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Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats
Open accessAbstract
Both insulin resistance and hyperinsulinemia have been reported to be independent risk factors for cardiovascular diseases. However, little is known regarding insulin signaling in the vascular tissues in insulin-resistant states. In this report, insulin signaling on the phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein (MAP) kinase pathways were compared in vascular tissues of lean and obese Zucker (fa/fa) rats in both ex vivo and in vivo studies. Ex vivo, insulin-stimulated tyrosine phosphorylation of insulin receptor beta subunits (IRbeta) in the aorta and microvessels of obese rats was significantly decreased compared with lean rats, although the protein levels of IRbeta in the 2 groups were not different. Insulin-induced tyrosine phosphorylation of insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) and their protein levels were decreased in the aorta of obese rats compared with lean rats. The association of p85 subunit to the IRS proteins and the IRS-associated PI 3-kinase activities stimulated by insulin in the aorta of obese rats were significantly decreased compared with the lean rats. In addition, insulin-stimulated serine phosphorylation of Akt, a downstream kinase of PI 3-kinase pathway, was also reduced significantly in isolated microvessels from obese rats compared with the lean rats. In euglycemic clamp studies, insulin infusion greatly increased tyrosine phosphorylation of IRbeta- and IRS-2-associated PI 3-kinase activity in the aorta of lean rats, but only slight increases were observed in obese rats. In contrast, insulin stimulated tyrosine phosphorylation of MAP kinase (ERK-1/2) equally in isolated microvessels of lean and obese rats, although basal tyrosine phosphorylation of ERK-1/2 was higher in the obese rats. To our knowledge, these data provided the first direct measurements of insulin signaling in the vascular tissues, and documented a selective resistance to PI 3-kinase (but not to MAP kinase pathway) in the vascular tissues of obese Zucker rats.
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“This observation is of important clinical significance, since diacylglycerol, long-chain fatty acyl CoAs, and ceramides all have been shown to cause serine phosphorylation of insulin resistance and IRS-1 and lead to the development of insulin resistance in skeletal muscle ( 59 , 60 ).”
From Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes (2009) · cites this paper as [60]
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“Vascular insulin resistance leads to downregulation of IRS-1 and 2 and decreased phosphorylation of Akt and eNOS, whereas the ET-1 pathway remains unaffected.”
From The Vasculature in Prediabetes (2018) · cites this paper as [48]
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Metadata
- Authors
- Jiang, Z. Y., Lin, Y.-W., Clemont, A., Feener, E. P., Hein, K. D., Igarashi, M., Yamauchi, T., White, M. F., & King, G. L.
- Affiliations
- Joslin Diabetes Center (US)
- Corresponding author
- King, George L.
- Venue
- Journal of Clinical Investigation
- Published
- 1999-08-15
- Volume
- 104
- Issue
- 4
- Pages
- 447-457
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC408521
- OpenAlex
- W2051269098
- Cited by
- 604
- References
- 56
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 10 · 2023: 15 · 2022: 15 · 2021: 19 · 2020: 13 · 2019: 13 · 2018: 10 · 2017: 24 · 2016: 28 · 2015: 24 · 2014: 23 · 2013: 27 · 2012: 35
- FWCI
- 12.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Joslin Diabetes Center
- National Institutes of Health (DK 36836)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-53105, DK36836, R01DK053105, P30DK036836)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- insulin resistance, MAPK signaling, ERK1/2, insulin receptor beta, IRS-1, insulin receptor substrate 2, p85 regulatory subunit, aorta, microvessels, obesity, Zucker rats, hyperinsulinemia, cardiovascular risk
- MeSH terms
- Animals, Aorta, Insulin, Insulin Resistance, Liver, Male, Microcirculation, Obesity, Phosphoproteins, Phosphorylation, Rats, Zucker, Receptor, Insulin, Recombinant Proteins, Tyrosine, Signal Transduction, Calcium-Calmodulin-Dependent Protein Kinases, Phosphatidylinositol 3-Kinases, Intracellular Signaling Peptides and Proteins, Rats, Insulin Receptor Substrate Proteins, In Vitro Techniques
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