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PKC-θ knockout mice are protected from fat-induced insulin resistance
Open accessAbstract
Insulin resistance plays a primary role in the development of type 2 diabetes and may be related to alterations in fat metabolism. Recent studies have suggested that local accumulation of fat metabolites inside skeletal muscle may activate a serine kinase cascade involving protein kinase C–θ (PKC-θ), leading to defects in insulin signaling and glucose transport in skeletal muscle. To test this hypothesis, we examined whether mice with inactivation of PKC-θ are protected from fat-induced insulin resistance in skeletal muscle. Skeletal muscle and hepatic insulin action as assessed during hyperinsulinemic-euglycemic clamps did not differ between WT and PKC-θ KO mice following saline infusion. A 5-hour lipid infusion decreased insulin-stimulated skeletal muscle glucose uptake in the WT mice that was associated with 40–50% decreases in insulin-stimulated tyrosine phosphorylation of insulin receptor substrate–1 (IRS-1) and IRS-1–associated PI3K activity. In contrast, PKC-θ inactivation prevented fat-induced defects in insulin signaling and glucose transport in skeletal muscle. In conclusion, our findings demonstrate that PKC-θ is a crucial component mediating fat-induced insulin resistance in skeletal muscle and suggest that PKC-θ is a potential therapeutic target for the treatment of type 2 diabetes.
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“Similar to IKK and JNK pathways, it induces serine or threonine phosphorylation or IR or IRS-1, resulting in impairment of insulin signaling [80,81].”
From Sarcopenic obesity, insulin resistance, and their implications in cardiovascular and metabolic consequences (2020) · cites this paper as [81]
In the citing paper
“The importance of activation of novel PKCs and serine phosphorylation of IRS1 for the development of insulin resistance was shown in mice without PKCθ,40 and in those with serine-to-alanine mutations in key residues of IRS1 (thereby preventing serine phosphorylation).41”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [40]
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Metadata
- Authors
- Kim, J. K., Fillmore, J. J., Sunshine, M. J., Albrecht, B., Higashimori, T., Kim, D.-W., Liu, Z.-X., Soos, T. J., Cline, G. W., O’Brien, W. R., Littman, D. R., & Shulman, G. I.
- Affiliations
- Yale University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Kim, Jason K.
- Venue
- Journal of Clinical Investigation
- Published
- 2004-09-15
- Volume
- 114
- Issue
- 6
- Pages
- 823-827
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC516267
- OpenAlex
- W2119595824
- Cited by
- 500
- References
- 31
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 8 · 2023: 5 · 2022: 13 · 2021: 13 · 2020: 14 · 2019: 18 · 2018: 18 · 2017: 17 · 2016: 16 · 2015: 22 · 2014: 21 · 2013: 35 · 2012: 35
- FWCI
- 11.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- Howard Hughes Medical Institute
- American Diabetes Association
- Yale University
- U.S. Public Health Service (P30 DK45735, R01 DK-40936)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01-DK40936, U24DK59635, R01DK080756, R01DK040936, U24DK059635, P30DK045735)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- protein kinase C theta, skeletal muscle insulin signaling, type 2 diabetes, lipid infusion, insulin-stimulated glucose uptake, IRS-1 tyrosine phosphorylation, hyperinsulinemic-euglycemic clamp, hepatic insulin action, therapeutic target
- MeSH terms
- Protein Kinase C-theta, Adipose Tissue, Animals, Blood Glucose, Diabetes Mellitus, Type 2, Fatty Acids, Nonesterified, Infusions, Intravenous, Insulin, Insulin Resistance, Isoenzymes, Lipids, Phosphoproteins, Phosphorylation, Protein Kinase C, Signal Transduction, Mice, Knockout, Muscle, Skeletal, Mice, Insulin Receptor Substrate Proteins
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