The DOI matches its Crossref record; 68 of the 68 references it cites were found in a registry or an index; 3 of the 73 sources its claims cite were checked for support.
Metabolic flexibility and insulin resistance
Open accessAbstract
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.
Overview
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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.
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Claims the paper makes
48 Not checked yet · 30 Own interpretation · 5 No basis given · 2 Partly supported · 1 Own result · accuracy not yet measured
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In the paper
“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)).”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
What the sources say
- Partly supportedcites [14] sourceExperimental — accuracy not yet measured
The Results report that nonoxidative glucose disposal no longer differed after adjustment for glucose disposal rate (P = 0.87), and that the difference in ΔRQ was abolished (P = 0.19). The paper defines ΔRQ as the change from fasting to steady-state RQ, but does not report the adjusted comparison as a difference in steady-state RQ itself. Its groups were participants with type 2 diabetes and obesity-matched participants without diabetes, rather than groups defined solely by insulin sensitivity. (LLM, conf=0.83)
plain- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Such muscle mitochondrial dysfunction was suggested to be an intrinsic characteristic of muscle cells, since fat oxidation in response to palmitate was lower in myotubes from insulin-resistant vs. insulin-sensitive individuals ([16](#r16), [61](#r61)).”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
What the sources say
- Partly supportedcites [16] sourceExperimental — accuracy not yet measured
The Fatty acid oxidation results report 26% lower palmitate-derived CO₂ production in myotubes from people with type 2 diabetes than in control myotubes. The paper compared diabetic and control donors, not groups classified as insulin-resistant and insulin-sensitive, and it found no significant decrease in total palmitate oxidation. (LLM, conf=0.86)
- Supportedcites [61] source
The section “Metabolic adaptability is an intrinsic characteristic of muscle cells” reports that the increase in myotube fat oxidation after palmitate exposure was positively correlated with donors’ insulin sensitivity. Figure 4 interprets this as greater capacity to increase fat oxidation in subjects with higher insulin sensitivity. The evidence is a correlation across donors, rather than a categorical comparison of two groups; it supports the claim’s direction. (LLM, conf=0.88)
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In the paper
“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.”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
What the sources say
- Not checked yetcites [14] source
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“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)).”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
What the sources say
- Not checked yetcites [51] source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“However, in response to excess energy as fat, lipodystrophic subjects have higher fat oxidation compared with control individuals ([51](#r51)).”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
What the sources say
- Not checked yetcites [51] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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)).”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
What the sources say
- Not checked yetcites [14] source
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In fact, fasting RQ is inversely related to metabolic flexibility to carbohydrate during a clamp ([Fig. 3*A*](#f3)).”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
plaincorrelational- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“On the basis of the RQ profile for metabolically flexible and inflexible subjects shown in [Fig. 2*D*](#f2), and considering an energy intake of 2,500 kcal/day (protein intake 20% of total energy), the metabolically inflexible individuals would accumulate ∼200 g more fat than flexible subjects after 1 wk of a high-fat diet (60% of total energy).”
§ Metabolic flexibility and insulin resistance > Abstract > Conclusions
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, we observed that metabolic flexibility to glucose was directly related to plasma adiponectin concentration.”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
What the sources say
- Not checked yetcites [14] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“The former group had on average a 22% less mitochondrial DNA copy number (marker of mitochondrial number) than control subjects.”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
What the sources say
- Not checked yetcites [62] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 16
- Probably not a substantial claim. 2
- The quote only partly states this claim. 1
In the paper
“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.”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
What the sources say
- Not checked yetcites [14] source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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).”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
plainn = 2- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Metabolic flexibility and insulin resistance > Abstract > Metabolic Flexibility in Individuals with Insulin Resistance, Obesity or Family History of Type 2 Diabetes
What the sources say
- Not checked yetcites [20] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“If skeletal muscle cannot match fat oxidation to lipid uptake, fat accumulation will ensue, which in turn will cause insulin resistance.”
§ Metabolic flexibility and insulin resistance > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Metabolic flexibility and insulin resistance > Abstract > Metabolic Flexibility in Individuals with Insulin Resistance, Obesity or Family History of Type 2 Diabetes
What the sources say
- Not checked yetcites [15] source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Metabolic flexibility and insulin resistance > Abstract > Metabolic Flexibility in Individuals with Insulin Resistance, Obesity or Family History of Type 2 Diabetes
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Metabolic inflexibility to glucose and impaired glucose storage during a hyperinsulinemic clamp is consistently reported in insulin-resistant subjects.”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
What the sources say
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“During postabsorptive conditions, diabetic individuals had higher RQ throughout the 6 h following the high-fat meal compared with nondiabetic subjects.”
§ Metabolic flexibility and insulin resistance > Abstract > Metabolic Flexibility in Individuals with Insulin Resistance, Obesity or Family History of Type 2 Diabetes
What the sources say
- Not checked yetcites [28] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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The quote only partly states this claim.
None of the sources cited for this claim have been checked yet.
