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

A. M. Fernández, J. K. Kim, S. Yakar, J. Dupont, C. Hernandez-Sanchez, A. L. Castle, J. Filmore, G. I. Shulman, D. Le Roith

Research output: Contribution to journalArticlepeer-review

318 Scopus citations


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.

Original languageEnglish
Pages (from-to)1926-1934
Number of pages9
JournalGenes and Development
Issue number15
StatePublished - 1 Aug 2001
Externally publishedYes


  • Dominant-negative
  • IGF-I receptor
  • Insulin receptor
  • Skeletal muscle
  • Transgenic
  • Type 2 diabetes


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