Muscle-Specific IRS-1 Ser→Ala Transgenic Mice Are Protected From Fat-Induced Insulin Resistance in Skeletal Muscle
Open accessAbstract
OBJECTIVE—Insulin resistance in skeletal muscle plays a critical role in the pathogenesis of type 2 diabetes, yet the cellular mechanisms responsible for insulin resistance are poorly understood. In this study, we examine the role of serine phosphorylation of insulin receptor substrate (IRS)-1 in mediating fat-induced insulin resistance in skeletal muscle in vivo. RESEARCH DESIGN AND METHODS—To directly assess the role of serine phosphorylation in mediating fat-induced insulin resistance in skeletal muscle, we generated muscle-specific IRS-1 Ser302, Ser307, and Ser612 mutated to alanine (Tg IRS-1 Ser→Ala) and IRS-1 wild-type (Tg IRS-1 WT) transgenic mice and examined insulin signaling and insulin action in skeletal muscle in vivo. RESULTS—Tg IRS-1 Ser→Ala mice were protected from fat-induced insulin resistance, as reflected by lower plasma glucose concentrations during a glucose tolerance test and increased insulin-stimulated muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. In contrast, Tg IRS-1 WT mice exhibited no improvement in glucose tolerance after high-fat feeding. Furthermore, Tg IRS-1 Ser→Ala mice displayed a significant increase in insulin-stimulated IRS-1–associated phosphatidylinositol 3-kinase activity and Akt phosphorylation in skeletal muscle in vivo compared with WT control littermates. CONCLUSIONS—These data demonstrate that serine phosphorylation of IRS-1 plays an important role in mediating fat-induced insulin resistance in skeletal muscle in vivo.
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Preventing IRS-1 serine phosphorylation by mutating key serine residues prevents high-fat feeding-induced insulin resistance in skeletal muscle.
“prevention of the IRS-1 serine phosphorylation by mutating key serine residues in the IRS-1 prevents the development of insulin resistance in skeletal muscle caused by high-fat feeding [169].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [169]
Activation of novel PKCs and serine phosphorylation of IRS1 are important for the development of insulin resistance.
“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 [41]
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- Authors
- Morino, K., Neschen, S., Bilz, S., Sono, S., Tsirigotis, D., Reznick, R. M., Moore, I., Nagai, Y., Samuel, V., Sebastian, D., White, M., Philbrick, W., & Shulman, G. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- Yale University (US)
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
- Boston Children's Hospital (US)
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2008-10-01
- Volume
- 57
- Issue
- 10
- Pages
- 2644-2651
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC2551673
- OpenAlex
- W2122939092
- Cited by
- 125
- References
- 40
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 5 · 2020: 3 · 2019: 4 · 2018: 8 · 2017: 5 · 2016: 4 · 2015: 10 · 2014: 10 · 2013: 11 · 2012: 13
- FWCI
- 5.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- American Diabetes Association
- Uehara Memorial Foundation
- U.S. Public Health Service (P30 DK45735, R01 DK-40936)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01-DK40936, U24DK76169, R01DK040936, U24DK059635, U24DK076169, 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 › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- IRS-1, IRS-1 serine phosphorylation, skeletal muscle insulin signaling, type 2 diabetes, high-fat diet, phosphatidylinositol 3-kinase, Akt phosphorylation, muscle glucose uptake, glucose tolerance
- MeSH terms
- Alanine, Animals, Dietary Fats, Female, Glucose Tolerance Test, Insulin, Insulin Resistance, Male, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation, Serine, Triglycerides, Blotting, Western, Glucose Clamp Technique, Muscle, Skeletal, Amino Acid Substitution, Immunoprecipitation, Mice, Insulin Receptor Substrate Proteins
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