In the paper
“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)).”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Accordingly, impaired metabolic flexibility may result from both a lower stimulated RQ and/or an elevated baseline RQ.”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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)).”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
What the sources say
- Not checked yetcites [45] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
What the sources say
- Not checked yetcites [18] source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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)).”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
What the sources say
- Not checked yetcites [19] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Metabolic flexibility and insulin resistance > Abstract > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Metabolic flexibility and insulin resistance > Abstract > Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
hedgedconditional- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true.
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.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“As such, metabolic inflexibility is at the core of the pathophysiology of insulin resistance (146).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [146]
In the citing paper
“In turn, metabolically inflexible individuals fail to adapt their fuel preference to changes in carbohydrate or lipid supplies (Galgani et al, 2008).”
From Mitochondrial response to nutrient availability and its role in metabolic disease (2014) · cites this paper as Galgani et al, 2008
In the citing paper
“Metabolic inflexibility is defined as an impaired capacity to switch between different energy substrates and is a hallmark of insulin resistance and type 2 diabetes mellitus (T2DM).”
From Mitochondrial response to nutrient availability and its role in metabolic disease (2014) · cites this paper as Galgani et al, 2008
In the citing paper
“Diverse mitochondrial parameters vary between insulin-resistant and insulin-sensitive subjects, such as mitochondrial number, structure, and function.”
From Mitochondrial response to nutrient availability and its role in metabolic disease (2014) · cites this paper as Galgani et al, 2008
In the citing paper
“This suggests that mitochondrial dysfunction might contribute to metabolic inflexibility and insulin resistance (Galgani et al, 2008).”
From Mitochondrial response to nutrient availability and its role in metabolic disease (2014) · cites this paper as Galgani et al, 2008
Citations
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Dysfunction of Mitochondria in Human Skeletal Muscle in Type 2 Diabetes
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Kelley, D. E., Goodpaster, B., Wing, R. R., & Simoneau, J.-A. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.6.e1130 · Cited by 1,096
Fuel selection in human skeletal muscle in insulin resistance: a reexamination.
Kelley, D. E., & Mandarino, L. J. (2000) · Diabetes · doi:10.2337/diabetes.49.5.677 · Cited by 1,017
Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes
Ritov, V. B., Menshikova, E. V., He, J., Ferrell, R. E., Goodpaster, B. H., & Kelley, D. E. (2005) · Diabetes · doi:10.2337/diabetes.54.1.8 · Cited by 887
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Items 101–200 of 528
Tsilingiris, D., Tzeravini, E., Koliaki, C. C., Dalamaga, Μ., & Kokkinos, A. D. (2021) · Current Obesity Reports · doi:10.1007/s13679-021-00434-0 · Cited by 60
“Monitoring of RQ in response to physiological or experimental nutritional challenges may thus serve as an indirect, non-invasive measure of whole-body metabolic flexibility [16].”
BackgroundIntermittent fasting influences immunity and metabolism
Marko, D. M., Conn, M. O., & Schertzer, J. D. (2024) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2024.04.014 · Cited by 62
Looking back into the future: 30 years of metabolomics at TNO
van der Greef, J., van Wietmarschen, H., van Ommen, B., & Verheij, E. R. (2013) · Mass Spectrometry Reviews · doi:10.1002/mas.21370 · Cited by 64
Rudwill, F., O’Gorman, D. J., Lefai, É., Chery, I., Zahariev, A., Normand, S., Pagano, A. F., Chopard, A., Damiot, A., Laurens, C., et al. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-02267 · Cited by 61
“(26) suggested that a number of additional metabolic challenges, besides the clamp, should be considered in the 1914 Rudwill et al Physical Inactivity and Metabolic Inflexibility J Clin Endocrinol Metab, May 2018, 103(5):1910–1920”
BackgroundSphingosine-1-Phosphate Metabolism in the Regulation of Obesity/Type 2 Diabetes
Guitton, J., Bandet, C. L., Mariko, M. L., Tan, S., Bourron, O., Benomar, Y., Hajduch, É., & Stunff, H. L. (2020) · Cells · doi:10.3390/cells9071682 · Cited by 66
“Obesity is a major public health problem, which results in over nutrition that leads to a net-positive energy balance characterized by the storage of excess fat in the subcutaneous and visceral adipose tissues, as well as in ectopic tissues, including skeletal muscles, liver, and pancreatic β cells [1].”
BackgroundLiang, H., Tantiwong, P., Sriwijitkamol, A., Shanmugasundaram, K., Mohan, S., Espinoza, S. E., DeFronzo, R. A., Dubé, J. J., & Musi, N. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2012.247510 · Cited by 59
“Decreased mitochondrial function has been proposed as a key determinant of metabolic inflexibility in insulin-resistant muscle (Galgani et al. 2008), although direct evidence supporting this concept is lacking.”
