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Cited by 532Metabolism, Diabetes, and CancerAdipose Tissue and MetabolismDiabetes, Cardiovascular Risks, and Lipoproteins

Metabolic flexibility and insulin resistance

Open access
Galgani, Jose E., Moro, Cedric, Ravussin, Eric·2008·American Journal of Physiology-Endocrinology and Metabolism
DOI 10.1152/ajpendo.90558.2008PMC PMC2584808
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Abstract

Metabolic flexibility is the capacity for the organism to adapt fuel oxidation to fuel availability. The inability to modify fuel oxidation in response to changes in nutrient availability has been implicated in the accumulation of intramyocellular lipid and insulin resistance. 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. Indeed, after controlling for insulin-stimulated glucose disposal rate (amount of glucose available for oxidation), metabolic flexibility is not altered in obesity regardless of the presence of type 2 diabetes. To understand how intramyocellular lipids accumulate and cause insulin resistance, the assessment of metabolic flexibility to high-fat diets is more relevant than metabolic flexibility during a hyperinsulinemic clamp. An impaired capacity to upregulate muscle lipid oxidation in the face of high lipid supply may lead to increased muscle fat accumulation and insulin resistance. Surprisingly, very few studies have investigated the response to high-fat diets. In this review, we discuss the role of glucose disposal rate, adipose tissue lipid storage, and mitochondrial function on metabolic flexibility. Additionally, we emphasize the bias of using the change in respiratory quotient to calculate metabolic flexibility and propose novel approaches to assess metabolic flexibility. On the basis of current evidence, one cannot conclude that impaired metabolic flexibility is responsible for the accumulation of intramyocellular lipid and insulin resistance. We propose to study metabolic flexibility in response to high-fat diets in individuals having contrasting degree of insulin sensitivity and/or mitochondrial characteristics.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that impaired metabolic flexibility during a hyperinsulinemic clamp in insulin-resistant subjects is largely a consequence of reduced insulin-stimulated glucose disposal, not a primary defect in fuel switching. It concludes that evidence linking impaired metabolic flexibility to intramyocellular lipid accumulation and insulin resistance is inconclusive, and calls for studies of metabolic flexibility to high-fat diets in individuals with contrasting insulin sensitivity and mitochondrial characteristics.

Key findings

  • During a hyperinsulinemic clamp, the commonly reported metabolic inflexibility in insulin-resistant subjects is mostly explained by lower cellular glucose uptake: insulin-stimulated glucose disposal rate explained ∼50% of the variance in the change in respiratory quotient (ΔRQ). In quartile analysis, the insulin-sensitive group (n = 25) had about a fourfold higher glucose disposal rate, nonoxidative glucose disposal rate, and steady-state RQ than the insulin-resistant group (n = 25), but after adjustment for glucose disposal rate there was no longer any difference in nonoxidative glucose disposal rate or steady-state RQ (P > 0.44).
  • The paper reports that after controlling for insulin-stimulated glucose disposal rate, metabolic flexibility is not altered in obesity regardless of type 2 diabetes, and no improvement in metabolic flexibility was observed after weight loss in type 2 diabetic individuals after controlling for glucose disposal rate.
  • Evidence does not support the hypothesis that impaired mitochondrial function leads to lower metabolic flexibility to lipid; mitochondrial dysfunction may coexist with high fuel oxidation and enhanced insulin sensitivity. In one cited study, subjects with a family history of type 2 diabetes had on average 22% less mitochondrial DNA copy number, related to a higher decrease in sleeping RQ after a 3-day isoenergetic high-fat diet, but not to the change in 24-h RQ.
  • The authors emphasize that using ΔRQ to calculate metabolic flexibility is biased by baseline RQ: in an illustrative example, two well-matched subjects both matched 24-h RQ to food quotient, yet one was classified as flexible (ΔRQ = −0.17) and the other as inflexible (ΔRQ = −0.07). They propose assessing the time to reach 50% of the expected change in RQ (ΔRQ50%) and studying responses to high-fat diets; based on RQ profiles, metabolically inflexible individuals could accumulate ∼200 g more fat than flexible subjects after 1 wk of a high-fat diet (60% of total energy).

