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

2001; Cold Spring Harbor Laboratory Press; Volume: 15; Issue: 15 Linguagem: Inglês

10.1101/gad.908001

1549-5477

Ana M. Fernández, Jason K. Kim, Shoshana Yakar, Joëlle Dupont, Catalina Hernández‐Sánchez, Arthur L. Castle, Jonathan Filmore, Gerald I. Shulman, Derek Le Roith,

Pancreatic function and 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 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.