BackgroundMitchell, C. M., Davy, B. M., Halliday, T. M., Hulver, M. W., Neilson, A. P., Ponder, M. A., & Davy, K. P. (2015) · Contemporary Clinical Trials · doi:10.1016/j.cct.2015.10.012 · Cited by 59
“consistent with metabolic endotoxemia, activate skeletal muscle TLR4 resulting in state ofmetabolic inflexibility consistentwith that observed in insulin resistance and T2D [25,26].”
BackgroundNutrition and Nonalcoholic Fatty Liver Disease
Chakravarthy, M. V., Waddell, T. K., Banerjee, R., & Guess, N. D. (2019) · Gastroenterology Clinics of North America · doi:10.1016/j.gtc.2019.09.003 · Cited by 67
Effects of Intermittent Fasting on Cardiometabolic Health: An Energy Metabolism Perspective
Dote‐Montero, M., Sánchez‐Delgado, G., & Ravussin, É. (2022) · Nutrients · doi:10.3390/nu14030489 · Cited by 66
“The capacity to rapidly adjust substrate oxidation to substrate availability and energy demand, known as metabolic flexibility, is considered central in the prevention of ectopic fat accumulation, which in turn induces peripheral insulin resistance [61,62].”
BackgroundSelf-citationNie, G., Hou, S., Zhang, M., & Peng, W. (2021) · BMJ Open · doi:10.1136/bmjopen-2020-041519 · Cited by 57
Tinius, R. A., Blankenship, M. M., Furgal, K. E., Cade, W. T., Pearson, K. J., Rowland, N. S., Pearson, R. C., Hoover, D. L., & Maples, J. M. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154142 · Cited by 54
“When adjusted for age, physical activity level, and ethnicity (all factors that have been connected to metabolic flexibility and/or insulin resistance in non-gravid populations(17, 47, 48)) the relationship between metabolic flexibility and postprandial HOMA-IR remained significant at the 4-hour time point.”
BackgroundAzevedo, V. Z., Silaghi, C. A., Maurel, T., Silaghi, H., Ratziu, V., & Pais, R. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2021.774030 · Cited by 59
“In these settings, insulin pulsatile secretion is impaired and leads to hyperinsulinemia and insulin resistance (30, 31).”
BackgroundFerretti, G., Fagoni, N., Taboni, A., Vinetti, G., & di Prampero, P. E. (2022) · European Journal of Applied Physiology · doi:10.1007/s00421-022-04901-x · Cited by 67
Belman, J., Bian, R. R., Habtemichael, E. N., Li, D. T., Jurczak, M. J., Alcázar-Román, A. R., McNally, L. J., Shulman, G. I., & Bogan, J. S. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.603977 · Cited by 56
“Thus, the idea that this protein may also function in fatty acid metabolism in adipocytes is plausible and may be important for metabolic flexibility (55).”
BackgroundIs Metabolic Flexibility Altered in Multiple Sclerosis Patients?
Mähler, A., Steiniger, J., Bock, M., Brandt, A. U., Haas, V. K., Boschmann, M., & Paul, F. (2012) · PLoS ONE · doi:10.1371/journal.pone.0043675 · Cited by 55
“[15] We relied on a standardized protocol that we designed to study metabolic alterations in patients with lipodystrophy.”
MethodRogowski, M. P., Flowers, M. T., Stamatikos, A., Ntambi, J. M., & Paton, C. M. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m035865 · Cited by 55
Keildson, S., Fadista, J., Ladenvall, C., Hedman, Å. K., Elgzyri, T., Small, K. S., Grundberg, E., Nica, A. C., Glass, D., Richards, J. B., et al. (2013) · Diabetes · doi:10.2337/db13-1301 · Cited by 55
“Given that PFKM catalyzes a rate-limiting step in the glycolytic pathway, we investigated whether the eQTL SNP (rs4547172) was associated with measures of oxidative fuel partitioning, that is, metabolic flexibility measured as the d respiratory quotient (RQ) (26).”
BackgroundFat Quality Influences the Obesogenic Effect of High Fat Diets
Crescenzo, R., Bianco, F., Mazzoli, A., Giacco, A., Cancelliere, R., Fabio, G. D., Zarrelli, A., Liverini, G., & Iossa, S. (2015) · Nutrients · doi:10.3390/nu7115480 · Cited by 57
“When the macronutrient composition of the diet is modified, fuel oxidation must be adjusted to achieve a new equilibrium [25].”
BackgroundInfluentialDiamanti‐Kandarakis, E., Papalou, O., Kandaraki, E., & Kassi, G. (2016) · European Journal of Endocrinology · doi:10.1530/eje-16-0616 · Cited by 55
Čiapaitė, J., van den Berg, S. A. A., Houten, S. M., Nicolay, K., van Dijk, K. W., & Jeneson, J. A. L. (2014) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2014.09.014 · Cited by 58
“Obesity-related skeletal muscle insulin resistance is associated with accumulation of intramyocellular triacylglycerols (TAG), altered carbohydrate and lipid metabolism, resulting in diminished metabolic flexibility and impaired energy production [4], which, in turn, is essential for supporting normal contractile func…”
BackgroundLipid metabolites as metabolic messengers in inter-organ communication
Liu, S., Alexander, R., & Lee, C. (2014) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2014.05.002 · Cited by 57
Phy, J. L. (2015) · Journal of Obesity & Weight loss Therapy · doi:10.4172/2165-7904.1000259 · Cited by 60
“This reduced activity of LPL in skeletal muscle, and subsequently reduced lipid oxidation, has been linked with weight gain in prospective studies [11,14,15].”