Methods

  • Narrative review; no primary experimental data are reported. The paper synthesizes human whole-body, skeletal muscle, and cultured myotube studies on metabolic flexibility, insulin resistance, obesity, type 2 diabetes, and family history of type 2 diabetes.
  • It discusses assessment paradigms including fasting RQ, euglycemic-hyperinsulinemic clamp, high-carbohydrate and high-fat meals/diets, and in vitro myotube substrate switching.
  • Main analysis is qualitative synthesis, with illustrative calculations and tables, including a table comparing steady-state RQ between subjects with high and low insulin-stimulated glucose disposal rate.

Limitations

  • Stated in paper: few studies have investigated metabolic flexibility to high-fat diets, and no studies have evaluated metabolic flexibility to lipid in subjects with contrasting degrees of insulin resistance; most studies used fasting RQ, which is not a reliable indicator of lipid oxidation capacity because it is strongly influenced by energy balance and dietary macronutrient composition.
  • Stated in paper: the causal link between mitochondrial abnormalities and metabolic inflexibility/insulin resistance remains to be established, and evidence indicating mitochondrial defects as a driving factor is far from conclusive or even unavailable.
  • Evident from text: as a narrative review, no systematic search or meta-analysis is described; conclusions depend on selected literature, and the paper notes that some cited comparisons failed to match groups for physical fitness, which could confound mitochondrial findings.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1152/ajpendo.90558.2008

Cites

68 of 68 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 73 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    After adjustment for differences in glucose disposal rates, there was no longer any difference in nonoxidative glucose disposal rate and steady-state RQ between insulin-sensitive and insulin-resistant groups.

    “However, after adjustment for differences in glucose disposal rates, there was no longer any difference in nonoxidative glucose disposal rate and steady-state RQ between groups (Ref. [14](#r14); [Table 2](#t2)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] source

      Not checked in the free run.

  • Findingreasoning

    Data corrected for glucose disposal rate indicate no difference in metabolic flexibility and nonoxidative glucose disposal rate between subjects with or without type 2 diabetes and matched for body mass index, sex, and race.

    “As a consequence, data corrected for glucose disposal rate, a mechanism proximal to glucose oxidation, indicates no difference in metabolic flexibility and nonoxidative glucose disposal rate between subjects with or without type 2 diabetes and matched for body mass index, sex, and race.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] source

      Not checked in the free run.

  • Findingcitation

    Patients with lipodystrophy have similar fat oxidation to control individuals when fed a eucaloric, mixed diet.

    “For instance, patients with lipodystrophy (partial or total absence of subcutaneous adipose tissue) have similar fat oxidation than control individuals when fed a eucaloric, mixed diet ([51](#r51)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] source

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  • Findingcitation

    In response to excess energy as fat, lipodystrophic subjects have higher fat oxidation compared with control individuals.

    “However, in response to excess energy as fat, lipodystrophic subjects have higher fat oxidation compared with control individuals ([51](#r51)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] source

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  • Findingcitation

    After controlling for glucose disposal rate, no improvement in metabolic flexibility is observed after weight loss in type 2 diabetic individuals subjected to a 1-yr intensive lifestyle intervention including energy restriction and increased physical activity.

    “Furthermore, after controlling for glucose disposal rate, no improvement in metabolic flexibility is observed after weight loss in type 2 diabetic individuals subjected to a 1-yr intensive lifestyle intervention including energy restriction and increased physical activity ([14](#r14)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] source

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  • May combine two claims. 16
  • Classified as probably not a substantial claim. 2
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingcitation

    Insulin-stimulated glucose disposal rate is the main determinant of the change in RQ during a clamp, explaining ∼50% of its variance.

    “We ([14](#r14)) recently described that insulin-stimulated glucose disposal rate is the main determinant of the change in RQ during a clamp, explaining ∼50% of its variance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] source

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    In two well-matched individuals under energy balance in a metabolic chamber, after one week on diets with different food quotients and then another week on a diet with FQ 0.75, subject A had a change in 24-h RQ (ΔRQ) of −0.17 and subject B had −0.07.

    “Using the ΔRQ as an index of metabolic flexibility, *subject A* will be characterized as flexible (ΔRQ = −0.17) and *subject B* as inflexible (ΔRQ = −0.07).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In response to a high-carbohydrate meal, individuals with a family history of diabetes had a higher plasma insulin concentration and a similar increase in RQ compared with control subjects.

    “However, in response to a high-carbohydrate meal (1,000 kcal, 76% energy from carbohydrate), individuals with a family history of diabetes had a higher plasma insulin concentration and a similar increase in RQ compared with control subjects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    If skeletal muscle cannot match fat oxidation to lipid uptake, fat accumulation will ensue, which in turn will cause insulin resistance.

