Development of Muscle Insulin Resistance After Liver Insulin Resistance in High-Fat–Fed Rats
Abstract
Muscle and hepatic insulin resistance are two major defects of non-insulin-dependent diabetes mellitus. Dietary factors may be important in the etiology of insulin resistance. We studied progressive changes in the development of high-fat–diet–induced insulin resistance in tissues of the adult male Wistar rat. In vivo insulin action was compared 3 days and 3 wk after isocaloric synthetic high-fat or high-starch feeding (59 and 10% cal as fat, respectively). Basal and insulin-stimulated glucose metabolism were assessed in the conscious 5- to 7-h fasted state with the euglycemic clamp (600 pM insulin) with a [3-3H]-glucose infusion. Fat feeding significantly reduced suppressibility of hepatic glucose output by insulin after both 3 days and 3 wk of diet (P < 0.01). However, a significant impairment of insulin-mediated peripheral glucose disposal was only present after 3 wk of diet. Further in vivo [3H]-2-deoxyglucose uptake studies supported this finding and demonstrated adipose but not muscle insulin resistance after 3 days of high-fat feeding. Muscle triglyceride accumulation due to fat feeding was not significant at 3 days but had doubled by 3 wk in red muscle (P < 0.001) compared with starch-fed controls. By 3 wk, high-fat—fed animals had developed significant glucose intolerance. We concludethat fat feeding induces insulin resistance in liver and adipose tissue before skeletal muscle with early metabolic changes favoring an oversupply of energy substrate to skeletal muscle relative to metabolic needs. This may generate later muscle insulin resistance.
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Three days of high-fat feeding in rats results specifically in hepatic steatosis and hepatic insulin resistance.
“Three days of high-fat feeding in rats results specifically in hepatic steatosis and hepatic insulin resistance.”
From Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease (2007) · cites this paper as [13]
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“As well as being an important site of fatty acid oxidation, the liver is also a major organ for de novo lipogenesis and its insulin sensitivity appears to be more vulnerable to the insult of lipid accumulation compared to muscle [8].”
BackgroundSelf-citationLong-term high-fat feeding leads to severe insulin resistance but not diabetes in Wistar rats
Chalkley, S. M., Hettiarachchi, M., Chisholm, D. J., & Kraegen, E. W. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00173.2001 · Cited by 140 · see citing works
“Previous studies from our institution with shortterm (3 wk-1 mo) high polyunsaturated fat-fed rats showed no metabolically significant hyperglycemia despite the induction of insulin resistance (23, 26, 37).”
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“The two most important tissues responsible for dietinduced insulin resistance are the liver and skeletal muscle [53-55], which means that activation of hepatic CB1 receptors likely results in the production/release of a soluble mediator(s) that is involved in inducing insulin resistance in skeletal muscle.”
BackgroundGan, S. K., Kriketos, A. D., Ellis, B. A., Thompson, C. H., Kraegen, E. W., & Chisholm, D. J. (2003) · Diabetes Care · doi:10.2337/diacare.26.6.1706 · Cited by 134 · see citing works
Self-citationMuscle Long‐Chain Acyl CoA Esters and Insulin Resistance
Cooney, G. J., Thompson, A. L., Furler, S. M., Ye, J.-M., & Kraegen, E. W. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb04276.x · Cited by 131 · see citing works
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Insulin action and signalling in fat and muscle from dexamethasone-treated rats
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“Whether the induction of hepatic Glc-6-Pase expression by glucose (32) and lipids contributes to the increased rate of hepatic glucose production that follows a high-carbohydrate (35) and high-fat diet (34) remains to be delineated.”
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“Previous studies have shown that an increase in circulating lipids results in the impaired suppression of hepatic glucose production by insulin (14, 20, 42), although whether this was due to increased gluconeogenesis or glycogenolysis was not known.”
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“In rats, the development of skeletal muscle insulin resistance took 3 days of high-fat feeding (36,37).”
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Developmental Changes in Histone macroH2A1-Mediated Gene Regulation
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“Previous studies of the effects of increased fatty acid delivery on liver insulin resistance have been done on male mice and rats (18, 19, 34), suggesting that the responses of females may be different.”
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“metabolic syndrome and type II diabetes mellitus (DM) [9].”
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“Specifically, defects in this series of reactions are directly associated with increased levels of plasma and intracellular free fatty acids and alterations in insulin signaling pathways [3, 4].”
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“Previous studies have shown that hepatic steatosis can occur as early as after 3 d of high-fat feeding (Kraegen et al. 1991; Samuel et al. 2004).”
- Authors
- Kraegen, E. W., Clark, P. W., Jenkins, A. B., Daley, E. A., Chisholm, D. J., & Storlien, L. H.
- Affiliations
- Garvan Institute of Medical Research (AU)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1991-11-01
- Volume
- 40
- Issue
- 11
- Pages
- 1397-1403
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2049881486
- Cited by
- 601
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 10 · 2023: 11 · 2022: 14 · 2021: 7 · 2020: 13 · 2019: 22 · 2018: 18 · 2017: 17 · 2016: 37 · 2015: 22 · 2014: 37 · 2013: 31 · 2012: 27
- FWCI
- 2.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Health and Medical Research Council
- National Medical Research Council
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- insulin resistance, high-fat diet, hepatic insulin resistance, skeletal muscle insulin resistance, adipose tissue insulin resistance, hepatic glucose production, impaired glucose tolerance, type 2 diabetes, dietary fat
- MeSH terms
- Animals, Dietary Fats, Glucose, Insulin, Insulin Resistance, Liver, Male, Muscles, Rats, Inbred Strains, Starch, Triglycerides, Rats
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