BackgroundMetabolic and Energy Imbalance in Dysglycemia-Based Chronic Disease
Kalra, S., Unnikrishnan, A., Baruah, M. P., Sahay, R. K., & Bantwal, G. (2021) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s286888 · Cited by 55
Johnson, S. A., Painter, M. S., Javurek, A. B., Ellersieck, M. R., Wiedmeyer, C. E., Thyfault, J. P., & Rosenfeld, C. S. (2015) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s2040174415001488 · Cited by 56
“In addition, the metabolic inflexibility concept that has gained favor in the obesity field suggests that obese individuals have an elevated RQ during both fasting and fed conditions, while lean individuals have low RQ during fasting and high RQ during fed conditions, respectively.(90,91) Again, the concept is that th…”
BackgroundWhite Adipose Tissue Dysfunction: Pathophysiology and Emergent Measurements
Santillana, N., Astudillo-Guerrero, C., D’Espessailles, A., & Cruz, G. (2023) · Nutrients · doi:10.3390/nu15071722 · Cited by 62
Huffman, K. M., Redman, L. M., Landerman, L. R., Pieper, C. F., Stevens, R. D., Muehlbauer, M. J., Wenner, B. R., Bain, J. R., Kraus, V. B., Newgard, C. B., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0028190 · Cited by 49
“One example is the shift from the use of fatty acids as the main energy source during fasting conditions towards glucose utilization in a fed state [3].”
BackgroundInfluentialSelf-citationBonomini, M., Liberato, L. D., Rosso, G. D., Stingone, A., Marinangeli, G., Consoli, A., Bertoli, S. V., Vecchi, A. D., Bosi, E., Russo, R., et al. (2013) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2013.04.007 · Cited by 51
Kůs, V., Flachs, P., Kuda, O., Bardová, K., Janovská, P., Svobodová, M., Jílková, Z. M., Rossmeisl, M., Wang‐Sattler, R., Yu, Z., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027126 · Cited by 51
“major health problem around the world [1,2].”
BackgroundEarly or delayed time-restricted feeding prevents metabolic impact of obesity in mice
Regmi, P., Chaudhary, R. K., Page, A. J., Hutchison, A. T., Vincent, A. D., Liu, B., & Heilbronn, L. K. (2020) · Journal of Endocrinology · doi:10.1530/joe-20-0404 · Cited by 51
Mitochondrial fat oxidation is essential for lipid-induced inflammation in skeletal muscle in mice
Warfel, J. D., Bermudez, E. M., Mendoza, T. M., Ghosh, S., Zhang, J., Elks, C. M., Mynatt, R., & Vandanmagsar, B. (2016) · Scientific Reports · doi:10.1038/srep37941 · Cited by 50
Metabolic syndrome and its association with nonalcoholic steatohepatitis
Bril, F., Sanyal, A., & Cusi, K. (2023) · Clinics in Liver Disease · doi:10.1016/j.cld.2023.01.002 · Cited by 52
Park, Y. J., Kim, S. C., Kim, J.-H., Anakk, S., Lee, J. M., Tseng, H.-T., Yechoor, V. K., Park, J., Choi, J. S., Jang, H. C., et al. (2011) · Journal of Lipid Research · doi:10.1194/jlr.m016048 · Cited by 50
Brun, J.-F., Myzia, J., Varlet-Marie, E., Raynaud de Mauverger, E., & Mercier, J. (2022) · Nutrients · doi:10.3390/nu14081605 · Cited by 48
“The ability of the mitochondria to switch from fat to carbohydrate oxidation in response to changing physiological conditions and therefore to adapt fuel oxidation to fuel availability has been termed metabolic flexibility [92], and its defect, termed metabolic inflexibility, is observed in insulin resistance and type…”
BackgroundJørgensen, W., Rud, K. A., Mortensen, O. H., Frandsen, L., Grunnet, N., & Quistorff, B. (2017) · Physiological Reports · doi:10.14814/phy2.13207 · Cited by 48
“The glucose-fatty acid cycle, the so called Randle-effect, as observed at the whole body level is sometimes loosely also referred to as “metabolic flexibility” (Kelley et al. 1999; Galgani et al. 2008) and lack of metabolic flexibility has been associated with type 2 diabetes (Kelley et al.”
