Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats

Jiang, Zhen Y.; Lin, You-Wei; Clemont, Allen; Feener, Edward P.; Hein, Katherine D.; Igarashi, Masahiko; Yamauchi, Teruaki; White, Morris F.; King, George L.

doi:10.1172/jci5971

Cited by 604Diabetes, Cardiovascular Risks, and LipoproteinsAdipokines, Inflammation, and Metabolic DiseasesMetabolism, Diabetes, and Cancer

Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats

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Jiang, Zhen Y., Lin, You-Wei, Clemont, Allen, Feener, Edward P., Hein, Katherine D., Igarashi, Masahiko, Yamauchi, Teruaki, White, Morris F. +1 more·1999·Journal of Clinical Investigation

DOI 10.1172/jci5971PMC PMC408521

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Abstract

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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Diacylglycerol, long-chain fatty acyl CoAs, and ceramides cause serine phosphorylation of IRS-1 and lead to insulin resistance in skeletal muscle.
“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]
The Discussion says elevated free fatty acids may impair insulin’s metabolic action and notes protein kinase C activation in skeletal muscle. It does not say that diacylglycerol, long-chain fatty acyl CoAs, or ceramides cause IRS-1 serine phosphorylation and thereby produce skeletal-muscle insulin resistance; its serine-phosphorylation discussion concerns the insulin receptor instead. Page numbers are unavailable in our copy. (LLM, conf=0.83)
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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.
“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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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.
ORCID: Jiang, Zhen Y.
Feener, Edward P.
White, Morris F.
King, George L.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1999-08-15
Volume: 104
Issue: 4
Pages: 447-457
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci5971
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 › Epidemiology › 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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Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats

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