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Originally published In Press as doi:10.1074/jbc.M202037200 on March 7, 2002

J. Biol. Chem., Vol. 277, Issue 20, 17677-17686, May 17, 2002
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Mice Deficient in the Insulin-regulated Membrane Aminopeptidase Show Substantial Decreases in Glucose Transporter GLUT4 Levels but Maintain Normal Glucose Homeostasis*

Susanna R. KellerDagger §, Ann C. Davis, and Kevin B. Clairmont

From the Dagger  University of Virginia, Department of Internal Medicine/Division of Endocrinology, Charlottesville, Virginia 22908 and the  Department of Metabolic Disorders Research, Bayer Corporation/Pharmaceutical Division, West Haven, Connecticut 06516

The insulin-regulated aminopeptidase (IRAP) is a zinc-dependent membrane aminopeptidase. It is the homologue of the human placental leucine aminopeptidase. In fat and muscle cells, IRAP colocalizes with the insulin-responsive glucose transporter GLUT4 in intracellular vesicles and redistributes to the cell surface in response to insulin, as GLUT4 does. To address the question of the physiological function of IRAP, we generated mice with a targeted disruption of the IRAP gene (IRAP-/-). Herein, we describe the characterization of these mice with regard to glucose homeostasis and regulation of GLUT4. Fed and fasted blood glucose and insulin levels in the IRAP-/- mice were normal. Whereas IRAP-/- mice responded to glucose administration like control mice, they exhibited an impaired response to insulin. Basal and insulin-stimulated glucose uptake in extensor digitorum longus muscle, and adipocytes isolated from IRAP-/- mice were decreased by 30-60% but were normal for soleus muscle from male IRAP-/- mice. Total GLUT4 levels were diminished by 40-85% in the IRAP-/- mice in the different muscles and in adipocytes. The relative distribution of GLUT4 in subcellular fractions of basal and insulin-stimulated IRAP-/- adipocytes was the same as in control cells. We conclude that IRAP-/- mice maintain normal glucose homeostasis despite decreased glucose uptake into muscle and fat cells. The absence of IRAP does not affect the subcellular distribution of GLUT4 in adipocytes. However, it leads to substantial decreases in GLUT4 expression.

* This work was supported by National Institutes of Health Grants DK25336 (to G. E. L.) and DK58051 (to S. R. K.).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.

§ To whom correspondence should be addressed: University of Virginia, Dept. of Internal Medicine-Division of Endocrinology, MR4 Bldg., Rm. 5147, Lane Rd., P.O. Box 801405, Charlottesville, VA 22908. Tel.: 434-243-5780; Fax: 434-924-9730; E-mail: srk4b@virginia.edu.

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