BackgroundTarpey, M. D., Davy, K. P., McMillan, R. P., Bowser, S. M., Halliday, T. M., Boutagy, N. E., Davy, B. M., Frisard, M. I., & Hulver, M. W. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.10.006 · Cited by 52
“com Metabolic inflexibility, defined as diminished capacity to adjust substrate oxidation in response to changes in substrate availability [15,16], has been implicated in the pathogenesis of obesity and the development of insulin resistance.”
BackgroundInfluentialMeyer, J. G., Softic, S., Basisty, N., Rardin, M. J., Verdin, E. M., Gibson, B. W., Ilkayeva, O., Newgard, C. B., Kahn, C. R., & Schilling, B. (2018) · PLoS ONE · doi:10.1371/journal.pone.0208973 · Cited by 52
Morris, E. M., Jackman, M. R., Meers, G. M.-E., Johnson, G. C., Lopez, J. L., MacLean, P. S., & Thyfault, J. P. (2013) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00179.2013 · Cited by 48
“As previously mentioned, reduced skeletal muscle mitochondrial respiratory capacity has been observed to be strongly correlated with metabolic inflexibility (10, 22), and improvements in mitochondrial respiratory capacity due to exercise parallel improvements in metabolic flexibility (35).”
BackgroundMethodInfluentialThe contribution of race and diabetes status to metabolic flexibility in humans
Stull, A. J., Galgani, J. E., Johnson, W. D., & Cefalu, W. T. (2010) · Metabolism · doi:10.1016/j.metabol.2009.12.020 · Cited by 47
“Galgani and colleagues (7) suggested that the GDR, baseline fasting RQ, and steady-state plasma free-fatty acid concentrations were important contributing factors to MF.”
BackgroundSelf-citationPrior, S. J., Ryan, A. S., Stevenson, T. G., & Goldberg, A. P. (2013) · Obesity · doi:10.1002/oby.20609 · Cited by 52
“Mitochondrial defects are also implicated in insulin-stimulated metabolic inflexibility [for review see (35)]; however, one would anticipate these mitochondrial defects would not preferentially limit fat or carbohydrate oxidation during exercise because the metabolic pathways of fatty acid oxidation and carbohydrate o…”
BackgroundSarra, D. D., Tosi, F., Bonin, C., Fiers, T., Kaufman, J., Signori, C., Zambotti, F., Dall'Alda, M., Caruso, B., Zanolin, M. E., et al. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-1161 · Cited by 47
“Moreover, it was hypothesized that metabolic inflexibility may lead to ectopic fat accumulation in insulin-sensitive tissues, such as liver and skeletal muscle (17).”
BackgroundRieusset, J. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.06.097 · Cited by 47
“Importantly, alterations in the immune-metabolism crosstalk promote metabolic diseases, and now it is well recognized that metabolic diseases, such as obesity and type 2 diabetes, are associated with metabolic inflexibility, inflammation and gut microbiota dysbiosis [2-4].”
Palmitate induces fat accumulation by activating C/EBPβ-mediated G0S2 expression in HepG2 cells
Zhao, N., Li, X.-Y., Wang, L., Feng, Z., Li, X.-F., Wen, Y., & Han, J. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i43.7705 · Cited by 47
Gilardi, F., Winkler, C., Quignodon, L., Diserens, J.-G., Toffoli, B., Schiffrin, M., Sardella, C., Preitner, F., & Desvergne, B. (2019) · Metabolism · doi:10.1016/j.metabol.2019.03.003 · Cited by 48
del Campo, A., Valenzuela, R., Videla, L. A., & Zúñiga‐Hernández, J. (2022) · Current Medicinal Chemistry · doi:10.2174/0929867330666221209093343 · Cited by 50
Bourlier, V., Saint-Laurent, C., Louche, K., Badin, P.-M., Thalamas, C., de Glisezinski, I., Langin, D., Sengenès, C., & Moro, C. (2013) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2013-1727 · Cited by 51
“Metabolic flexibility has been linked to ectopic fat deposition and insulin resistance (9, 10), and can be improved by diet-induced weight loss and exercise training (11, 12).”
BackgroundSelf-citationPrasad, V., Lorenz, J. N., Miller, M. L., et al. (2013) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2013.09.013 · Cited by 46
“, the ability to adjust substrate oxidation to substrate availability [42], when the mice are fed a high fat diet.”
BackgroundBergouignan, A., Momken, I., Lefai, É., Antoun, E., Schoeller, D. A., Platat, C., Chery, I., Zahariev, A., Vidal, H., Gabert, L., et al. (2013) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.112.057075 · Cited by 46
“A mechanistically lower AEE would favor a low energy turnover of intramuscular triglycerides (IMTGs) leading to cytosolic accumulation of fatty acid metabolites and disruption of the early steps in insulin signal transduction (34).”
