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Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes
Open accessAbstract
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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“IGF1 acts primarily on skeletal muscle, where it elicits its insulin-sensitizing effects [228] (Figure 2).”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [228]
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Muscle insulin-like growth factor-I modulates murine craniofacial bone growth
Kok, H. J., Crowder, C., Chee, L. K. M., Choi, H., Lin, N., & Barton, E. (2021) · European Cells and Materials · doi:10.22203/ecm.v042a06 · Cited by 4
Unraveling the mysteries of hepatic insulin signaling: deconvoluting the nuclear targets of insulin
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Lee, J.-H., Jung, I., Tu‐Sekine, B., Jin, S., Anokye‐Danso, F., Ahima, R. S., & Kim, S. F. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26062395 · Cited by 5
Nishimura, A., Kobayashi, K., Yagasaki, H., Saito, T., Nagamine, K., Mitsui, Y., Mochizuki, M., Satoh, K., Kobayashi, K., Sano, T., et al. (2011) · Clinical Pediatric Endocrinology · doi:10.1297/cpe.20.73 · Cited by 3
Type 2 Diabetes Mellitus as a Risk Factor for Alzheimer’s Disease
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Aging and the Metabolic Syndrome
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Animal Models of Hyperinsulinemia, Insulin Resistance, and Cancer
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Self-citationThe Role of IGF-1 and Hormone Binding Proteins in Understanding Insulin-Associated Equine Laminitis
Nanayakkara, S. N. (1905) · Queensland University of Technology · doi:10.5204/thesis.eprints.118300 · Cited by 3
Associations of IGF-1 and IGFBP-3 with Aging and the Development of Age-Associated Diseases
Константиновна, И. А., Matchekhina, L. V., Melnitskaia, A. A., & Strazhesko, I. D. (2024) · Advances in Gerontology · doi:10.1134/s2079057025600041 · Cited by 2
Metadata
- 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
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2001-08-01
- Volume
- 15
- Issue
- 15
- Pages
- 1926-1934
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC312754
- 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
- hybrid
- doi.org
- 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 › Endocrinology, Diabetes and Metabolism › 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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