    “If skeletal muscle cannot match fat oxidation to lipid uptake, fat accumulation will ensue, which in turn will cause insulin resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    In vitro adaptability was positively related to aerobic capacity, suggesting that myotubes from lean, fit, insulin-sensitive subjects are more metabolically flexible in response to palmitate exposure in vitro.

    “In addition, in vitro adaptability was positively related to aerobic capacity, suggesting that myotubes established from lean, fit, insulin-sensitive subjects are more metabolically flexible in response to palmitate exposure in vitro.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Impaired mitochondrial lipid oxidation could simply be the result of reduced energy demand and not necessarily due to impaired substrate switching.

    “On the other hand, such impaired mitochondrial lipid oxidation could simply be the result of reduced energy demand and not necessarily due to impaired substrate switching.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Using ΔRQ as an index of metabolic flexibility, subject A is characterized as flexible and subject B as inflexible.

    “Using the ΔRQ as an index of metabolic flexibility, *subject A* will be characterized as flexible (ΔRQ = −0.17) and *subject B* as inflexible (ΔRQ = −0.07).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Differences in baseline RQ and the timing required to match 24-h RQ to FQ affect the assessment of metabolic flexibility.

    “Consequently, the assessment of metabolic flexibility should take into account the differences in baseline RQ and the timing required to match 24-h RQ to FQ.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Metabolic inflexibility to glucose and impaired glucose storage during a hyperinsulinemic clamp is consistently reported in insulin-resistant subjects.

    “Metabolic inflexibility to glucose and impaired glucose storage during a hyperinsulinemic clamp is consistently reported in insulin-resistant subjects.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] source

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    • cites [24] source

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    • cites [61] source

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  • The quote only partly states this claim.

    Premisecitation

    In diabetic individuals, leg RQ was higher throughout the 6 h following a high-fat meal compared with nondiabetic subjects.

    “During postabsorptive conditions, diabetic individuals had higher RQ throughout the 6 h following the high-fat meal compared with nondiabetic subjects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High plasma FFA concentration impairs insulin-stimulated glucose disposal rate and decreases intracellular glucose, which in turn reduces glucose oxidation and consequently enhances lipid oxidation.

    “Additionally, high plasma FFA concentration impairs insulin-stimulated glucose disposal rate and decreases intracellular glucose, which in turn reduces glucose oxidation and consequently enhances lipid oxidation ([2](#r2), [8](#r8)).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] source

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    • cites [8] source

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  • May combine two claims.

    Interpretationnone given

    Metabolic flexibility also depends on the rate at which nutrients are available to the cells, the ability of adipose tissue to handle fatty acids, and the method used for its calculation (i.e., ΔRQ).

    “However, metabolic flexibility also depends on the rate at which nutrients are available to the cells, the ability of adipose tissue to handle fatty acids and even the method used for its calculation (i.e., ΔRQ).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Impaired metabolic flexibility may result from both a lower stimulated RQ and/or an elevated baseline RQ.

    “Accordingly, impaired metabolic flexibility may result from both a lower stimulated RQ and/or an elevated baseline RQ.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Comparisons among obese, diabetic, and lean individuals have failed to appropriately match the groups for physical fitness, opening up the possibility that mitochondrial dysfunction may be related to lower physical activity in metabolically inflexible subjects.

    “However, comparisons among obese, diabetic, and lean individuals have failed to appropriately match the groups for physical fitness, opening up the possibility that mitochondrial dysfunction may be related to lower physical activity in metabolically inflexible subjects ([45](#r45)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High-fat diets increase mitochondrial biogenesis and fat oxidation in parallel with a decrease in insulin sensitivity.

    “This is in line with the finding that high-fat diets increase mitochondrial biogenesis and fat oxidation in parallel with a decrease in insulin sensitivity ([18](#r18)), possibly as a consequence of increased partially oxidized lipid intermediates.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice with muscle-specific PGC1α deletion have defective mitochondrial function but have increased metabolic rate, lower RQ, and improved insulin-stimulated glucose uptake in skeletal muscle compared with wild-type animals.