BackgroundMayor, F., Cruces‐Sande, M., Arcones, A. C., Vila‐Bedmar, R., Briones, A. M., Salaíces, M., & Murga, C. (2017) · Cellular Signalling · doi:10.1016/j.cellsig.2017.04.002 · Cited by 46
Chrononutrition during Pregnancy: A Review on Maternal Night-Time Eating
Loy, S. L., Loo, R. S. X., Godfrey, K. M., Chong, Y. S., Shek, L. P., Tan, K. H., Chong, S. C., Chan, J. K. Y., & Yap, F. K. P. (2020) · Nutrients · doi:10.3390/nu12092783 · Cited by 46
“Fatty acids are the main energy source during overnight fasting [35,36].”
BackgroundMuscle mass and functional correlates of insulin sensitivity in lean young Indian men
Unni, U., Ramakrishnan, G., Raj, T., Kishore, R., Thomas, T., Vaz, M., & Kurpad, A. (2009) · European Journal of Clinical Nutrition · doi:10.1038/ejcn.2009.32 · Cited by 51
“This was significantly correlated with glucose disposal rate in the present study indicating a dependence on glucose transport across membranes, but not correlated with fasting plasma glucose, insulin or adiponectin as has been demonstrated in obese or diabetic subjects (Galgani et al., 2008a).”
BackgroundResultSaben, J. L., Bales, E. S., Jackman, M. R., Orlicky, D. J., MacLean, P. S., & McManaman, J. L. (2014) · PLoS ONE · doi:10.1371/journal.pone.0098066 · Cited by 44
“Diet-induced obesity has been shown to impair AMPK regulation by leptin, insulin, and sympathetic neural efferent’s in other tissues [56], and aspects of AMPK function appear to be restored with weight loss [57,58].”
BackgroundEarly metabolic improvement following bariatric surgery in morbidly obese adolescents
Teeple, E. A., TEICH, S. A., Schuster, D. P., & Michalsky, M. P. (2011) · Pediatric Blood & Cancer · doi:10.1002/pbc.23370 · Cited by 45
“In an effort to assign an overall explanation for these associated changes, ‘‘metabolic flexibility’’ has recently been described as the ability to transition between oxidation of different fuel substrates dependent on availability [17].”
BackgroundMitophagy and Mitochondrial Quality Control Mechanisms in the Heart
Gottlieb, R. A., & Thomas, A. (2017) · Current Pathobiology Reports · doi:10.1007/s40139-017-0133-y · Cited by 50
Dynamic mitochondrial responses to a high-fat diet in Drosophila melanogaster
Cormier, R. P. J., Champigny, C. M., Simard, C. J., St‐Cœur, P., & Pichaud, N. (2019) · Scientific Reports · doi:10.1038/s41598-018-36060-5 · Cited by 48
Metabolic flexibility and obesity in children and youth
Aucouturier, J., Duché, P., & Timmons, B. W. (2011) · Obesity Reviews · doi:10.1111/j.1467-789x.2010.00812.x · Cited by 43
“However, metabolic flexibility to lipid is also important because the ability to adapt fat utilization to availability determines the accumulation of fat in ectopic fat depots and the subsequent development of insulin resistance (54).”
BackgroundThe fasting‐feeding metabolic transition regulates mitochondrial dynamics
Castro‐Sepúlveda, M., Morio, B., Tuñón‐Suárez, M., Jannas-Vela, S., Díaz‐Castro, F., Rieusset, J., & Zbinden‐Foncea, H. (2021) · The FASEB Journal · doi:10.1096/fj.202100929r · Cited by 43
“The cells of the three donors were pooled and divided into three conditions for four hours; (1) Glucose; DMEM (does not contain glucose, pyruvate, and glutamine [Invitrogen]) supplemented with 10% dialyzed FBS, 10 mM glucose, and penicillin/streptomycin.”
MethodMeta-inflammation and cardiometabolic disease in obesity: Can heat therapy help?
Ely, B. R., Clayton, Z. S., McCurdy, C. E., Pfeiffer, J. D., & Minson, C. T. (2017) · Temperature · doi:10.1080/23328940.2017.1384089 · Cited by 46
“This results in systemic insulin resistance with an impaired ability of cells to transport glucose or suppress glucose production, creating a more metabolically inflexible profile.(23) In addition, adipokines such as leptin and adiponectin are altered in obesity,(24) with adiponectin in particular at much lower circul…”
BackgroundBezafibrate improves insulin sensitivity and metabolic flexibility in STZ-induced diabetic mice
Franko, A., Huypens, P., Neschen, S., Irmler, M., Rozman, J., Rathkolb, B., Neff, F., Prehn, C., Dubois, G., Baumann, M., et al. (2016) · Diabetes · doi:10.2337/db15-1670 · Cited by 42
“4E) outlined that the lower RER observed during the first half of the dark phase resulted from a marked delay in food intake in BEZ-treated STZ mice.”
