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Originally published In Press as doi:10.1074/jbc.M005119200 on August 21, 2000

J. Biol. Chem., Vol. 275, Issue 44, 34471-34477, November 3, 2000
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Sustained Expression of Exendin-4 Does Not Perturb Glucose Homeostasis, beta -Cell Mass, or Food Intake in Metallothionein-Preproexendin Transgenic Mice*

Laurie BaggioDagger §, Feisal Adatia, Troels Bock||, Patricia L. Brubaker**, and Daniel J. Drucker**Dagger Dagger

From the Departments of Dagger  Laboratory Medicine and Pathobiology, ** Medicine, and  Physiology, Toronto General Hospital, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario M5G 2C4, Canada and the || Bartholin Instituttet, Kobenhavns Kommunehospital, Copenhagen, Denmark

Activation of glucagon-like peptide (GLP)-1 receptor signaling promotes glucose lowering via multiple mechanisms, including regulation of food intake, glucose-dependent insulin secretion, and stimulation of beta -cell mass. As GLP-1 exhibits a short t1/2 in vivo, the biological consequences of prolonged GLP-1 receptor signaling remains unclear. To address this question, we have now generated metallothionein promoter-preproexendin (MT-Ex) transgenic mice. MT-Ex mice process preproexendin correctly, as is made evident by detection of circulating plasma exendin-4 immunoreactivity using high pressure liquid chromatography and an exendin-4-specific radioimmunoassay. Despite elevated levels of exendin-4, fasting plasma glucose and glucose clearance following oral and intraperitoneal glucose tolerance tests are normal in MT-Ex mice. Induction of transgene expression significantly reduced glycemic excursion during both oral and intraperitoneal glucose tolerance tests (p < 0.05) and increased levels of glucose-stimulated insulin following oral glucose administration (p < 0.05). Despite evidence that exendin-4 may induce beta -cell proliferation, beta -cell mass and islet histology were normal in MT-Ex mice. MT-Ex mice exhibited no differences in basal food intake or body weight; however, induction of exendin-4 expression was associated with reduced short term food ingestion (p < 0.05). In contrast, short term water intake was significantly reduced in the absence of zinc in fluid-restricted MT-Ex mice (p < 0.05). These findings illustrate that sustained elevation of circulating exendin-4 is not invariably associated with changes in glucose homeostasis, increased beta -cell mass, or reduction in food intake in mice in vivo.

* This work was supported in part by grants from the Canadian Diabetes Association (to P. L. B. and D. J. D.) and the Juvenile Diabetes Foundation International (to D. J. D.).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.

§ Supported by a studentship award from the Medical Research Council of Canada.

Dagger Dagger Senior Scientist of the Medical Research Council of Canada and a member of the Scientific Advisory Board of Amylin Pharmaceuticals Inc. To whom correspondence should be addressed: Toronto General Hospital, 101 College St., CCRW3-845, Toronto M5G 2C4, Ontario, Canada. Tel.: 416-340-4125; Fax: 416-978-4108; E-mail: d.drucker@utoronto.ca.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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