Lipid and insulin infusion-induced skeletal muscle insulin resistance is likely due to metabolic feedback and not changes in IRS-1, Akt, or AS160 phosphorylation
Open accessAbstract
Type 2 diabetes is characterized by hyperlipidemia, hyperinsulinemia, and insulin resistance. The aim of this study was to investigate whether acute hyperlipidemia-induced insulin resistance in the presence of hyperinsulinemia was due to defective insulin signaling. Hyperinsulinemia (∼300 mU/l) with hyperlipidemia or glycerol (control) was produced in cannulated male Wistar rats for 0.5, 1 h, 3 h, or 5 h. The glucose infusion rate required to maintain euglycemia was significantly reduced by 3 h with lipid infusion and was further reduced after 5 h of infusion, with no difference in plasma insulin levels, indicating development of insulin resistance. Consistent with this finding, in vivo skeletal muscle glucose uptake (31%, P < 0.05) and glycogen synthesis rate (38%, P < 0.02) were significantly reduced after 5 h compared with 3 h of lipid infusion. Despite the development of insulin resistance, there was no difference in the phosphorylation state of multiple insulin-signaling intermediates or muscle diacylglyceride and ceramide content over the same time course. However, there was an increase in cumulative exposure to long-chain acyl-CoA (70%) with lipid infusion. Interestingly, although muscle pyruvate dehydrogenase kinase 4 protein content was decreased in hyperinsulinemic glycerol-infused rats, this decrease was blunted in muscle from hyperinsulinemic lipid-infused rats. Decreased pyruvate dehydrogenase complex activity was also observed in lipid- and insulin-infused animals (43%). Overall, these results suggest that acute reductions in muscle glucose metabolism in rats with hyperlipidemia and hyperinsulinemia are more likely a result of substrate competition than a significant early defect in insulin action or signaling.
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Even following a short period of overfeeding, cardiac and skeletal muscle develop insulin resistance in order to divert the excess energy into adipose tissue.
“Even following a short period of overfeeding, cardiac and skeletal muscle develop insulin resistance in order to divert the excess energy into adipose tissue [125].”
From The Pathophysiology of Gestational Diabetes Mellitus (2018) · cites this paper as [125]
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- Authors
- Hoy, A. J., Brandon, A. E., Turner, N., Watt, M. J., Bruce, C. R., Cooney, G. J., & Kraegen, E. W.
- Affiliations
- Garvan Institute of Medical Research (AU)
- ORCID
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2009-07
- Volume
- 297
- Issue
- 1
- Pages
- E67-E75
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC2711668
- OpenAlex
- W2160416826
- Cited by
- 92
- References
- 9
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 5 · 2023: 8 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 6 · 2018: 7 · 2017: 3 · 2016: 6 · 2015: 4 · 2014: 4 · 2013: 6 · 2012: 7
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK067509, DK-067509)
- 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 › Diet, Metabolism, and Disease
- Keywords
- skeletal muscle insulin resistance, hyperlipidemia, hyperinsulinemia, lipid infusion, insulin signaling, IRS-1 phosphorylation, Akt phosphorylation, AS160 phosphorylation, substrate competition, PDK4, pyruvate dehydrogenase complex, muscle glucose uptake, glycogen synthesis, long-chain acyl-CoA, diacylglycerol, ceramide, type 2 diabetes
- MeSH terms
- Animals, Blood Glucose, Glycogen, Infusions, Intravenous, Insulin, Insulin Resistance, Lipids, Male, Phosphorylation, Rats, Wistar, Muscle, Skeletal, GTPase-Activating Proteins, Feedback, Physiological, Oncogene Protein v-akt, Rats, Metabolic Networks and Pathways, Insulin Receptor Substrate Proteins
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