BackgroundMethodInfluentialGlucose Tolerance is Linked to Postprandial Fuel Use Independent of Exercise Dose
Gilbertson, N. M., Eichner, N. Z. M., François, M. E., Gaitán, J. M., Heiston, E. M., WELTMAN, A. L., & Malin, S. K. (2018) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000001667 · Cited by 42
Veleba, J., Kopecký, J., Janovská, P., Kuda, O., Horakova, O., Malínská, H., Kazdová, L., Oliyarnyk, O., Škop, V., Trnovská, J., et al. (2015) · Nutrition & Metabolism · doi:10.1186/s12986-015-0047-9 · Cited by 43
“carbohydrates, which is usually impaired in insulinresistant individuals [27].”
BackgroundMaples, J. M., Brault, J. J., Witczak, C. A., Park, S., Hubal, M. J., Weber, T. M., Houmard, J. A., & Shewchuk, B. M. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00505.2014 · Cited by 39
Jousse, C., Muranishi, Y., Parry, L., Montaurier, C., Even, P. C., Launay, J., Carraro, V., Maurin, A., Avérous, J., Chaveroux, C., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0104896 · Cited by 38
“Indeed, changes in mitochondrial number and function in skeletal muscle and WAT in response to a high-fat-diet have been previously published [30–32].”
BackgroundGonzález-Franquesa, A., Gama-Pérez, P., Kulis, M., Szczepanowska, K., Dahdah, N., Moreno-Gomez, S., Latorre, A., Fernandez‐Ruiz, R., Aguilar‐Mogas, A., Hoffman, A., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102353 · Cited by 48
“Our current approach, combining nutritional and exercise interventions, has proved successful in the recovery of nearly all phenotypical metabolic alterations in diet-induced obese animals, a model that resembles the early stages of human obesity-related T2D pathology [9,10].”
BackgroundSjögren, R. J. O., Rizo‐Roca, D., Chibalin, A., Chorell, E., Furrer, R., Katayama, S., Harada, J., Karlsson, H., Handschin, C., Möritz, T., et al. (2021) · Diabetologia · doi:10.1007/s00125-021-05481-9 · Cited by 41
Shi, W., Hegeman, M. A., Doncheva, A. I., Bekkenkamp‐Grovenstein, M., de Boer, V. C. J., & Keijer, J. (2019) · Nutrients · doi:10.3390/nu11102439 · Cited by 37
“Metabolic flexibility on the whole-body level is defined as the ability to readily switch between carbohydrate oxidation and fatty acid oxidation in response to a physiological or nutritional intervention [32].”
BackgroundMorris, E. M., Noland, R. D., Allen, J., McCoin, C. S., Xia, Q., Koestler, D. C., Shook, R. P., Lighton, J. R. B., Christianson, J. A., & Thyfault, J. P. (2020) · Obesity · doi:10.1002/oby.22925 · Cited by 36
“We calculated metabolic flexibility, the capacity to adapt substrate use based on changes in substrate availability, as the difference in average daily respiratory quotient during HFHS feeding and LFD feeding (Figure 3B) (25,26).”
BackgroundMethodDuivenvoorde, L. P. M., van Schothorst, E. M., Swarts, H. J. M., Kuda, O., Steenbergh, E., Termeulen, S., Kopecký, J., & Keijer, J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0128515 · Cited by 38
“Fasting RER values were also similar between HFs and HFpu mice, indicating that mice do not differ in the flexibility to switch to the mobilization and oxidation of stored lipids [68].”
Samocha‐Bonet, D., Heilbronn, L. K., Lichtenberg, D. A., & Campbell, L. V. (2009) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2009.09.008 · Cited by 36
Fernández-Verdejo, R., Bajpeyi, S., Ravussin, E., & Galgani, J. E. (2018) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00126.2018 · Cited by 34
“Metabolic flexibility (MetFlex) is the capacity to adapt fuel oxidation to fuel availability (12).”
BackgroundSelf-citationCarstens, M. T., Goedecke, J. H., Dugas, L., Evans, J., Kroff, J., Levitt, N. S., & Lambert, E. V. (2013) · Nutrition & Metabolism · doi:10.1186/1743-7075-10-8 · Cited by 34
“However, unlike previous studies, the present study demonstrated these relationships using simple fasted resting measures of substrate oxidation, against self-reported, habitual dietary fat intake, without any manipulation of diet, or induced glycaemia [16].”
BackgroundResultPohlmeier, A. M., Phy, J. L., Watkins, P., Boylan, M., Spallholz, J., Harris, K. S., & Cooper, J. A. (2014) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2014-0073 · Cited by 34
“The association between insulin resistance and metabolic inflexibility has been previously demonstrated in women with PCOS and other populations exhibiting insulin resistance, such as individuals with obesity and type 2 diabetes (Zurlo et al. 1990; Galgani et al. 2008; Di Sarra et al. 2013).”
InfluentialFrankó, A., Neschen, S., Rozman, J., Rathkolb, B., Aichler, M., Feuchtinger, A., Brachthäuser, L., Neff, F., Kovářová, M., Wolf, E., et al. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2016.12.007 · Cited by 34
“Metabolic flexibility is assumed as the ability to change substrate oxidation from fat to carbohydrate and its malfunction is intimately related to insulin resistance and ectopic lipid accumulation [36].”
