalamus-specific Irs2 knockdown (βHT-IRS2) mice. Expression of Irs2 mRNA was reduced by approximately 90% in pancreatic islets and was markedly reduced in the arcuate nucleus of the hypothalamus. By contrast, Irs2 expression in liver, muscle, and adipose tissue of βHT-IRS2 mice was indistinguishable from that of control mice. The βHT-IRS2 mice displayed obesity and leptin resistance. At 4 weeks of age, the βHT-IRS2 mice showed normal insulin sensitivity, but at 8 and 12 weeks, they were insulin resistant with progressive obesity. Despite their normal insulin sensitivity at 8 weeks with caloric restriction, the βHT-IRS2 mice exhibited glucose intolerance and impaired glucose-induced insulin secretion. β Cell mass and β cell proliferation in the βHT-IRS2 mice were reduced significantly at 8 and 12 weeks but not at 10 days. Insulin secretion, normalized by cell number per islet, was significantly increased at high glucose concentrations in the βHT-IRS2 mice. We conclude that, in β cells and the hypothalamus, Irs2 is crucially involved in the regulation of β cell mass and leptin sensitivity.

Authors

Naoto Kubota, Yasuo Terauchi, Kazuyuki Tobe, Wataru Yano, Ryo Suzuki, Kohjiro Ueki, Iseki Takamoto, Hidemi Satoh, Toshiyuki Maki, Tetsuya Kubota, Masao Moroi, Miki Okada-Iwabu, Osamu Ezaki, Ryozo Nagai, Yoichi Ueta, Takashi Kadowaki, Tetsuo Noda

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Figure 7

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Normal expression of Pdx1, normal insulin contents and increased insulin...
Normal expression of Pdx1, normal insulin contents and increased insulin secretion in βHT-IRS2 mice. (A) Immunohistochemical study of Pdx1 in control and βHT-IRS2 mice at 8 weeks (left panels) and at 12 weeks (right panels). Representative islets viewed on a computer monitor are shown. Original magnification ×100 (upper panels); ×200 (lower panels). (B) Taqman PCR analysis of Pdx1, Hnf1α, Hnf4α, and Foxo1 mRNA levels, normalized to β-actin mRNA levels in control (black bars) and βHT-IRS2 mice (white bars) at 8 weeks (left) and at 12 weeks (right). (C) Insulin secretion per islet (left) and insulin secretion normalized by cell number per islet (right) during static incubation of islets from control and βHT-IRS2 mice for 1 hour at the glucose levels indicated. Values are expressed as means ± SE (n = 5). Data were obtained in 3 independent experiments. (D) Insulin content per islet (left) and insulin content normalized by cell number per islet (right) in control and βHT-IRS2 mice. Values are expressed as means ± SE (n = 5). Data were obtained in 3 independent experiments. (E) Insulin secretion per islet during static incubation of islets from control and βHT-IRS2 mice for 1 hour at the glucose levels indicated with and without LY294002 (LY). Data were obtained in 3 independent experiments. *P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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