Cited by 500Metabolism, Diabetes, and CancerDiabetes, Cardiovascular Risks, and LipoproteinsAdipokines, Inflammation, and Metabolic Diseases

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PKC-θ knockout mice are protected from fat-induced insulin resistance

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Kim, Jason K., Fillmore, Jonathan J., Sunshine, Mary Jean, Albrecht, Bjoern, Higashimori, Takamasa, Kim, Dong-Wook, Liu, Zhen-Xiang, Soos, Timothy J., Cline, Gary W., O’Brien, William R., Littman, Dan R., Shulman, Gerald I.·2004·Journal of Clinical Investigation

DOI 10.1172/jci200422230PMC PMC516267

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Abstract

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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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.
ORCID: Kim, Jason K.
Sunshine, Mary Jean
Kim, Dong-Wook
Cline, Gary W.
Littman, Dan R.
Shulman, Gerald I.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2004-09-15
Volume: 114
Issue: 6
Pages: 823-827
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci200422230
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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PKC-θ knockout mice are protected from fat-induced insulin resistance

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