Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes
- Ana M. Fernández1,
- Jason K. Kim3,
- Shoshana Yakar1,
- Joëlle Dupont1,
- Catalina Hernandez-Sanchez1,
- Arthur L. Castle2,
- Jonathan Filmore4,
- Gerald I. Shulman3,4, and
- Derek Le Roith1,5
- 1Clinical Endocrinology Branch and 2Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, Maryland 20892, USA; 3Howard Hughes Medical Institute and the 4Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA
Abstract
Peripheral insulin resistance and impaired insulin action are the primary characteristics of type 2 diabetes. The first observable defect in this major disorder occurs in muscle, where glucose disposal in response to insulin is impaired. We have developed a transgenic mouse with a dominant-negative insulin-like growth factor-I receptor (KR–IGF-IR) specifically targeted to the skeletal muscle. Expression of KR–IGF-IR resulted in the formation of hybrid receptors between the mutant and the endogenous IGF-I and insulin receptors, thereby abrogating the normal function of these receptors and leading to insulin resistance. Pancreatic β-cell dysfunction developed at a relative early age, resulting in diabetes. These mice provide an excellent model to study the molecular mechanisms underlying the development of human type 2 diabetes.
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Footnotes
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↵5 Corresponding author.
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E-MAIL Derek{at}helix.nih.gov; FAX (301) 480-4386.
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.908001.
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- Received April 30, 2001.
- Accepted June 14, 2001.
- Cold Spring Harbor Laboratory Press
