Fuel selection in human skeletal muscle in insulin resistance: a reexamination.

Kelley, D E; Mandarino, L J

doi:10.2337/diabetes.49.5.677

Cited by 1,017Metabolism, Diabetes, and CancerDiabetes, Cardiovascular Risks, and LipoproteinsAdipose Tissue and Metabolism

Fuel selection in human skeletal muscle in insulin resistance: a reexamination.

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Kelley, D E, Mandarino, L J·2000·Diabetes

DOI 10.2337/diabetes.49.5.677

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Abstract

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 characterized by metabolic alterations that involve mitochondrial defects causing reduced oxidation in skeletal muscle.
“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]
In “Metabolic Inflexibility of Fatty Acid Utilization in Insulin Resistance” (page unavailable), the paper reports reduced skeletal-muscle lipid oxidation in obese subjects during fasting, but greater oxidation during insulin infusion. In “Mechanisms Limiting Fat Use in Human Muscle” (page unavailable), it says reduced oxidative-enzyme activity may reflect reduced mitochondrial content or function; it does not establish mitochondrial defects as the cause of reduced oxidation. (LLM, conf=0.88)
Experimental — accuracy not yet measured
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.
“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]
The sections on increased muscle lipid concentrations and metabolic inflexibility report triglyceride accumulation, insulin resistance, and reduced fasting lipid oxidation in obesity. The paper qualifies the oxidation finding by condition: muscle lipid oxidation is greater during insulin infusion than in lean subjects. Our copy does not address impaired glucose-induced thermogenesis (searched: thermogenesis and thermogenic response to glucose); the indexed passages provide no page numbers. (LLM, conf=0.88)
Experimental — accuracy not yet measured
The down-regulation of Mfn2 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, characterized by impaired muscle glucose oxidation and fatty acid oxidation.
“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]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Insulin resistance associated with obesity and type 2 diabetes is characterized by reduced oxidative capacities in skeletal muscle.
“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]
During high-intensity exercise, obese individuals and patients with T2DM can increase RER to values comparable to those observed in lean individuals.
“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
The ‘Metabolic inflexibility of fatty acid utilization in insulin resistance’ section compares leg RQ in lean, obese, and type 2 diabetic subjects during fasting and insulin infusion, not exercise. A search for high-intensity exercise and respiratory exchange ratio found no passage establishing that the groups reach comparable RER values during exercise. (LLM, conf=0.76)
Experimental — accuracy not yet measured

A mismatch between lipid availability and lipid oxidation may induce ectopic fat deposition and lipotoxicity.
“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]
Nutrient-induced substrate switching is often compromised in obesity and type 2 diabetes.
“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
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.
“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).”
From Skeletal muscle mitochondria in insulin resistance: differences in intermyofibrillar versus subsarcolemmal subpopulations and relationship to metabolic flexibility (2011) · cites this paper as [36]
Skeletal muscle is highly reliant on fatty acid oxidation during fasting conditions but displays considerable plasticity in fuel oxidation, exemplified by rapid switching between carbohydrate and lipid in response to insulin.
“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.”
From Skeletal muscle mitochondria in insulin resistance: differences in intermyofibrillar versus subsarcolemmal subpopulations and relationship to metabolic flexibility (2011) · cites this paper as [36]
Skeletal muscle oxidative and fat-metabolism defects track closely with insulin sensitivity and are thought to help cause insulin resistance.
“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]
Insulin-resistant obese patients manifest a lesser reliance on fatty acid oxidation compared with lean individuals and do not show increased fatty acid oxidation after fasting or reduced fatty acid oxidation after insulin infusion.
“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]
Metabolic flexibility assessed by the ability to switch from fat to carbohydrate oxidation is usually impaired during a hyperinsulinemic clamp in insulin-resistant subjects.
“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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Randle PJ, Garland PB, Hales CN, Newsholme EA: The glucose fatty acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mel- DIABETES, VOL. 49, MAY 2000 litus. Lancet i:7285-7289, 1963
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“However, during high-intensity exercise, obese individuals and patients with T2DM can increase the RER to values comparable to those observed in lean individuals (Kelley and Mandarino, 2000).”
Background
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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
DOI: 10.2337/diabetes.49.5.677
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 › 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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Fuel selection in human skeletal muscle in insulin resistance: a reexamination.

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