PreprintCited by 369Metabolism, Diabetes, and CancerGrowth Hormone and Insulin-like Growth FactorsPancreatic function and diabetes

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

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Fernández, Ana M., Kim, Jason K., Yakar, Shoshana, Dupont, Joëlle, Hernandez-Sanchez, Catalina, Castle, Arthur L., Filmore, Jonathan, Shulman, Gerald I. +1 more·2001·Genes & Development

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 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.

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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.
Affiliations
National Institutes of Health (US)
Venue
Genes & Development
Published
2001-08-01
Volume
15
Issue
15
Pages
1926-1934
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
OpenAlex
W2125231550
Cited by
369
References
33
Citations by year
2026: 5 · 2025: 4 · 2024: 8 · 2023: 14 · 2022: 11 · 2021: 18 · 2020: 15 · 2019: 7 · 2018: 7 · 2017: 12 · 2016: 16 · 2015: 25 · 2014: 15 · 2013: 13 · 2012: 19
Type
posted content
Language
en
Open access
Licence
other-oa
Locations
  • Genes & Development (publishedVersion, other-oa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • Ministerio de Educación y Cultura
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080756, R01DK040936)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
type 2 diabetes, insulin resistance, IGF-1 receptor, insulin receptor, skeletal muscle, dominant negative receptor, hybrid receptors, transgenic mouse model, beta-cell dysfunction, glucose disposal
MeSH terms
Insulin Secretion, Aging, Animals, Blood Glucose, Diabetes Mellitus, Type 2, Fatty Acids, Nonesterified, Glucose, Humans, Hyperinsulinism, Insulin, Insulin Resistance, Islets of Langerhans, Liver, Mice, Transgenic, Prediabetic State, Receptor, Insulin, Triglycerides, Glucose Clamp Technique, Mutagenesis, Site-Directed, Receptor, IGF Type 1, Muscle, Skeletal, Mice

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