    “Similarly, mice with muscle-specific PGC1α (PPARγ coactivator-1α) deletion have defective mitochondrial function (e.g., lower staining for cytochrome *c* oxidase and succinate dehydrogenase); however, they have increased metabolic rate, lower RQ, and improved insulin-stimulated glucose uptake in skeletal muscle compared with wild-type animals ([19](#r19)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Individuals able to increase fat oxidation quickly in response to day-to-day changes in fat intake will eventually have lower muscle fat accumulation and be less prone to insulin resistance compared with slower adapters.

    “Individuals able to increase fat oxidation quickly in response to day-to-day changes in fat intake will eventually have lower muscle fat accumulation and be less prone to insulin resistance compared with slower adapters.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The speed of adaptation of fat oxidation to high fat intake will probably impact the amount of lipid accumulation in muscle and therefore impact insulin sensitivity.

    “The answer is yes, since the speed of the adaptation will probably impact the amount of lipid accumulation in the muscle and therefore impact insulin sensitivity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationcitation

    Since vo2max has been shown to be directly related to muscle mitochondrial density, one could expect an improved metabolic flexibility in young vs. elderly individuals.

    “Since vo2max has been shown to be directly related to muscle mitochondrial density ([62](#r62), [63](#r63)), one could expect an improved metabolic flexibility in young vs. elderly individuals.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [62] source

      Not checked in the free run.

    • cites [63] source

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19 of 19

  • The paper relies on this without support.

    The switch in fuel oxidation depends on the type and amount of nutrient available for oxidation at the cellular level.

    “The switch in fuel oxidation will depend on the type and amount of nutrient available for oxidation at the cellular level.”

  • The paper relies on this without support.

    Increased availability of carbohydrate rapidly increases carbohydrate oxidation and suppresses lipid oxidation.

    “Increased availability of carbohydrate results in a rapid increase in carbohydrate oxidation associated with concomitant suppression of lipid oxidation.”

  • The paper relies on this without support.

    When dietary fat intake increases, lipid oxidation increases slowly and progressively while carbohydrate oxidation is suppressed.

    “However, when dietary fat intake increases, one observes a much slower progressive increase in lipid oxidation paralleled by suppression of carbohydrate oxidation.”

  • The paper relies on this without support.

    After 7–10 days, all individuals will be in equilibrium between 24-h RQ and FQ.

    “since after 7–10 days it is generally expected that all individuals will be in equilibrium between 24-h RQ and FQ.”

  • The paper relies on this without support.

    The ΔRQ50% is in the range of 1–2 days in response to high-carbohydrate diets and in the range of 3–5 days in response to high-fat diets.

    “Such a ΔRQ50% may be in the range of 1–2 days in response to high-carbohydrate diets and in the range of 3–5 days in response to high-fat diets.”

  • The paper relies on this without support.

    The adaptation of fat oxidation to high fat intake cannot take much more time than that required to deplete glycogen stores, i.e., a few days to a week.

    “However, this adaptation cannot take much more time than that required to deplete the glycogen stores, i.e., a few days to a week.”
6 of 6

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Related

Authors
Galgani, J. E., Moro, C., & Ravussin, E.
Venue
American Journal of Physiology-Endocrinology and Metabolism
Publisher
American Physiological Society
Published
2008-11
Volume
295
Issue
5
Pages
E1009-E1017
ISSN
  • 0193-1849 (ISSN-L)
  • 1522-1555
DOI
10.1152/ajpendo.90558.2008
PMC
PMC2584808
OpenAlex
W2168445785
Cited by
532
References
68
Citations by year
2026: 36 · 2025: 40 · 2024: 17 · 2023: 22 · 2022: 38 · 2021: 36 · 2020: 46 · 2019: 34 · 2018: 32 · 2017: 38 · 2016: 21 · 2015: 28 · 2014: 39 · 2013: 40 · 2012: 17
FWCI
1.24
Type
journal article
Language
en
Open access
Locations
  • American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Universidad de Chile (submittedVersion)
Funders
  • National Institute on Aging (U01AG020478)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK060412, R01-DK-60412)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
metabolic flexibility, insulin resistance, intramyocellular lipid, glucose disposal rate, hyperinsulinemic-euglycemic clamp, respiratory quotient, high-fat diet, mitochondrial function, fuel oxidation, type 2 diabetes, obesity
MeSH terms
Animals, Diabetes Mellitus, Type 2, Energy Metabolism, Humans, Insulin Resistance, Mitochondria, Obesity, Muscle, Skeletal, Carbohydrate Metabolism, Lipid Metabolism

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