Insulin-like growth factor binding protein-3 leads to insulin resistance in adipocytes
Abstract
CONTEXT: Transgenic mice overexpressing IGF binding protein-3 (IGFBP-3) have insulin resistance with reduced uptake of 2-deoxyglucose in muscle and adipose tissue. OBJECTIVE: Our aim was to investigate the effects of IGFBP-3 on glucose uptake in adipocytes. RESULTS: In 3T3-L1 adipocytes, IGFBP-3 reduced insulin-stimulated but not basal glucose uptake. This was independent of IGF binding because IGFBP-2 and IGFBP-1 had no effect, whereas two non-IGF binding mutants of IGFBP-3 were inhibitory. The effect of IGFBP-3 was independent of the blockade of the IGF-I receptor. A mutant form of IGFBP-3 that does not translocate to the nucleus or bind retinoid X receptor-alpha was able to inhibit insulin-stimulated glucose uptake, indicating that nuclear translocation and retinoid X receptor-alpha binding are not essential for this IGFBP-3 action. IGFBP-3 reduced insulin-stimulated glucose transporter-4 translocation to the plasma membrane and reduced threonine phosphorylation of Akt. Collectively, our data indicate that IGFBP-3 impacts on the insulin signaling pathway to inhibit insulin-stimulated glucose uptake independent of IGFs and through nonnuclear mechanisms. Finally, we showed that IGFBP-3 inhibited insulin-stimulated glucose uptake in omental but not s.c. adipose tissue explants. CONCLUSION: IGFBP-3 may contribute to insulin resistance in adipocytes.
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IGFBP3 causes insulin resistance independently of IGF binding, as shown by decreased GLUT4 translocation and reduced Akt phosphorylation in response to insulin in adipocytes and omental adipose explants.
“IGFBP3 has been shown to cause insulin resistance independently of IGF binding, as evidenced by decreased GLUT4 translocation to the plasma membrane as well as reduced Akt phosphorylation in response to insulin in adipocytes and omental adipose explants (45).”
From Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity (2015) · cites this paper as [45]
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- Authors
- Chan, S. S. Y., Twigg, S. M., Firth, S. M., & Baxter, R. C.
- Affiliations
- Royal North Shore Hospital (AU)
- The University of Sydney (AU)
- Corresponding author
- Chan, Sophie S. Y.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2005-12
- Volume
- 90
- Issue
- 12
- Pages
- 6588-6595
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2001227905
- Cited by
- 84
- References
- 31
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 1 · 2022: 1 · 2020: 2 · 2019: 5 · 2018: 3 · 2017: 3 · 2016: 5 · 2015: 1 · 2014: 3 · 2013: 10 · 2012: 5
- FWCI
- 3.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Sydney
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- insulin-like growth factor binding protein-3, insulin resistance, adipocytes, glucose uptake, insulin signaling, retinoid X receptor alpha, nuclear translocation, IGF-1 receptor, omental adipose tissue, transgenic mice
- MeSH terms
- Adipose Tissue, Animals, Biological Transport, Cell Membrane, Deoxyglucose, Humans, Insulin, Insulin Resistance, Insulin-Like Growth Factor I, Omentum, Phosphorylation, Receptor, Insulin, Recombinant Proteins, Receptor, IGF Type 1, Adipocytes, Insulin-Like Growth Factor Binding Protein 3, Subcutaneous Tissue, 3T3-L1 Cells, Proto-Oncogene Proteins c-akt, Glucose Transporter Type 4, Mice, In Vitro Techniques
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