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Originally published In Press as doi:10.1074/jbc.M206314200 on July 5, 2002

J. Biol. Chem., Vol. 277, Issue 39, 36740-36747, September 27, 2002
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Effects of Mutations in the Insulin-like Growth Factor Signaling System on Embryonic Pancreas Development and beta -Cell Compensation to Insulin Resistance*

Yoshiaki KidoDagger §, Jun NakaeDagger , Marta Letizia HribalDagger , Shouhong Xuan, Argiris Efstratiadis, and Domenico AcciliDagger ||

From the Dagger  Department of Medicine and the  Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, New York 10032

Insulin and insulin-like growth factors (IGF) play overlapping and complementary roles in pancreatic beta -cell function and peripheral metabolism. In this study, we have analyzed mice bearing loss-of-function mutations of the insulin/IGF signaling systems. Combined inactivation of insulin receptor (Insr) and Igf1 receptor (Igf1r), but not of either receptor alone, resulted in a 90% decrease in the size of the exocrine pancreas, because of decreased cellular proliferation. In contrast to the findings in the exocrine compartment, endocrine alpha - and beta -cell development was unperturbed. Combined ablation of Igf1 and Igf2, the ligands for these two receptors, resulted in an identical phenotype. We also examined the effect of heterozygous null Igf1r mutations on glucose homeostasis in adult mice. Igf1r haploinsufficiency did not affect insulin action and compensatory beta -cell growth in insulin-resistant mice with combined Insr and Igf1r heterozygous null mutations, resulting in a considerably milder phenotype than combined haploinsufficiency for Insr and its main signaling substrates, Irs1 and Irs2. We conclude that Igf1r and Insr are required for embryonic development of the exocrine but not of the endocrine pancreas and that defects of Igf1r do not alter glucose homeostasis as long as the insulin receptor system remains intact.

* This work was supported by National Institutes of Health Grants DK58282 and DK57539 (to D. A.) and Juvenile Diabetes Research Foundation Grant 893 (to D. A. and A. E.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Present address: Second Dept. of Internal Medicine, Kobe University School of Medicine, Kobe 650-0017, Japan.

|| To whom correspondence should be addressed: Berrie Research Pavilion, 1150 St. Nicholas Ave., Rm. 238, New York, NY 10032. Tel.: 212-851-5332; Fax: 212-851-5331; E-mail: da230@columbia.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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