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 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.

[1]  Y. Kido,et al.  Impaired glucose tolerance in mice with a targeted impairment of insulin action in muscle and adipose tissue , 1998, Nature Genetics.

[2]  C. Roberts,et al.  Role of tyrosine kinase activity in signal transduction by the insulin-like growth factor-I (IGF-I) receptor. Characterization of kinase-deficient IGF-I receptors and the action of an IGF-I-mimetic antibody (alpha IR-3). , 1993, The Journal of biological chemistry.

[3]  C. Kahn,et al.  Exercise modulates postreceptor insulin signaling and glucose transport in muscle-specific insulin receptor knockout mice. , 1999, The Journal of clinical investigation.

[4]  S. Edén,et al.  Different effects of IGF-I on insulin-stimulated glucose uptake in adipose tissue and skeletal muscle. , 2000, American journal of physiology. Endocrinology and metabolism.

[5]  E. Ravussin,et al.  Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. , 1993, The New England journal of medicine.

[6]  A. Stenbit,et al.  Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4 , 1995, Nature.

[7]  C T Roberts,et al.  Molecular and cellular aspects of the insulin-like growth factor I receptor. , 1995, Endocrine reviews.

[8]  C. Kahn,et al.  Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. , 2000, Molecular cell.

[9]  S. Jacobs,et al.  Insulin/IGF‐I receptor hybrids: A mechanism for increasing receptor diversity , 1992, Journal of cellular biochemistry.

[10]  J. Treadway,et al.  Insulin/IGF‐1 hybrid receptors: Implications for the dominant‐negative phenotype in syndromes of insulin resistance , 1992, Journal of cellular biochemistry.

[11]  R G Shulman,et al.  Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. , 1990, The New England journal of medicine.

[12]  Y. Kido,et al.  Expression of kinase-inactive mutant insulin receptors does not rescue insulin receptor-deficient mice from perinatal death , 1999, Diabetologia.

[13]  C. Kahn,et al.  Tissue-Specific Knockout of the Insulin Receptor in Pancreatic β Cells Creates an Insulin Secretory Defect Similar to that in Type 2 Diabetes , 1999, Cell.

[14]  C. Kahn,et al.  Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle. , 2000, The Journal of clinical investigation.

[15]  B. Lamothe,et al.  Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality. , 1996, EMBO Journal.

[16]  E. Obberghen,et al.  Effect of IGF-I on Phosphatidylinositol 3-Kinase in Soleus Muscle of Lean and Insulin-Resistant Obese Mice , 1996, Diabetes.

[17]  C. R. Kahn,et al.  Genetics of non-insulin-dependent (type-II) diabetes mellitus. , 1996, Annual review of medicine.

[18]  G. Sesti,et al.  Increased expression of insulin/insulin-like growth factor-I hybrid receptors in skeletal muscle of noninsulin-dependent diabetes mellitus subjects. , 1996, The Journal of clinical investigation.

[19]  C. Kahn,et al.  Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance , 2000, Nature Medicine.

[20]  J. F. Caro,et al.  Insulin-Like Growth Factor-1 Therapy in Diabetes: Physiologic Basis, Clinical Benefits, and Risks , 1994, Annals of Internal Medicine.

[21]  D. Leroith,et al.  Normal growth and development in the absence of hepatic insulin-like growth factor I. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[22]  J. Dupont,et al.  Nutritional state regulates insulin receptor and IRS-1 phosphorylation and expression in chicken. , 1998, American journal of physiology. Endocrinology and metabolism.

[23]  G. Sesti,et al.  Expression of Insulin/IGF-I Hybrid Receptors Is Increased in Skeletal Muscle of Patients With Chronic Primary Hyperinsulinemia , 1998, Diabetes.

[24]  R. Jaenisch,et al.  A generic intron increases gene expression in transgenic mice , 1991, Molecular and cellular biology.

[25]  C. Roberts,et al.  TPA-induced neurite formation in a neuroblastoma cell line (SH-SY5Y) is associated with increased IGF-I receptor mRNA and binding. , 1989, Brain research. Molecular brain research.

[26]  C. Kahn,et al.  A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. , 1998, Molecular cell.

[27]  M. White,et al.  Insulin Receptor Substrate-2 Is Not Necessary for Insulin- and Exercise-stimulated Glucose Transport in Skeletal Muscle* , 1999, The Journal of Biological Chemistry.

[28]  Mark D. Johnson,et al.  Early neonatal death in mice homozygous for a null allele of the insulin receptor gene , 1996, Nature Genetics.

[29]  C. Burant,et al.  Troglitazone action is independent of adipose tissue. , 1997, The Journal of clinical investigation.

[30]  R. DeFronzo.  PATHOGENESIS OF TYPE 2 DIABETES: METABOLIC AND MOLECULAR IMPLICATIONS FOR IDENTIFYING DIABETES GENES , 1997 .

[31]  Y. Le Marchand-Brustel,et al.  Expression of a dominant-negative mutant human insulin receptor in the muscle of transgenic mice. , 1994, The Journal of biological chemistry.