Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes

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...

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Bibliographic Details
Published in:	Genes & development Vol. 15; no. 15; pp. 1926 - 1934
Main Authors:	Fernández, A M, Kim, J K, Yakar, S, Dupont, J, Hernandez-Sanchez, C, Castle, A L, Filmore, J, Shulman, G I, Le Roith, D
Format:	Journal Article
Language:	English
Published:	United States Cold Spring Harbor Laboratory Press 01-08-2001
Subjects:	Aging Animals Blood Glucose - metabolism Diabetes Mellitus, Type 2 - blood Diabetes Mellitus, Type 2 - genetics Diabetes Mellitus, Type 2 - physiopathology Fatty Acids, Nonesterified - blood Glucose - metabolism Glucose Clamp Technique Humans Hyperinsulinism Insulin - metabolism Insulin - pharmacology insulin receptors Insulin Resistance - genetics Insulin Secretion Islets of Langerhans - metabolism Life Sciences Liver - metabolism Mice Mice, Transgenic Muscle, Skeletal - drug effects Muscle, Skeletal - metabolism Mutagenesis, Site-Directed Prediabetic State - blood Prediabetic State - genetics Prediabetic State - physiopathology Receptor, IGF Type 1 - genetics Receptor, IGF Type 1 - physiology Receptor, Insulin - genetics Receptor, Insulin - physiology Research Paper Triglycerides - blood Triglycerides - metabolism IGF-I receptor transgenic type 2 diabetes insulin receptor skeletal muscle dominant-negative
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Summary:	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 beta-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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 Corresponding author.
ISSN:	0890-9369 1549-5477
DOI:	10.1101/gad.908001