Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes
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Open Access
- 1 August 2001
- journal article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 15 (15) , 1926-1934
- https://doi.org/10.1101/gad.908001
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.Keywords
This publication has 33 references indexed in Scilit:
- Loss of Insulin Signaling in Hepatocytes Leads to Severe Insulin Resistance and Progressive Hepatic DysfunctionMolecular Cell, 2000
- Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscleJournal of Clinical Investigation, 2000
- Exercise modulates postreceptor insulin signaling and glucose transport in muscle-specific insulin receptor knockout miceJournal of Clinical Investigation, 1999
- Tissue-Specific Knockout of the Insulin Receptor in Pancreatic β Cells Creates an Insulin Secretory Defect Similar to that in Type 2 DiabetesCell, 1999
- Troglitazone action is independent of adipose tissue.Journal of Clinical Investigation, 1997
- Increased expression of insulin/insulin-like growth factor-I hybrid receptors in skeletal muscle of noninsulin-dependent diabetes mellitus subjects.Journal of Clinical Investigation, 1996
- Early neonatal death in mice homozygous for a null allele of the insulin receptor geneNature Genetics, 1996
- Insulin/IGF-I receptor hybrids: A mechanism for increasing receptor diversityJournal of Cellular Biochemistry, 1992
- Insulin/IGF-1 hybrid receptors: Implications for the dominant-negative phenotype in syndromes of insulin resistanceJournal of Cellular Biochemistry, 1992
- Quantitation of Muscle Glycogen Synthesis in Normal Subjects and Subjects with Non-Insulin-Dependent Diabetes by13C Nuclear Magnetic Resonance SpectroscopyNew England Journal of Medicine, 1990