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

• 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
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.908001

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.