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J. Biol. Chem., Vol. 279, Issue 24, 25039-25049, June 11, 2004

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Both Insulin Signaling Defects in the Liver and Obesity Contribute to Insulin Resistance and Cause Diabetes in Irs2^–/– Mice^*

Ryo Suzuki, Kazuyuki Tobe, Masashi Aoyama, Atsushi Inoue, Kentaro Sakamoto, Toshimasa Yamauchi, Junji Kamon, Naoto Kubota, Yasuo Terauchi, Hironobu Yoshimatsu¶, Munehide Matsuhisa||, Shoichiro Nagasaka**, Hitomi Ogata, Kumpei Tokuyama, Ryozo Nagai, and Takashi Kadowaki

From the Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Corporation, Kawaguchi 332-0012, the ^¶Department of Internal Medicine, School of Medicine, Oita Medical University, Oita 879-5593, the ^||Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita 565-0871, the ^**Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical School, Minamikawachi 329-0498, and the Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-8577, Japan

We previously reported that insulin receptor substrate-2 (IRS-2)-deficient mice develop diabetes as a result of insulin resistance in the liver and failure of -cell hyperplasia. In this study we introduced the IRS-2 gene specifically into the liver of Irs2^–/– mice with adenovirus vectors. Glucose tolerance tests revealed that the IRS-2 restoration in the liver ameliorated the hyperglycemia, but the improvement in hyperinsulinemia was only partial. Endogenous glucose production (EGP) and the rate of glucose disappearance (Rd) were measured during hyperinsulinemic-euglycemic clamp studies: EGP was increased 2-fold in the Irs2^–/– mice, while Rd decreased by 50%. Restoration of IRS-2 in the liver suppressed EGP to a level similar to that in wild-type mice, but Rd remained decreased in the Adeno-IRS-2-infected Irs2^–/– mice. Irs2^–/– mice also exhibit obesity and hyperleptinemia associated with impairment of hypothalamic phosphatidylinositol 3-kinase activation. Continuous intracerebroventricular leptin infusion or caloric restriction yielded Irs2^–/– mice whose adiposity was comparable to that of Irs2^+/+ mice, and both the hyperglycemia and the hyperinsulinemia of these mice improved with increased Rd albeit partially. Finally combination treatment consisting of adenovirus-mediated gene transfer of IRS-2 and continuous intracerebroventricular leptin infusion completely reversed the hyperglycemia and hyperinsulinemia in Irs2^–/– mice. EGP and Rd also became normal in these mice as well as in mice treated by caloric restriction plus adenoviral gene transfer. We therefore concluded that a combination of increased EGP due to insulin signaling defects in the liver and reduced Rd due to obesity accounts for the systemic insulin resistance in Irs2^–/– mice.

Received for publication, October 31, 2003 , and in revised form, March 1, 2004.

^* This work was supported by a grant-in-aid for the development of innovative technology and a grant-in-aid for creative basic research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to T. K. and K. T.) and by Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research (to T. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel.: 81-3-5800-8818; Fax: 81-3-5689-7209; E-mail: kadowaki-3im{at}h.u-tokyo.ac.jp.

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