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Fuel selection in human skeletal muscle in insulin resistance: a reexamination.
Open accessAbstract
For many years, the Randle glucose fatty acid cycle has been invoked to explain insulin resistance in skeletal muscle of patients with type 2 diabetes or obesity. Increased fat oxidation was hypothesized to reduce glucose metabolism. The results of a number of investigations have shown that artificially increasing fat oxidation by provision of excess lipid does decrease glucose oxidation in the whole body. However, results obtained with rodent or human systems that more directly examined muscle fuel selection have found that skeletal muscle in insulin resistance is accompanied by increased, rather than decreased, muscle glucose oxidation under basal conditions and decreased glucose oxidation under insulin-stimulated circumstances, producing a state of "metabolic inflexibility." Such a situation could contribute to the accumulation of triglyceride within the myocyte, as has been observed in insulin resistance. Recent knowledge of insulin receptor signaling indicates that the accumulation of lipid products in muscle can interfere with insulin signaling and produce insulin resistance. Therefore, although the Randle cycle is a valid physiological principle, it may not explain insulin resistance in skeletal muscle.
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“Obesity is also characterized by metabolic alterations that involve mitochondrial defects causing reduced oxidation in skeletal muscle (12,13).”
From Expression of Mfn2, the Charcot-Marie-Tooth Neuropathy Type 2A Gene, in Human Skeletal Muscle (2005) · cites this paper as [13]
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“Skeletal muscle in human obesity is characterized by metabolic alterations, including insulin resistance, accumulation of intracellular triglycerides, reduced oxidation processes, and impaired glucose-induced thermogenesis (36”
From Mitofusin-2 Determines Mitochondrial Network Architecture and Mitochondrial Metabolism (2003) · cites this paper as [37]
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“The down-regulation of Mfn2 detected in skeletal muscle from obese subjects or obese rats together with the observation that Mfn2 promotes mitochondrial metabolism may explain some of the metabolic alterations observed during obesity and characterized by impaired muscle glucose oxidation and fatty acid oxidation (36-39”
From Mitofusin-2 Determines Mitochondrial Network Architecture and Mitochondrial Metabolism (2003) · cites this paper as [37]
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“Interestingly, insulin resistance associated with obesity and type 2 diabetes is characterized by reduced oxidative capacities in skeletal muscle (1,9,13).”
From Expression of Mfn2, the Charcot-Marie-Tooth Neuropathy Type 2A Gene, in Human Skeletal Muscle (2005) · cites this paper as [13]
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In the citing paper
“during high-intensity exercise, obese individuals and patients with T2DM can increase the RER to values comparable to those observed in lean individuals”
From Effect of Exercise Training on Fat Loss—Energetic Perspectives and the Role of Improved Adipose Tissue Function and Body Fat Distribution (2021) · cites this paper as Kelley and Mandarino, 2000
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“A mismatch between availability and oxidation of lipids might induce ectopic fat deposition and lipotoxicity (17,24).”
From Metabolic flexibility to lipid availability during exercise is enhanced in individuals with high insulin sensitivity (2018) · cites this paper as [17]
In the citing paper
“In recent years it has become increasingly apparent that nutrient-induced substrate switching is often compromised in the settings of obesity and type 2 diabetes (Kelley and Mandarino, 2000).”
From Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle (2012) · cites this paper as Kelley and Mandarino, 2000
In the citing paper
“There has been considerable published evidence for lower fasting lipid oxidation and lower ΔRQ in obesity and T2DM, at both the whole-body level and the tissue level (36–38).”
In the citing paper
“Skeletal muscle is highly reliant on fatty acid oxidation during fasting conditions but, more importantly, displays considerable plasticity in fuel oxidation, which is best exemplified by rapid switching between carbohydrate and lipid in response to insulin.”
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“Defects in skeletal muscle oxidative capacity and fat metabolism are highly correlated with insulin sensitivity (IS) (1,5,12) and are believed to contribute to the pathogenesis of insulin resistance (13,14).”
From Dynamic changes in fat oxidation in human primary myocytes mirror metabolic characteristics of the donor (2005) · cites this paper as [14]
In the citing paper
“Insulin-resistant obese patients however manifested a lesser reliance on fatty acid oxidation compared with lean individuals and did not show increased fatty acid oxidation after fasting or reduced fatty acid oxidation after insulin infusion.”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [9]
In the citing paper
“The metabolic flexibility assessed by the ability to switch from fat to carbohydrate oxidation is usually impaired during a hyperinsulinemic clamp in insulin-resistant subjects; however, this “metabolic inflexibility” is mostly the consequence of impaired cellular glucose uptake.”
From Metabolic flexibility and insulin resistance (2008) · cites this paper as [26]
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BackgroundAgeing, adipose tissue, fatty acids and inflammation
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Metadata
- Authors
- Kelley, D. E., & Mandarino, L. J.
- Affiliations
- University of Pittsburgh (US)
- ORCID
- Mandarino, L J
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2000-05-01
- Volume
- 49
- Issue
- 5
- Pages
- 677-683
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2164122881
- Cited by
- 1,017
- References
- 72
- Citations by year
- 2026: 31 · 2025: 28 · 2024: 25 · 2023: 39 · 2022: 41 · 2021: 49 · 2020: 37 · 2019: 26 · 2018: 51 · 2017: 38 · 2016: 39 · 2015: 43 · 2014: 35 · 2013: 57 · 2012: 43
- FWCI
- 1.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- 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 › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- insulin resistance, skeletal muscle, fuel selection, Randle cycle, glucose oxidation, fat oxidation, metabolic inflexibility, type 2 diabetes, obesity, insulin signaling, insulin receptor signaling, intramyocellular triglyceride, lipid accumulation
- MeSH terms
- Animals, Fatty Acids, Glucose, Humans, Insulin Resistance, Muscle, Skeletal, Lipid Metabolism
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