BackgroundA mathematical model of calcium dynamics: Obesity and mitochondria-associated ER membranes
Han, J. M., & Periwal, V. (2019) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006661 · Cited by 34
“Metabolic flexibility refers to the ability of the organism to adapt its fuel source, depending on availability and need [41], and emerging evidence suggests the involvement of MAMs in this adaptation [42].”
BackgroundBresciani, N., Demagny, H., Lemos, V., Pontanari, F., Li, X., Sun, Y., Li, H., Perino, A., Auwerx, J. H., & Schoonjans, K. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.05.040 · Cited by 34
Cappelli, A. P. G., Zoppi, C. C., Barbosa, H., Costa, J. M., Protzek, A. O. P., Morato, P. N., Boschero, A. C., & Carneiro, E. M. (2013) · Liver International · doi:10.1111/liv.12291 · Cited by 33
“These effects have been reported in obese insulin resistant and diabetic humans and rodents (25, 26).”
BackgroundIssues and Misconceptions About Obesity
Flatt, J. P. (2011) · Obesity · doi:10.1038/oby.2011.7 · Cited by 33
“There is no reason to think that the way in which the organism is poised in regulating the relative use of CHO and fat should not be affected by inherited metabolic and hormonal differences (53).”
BackgroundKahlhöfer, J., Lagerpusch, M., Enderle, J., Eggeling, B., Braun, W., Pape, D., Müller, M. J., & Bosy‐Westphal, A. (2014) · European Journal of Clinical Nutrition · doi:10.1038/ejcn.2014.132 · Cited by 31
Daily variation of serum acylcarnitines and amino acids
Thompson, D. K., Sloane, R. J., Bain, J. R., Stevens, R. D., Newgard, C. B., Pieper, C. F., & Kraus, V. B. (2011) · Metabolomics · doi:10.1007/s11306-011-0345-9 · Cited by 32
“Furthermore, this approach appears particularly well-suited for future studies focused on metabolic flexibility, generally understood as the capacity to appropriately match fuel oxidation with substrate availability ( Galgani et al. 2008 ).”
BackgroundApplication of combined omics platforms to accelerate biomedical discovery in diabesity
Kurland, I. J., Accili, D., Burant, C., Fischer, S. M., Kahn, B. B., Newgard, C. B., Ramagiri, S., Ronnett, G. V., Ryals, J. A., Sanders, M., et al. (2013) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12116 · Cited by 33
Khamoui, A. V., Desai, M., Ross, M. G., & Rossiter, H. B. (2018) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s2040174418000594 · Cited by 32
Cardiorespiratory Fitness, Physical Activity, and Insulin Resistance in Children
Haapala, E. A., Wiklund, P., Lintu, N., Tompuri, T., Väistö, J., Finni, T. J., Tarkka, I. M., KEMPPAINEN, T., BARKER, A. R., Ekelund, U., et al. (2019) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000002216 · Cited by 30
Gene-Environmental Interactions as Metabolic Drivers of Nonalcoholic Steatohepatitis
Albhaisi, S. A. M., & Sanyal, A. J. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.665987 · Cited by 28
“Metabolic flexibility refers to the body’s ability to adequately handle substrates and maintain energy homeostasis (Figure 1) (36).”
BackgroundRhodes, P., Craigon, J., Gray, C. L., Rhind, S., Loughna, P. T., & Gardner, D. S. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007393 · Cited by 29
“longer exposure to the obesogenic environment), overt peripheral insulin resistance would perhaps be more likely to develop and be more pronounced in those sheep undernourished during late gestation [52].”
BackgroundLipolytic Markers, Insulin and Resting Fat Oxidation are Associated with Maximal Fat Oxidation
Robinson, S., Chambers, E. S., Fletcher, G., & Wallis, G. A. (2016) · International Journal of Sports Medicine · doi:10.1055/s-0042-100291 · Cited by 31
“Studies of metabolic flexibility have shown that dietary nutrient intake and energy balance can affect resting substrate oxidation and subsequent responses to metabolic challenges [16].”
BackgroundInflexibility of AMPK-mediated metabolic reprogramming in mitochondrial disease
Lin, D., Kao, S., Ho, C. S., Wei, Y., Hung, P., Hsu, M., Wu, T., Wang, T.-J., Jian, Y.-R., Lee, T., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.20617 · Cited by 31
“Metabolic flexibility is the capacity of an organism to adapt fuel utilization to fuel availability [49].”
BackgroundMetabolic inflexibility in women with polycystic ovary syndrome: a systematic review
Rimmer, M., Tan, B. K., Teede, H., Thangaratinam, S., & H. Al Wattar, B. (2020) · Gynecological Endocrinology · doi:10.1080/09513590.2019.1698025 · Cited by 29
“skeletal muscles) inducing lipotoxicity with worsening insulin resistance [5].”
BackgroundSilver, H. J., Kang, H., Keil, C. D., Muldowney, J. A. S., Kocalis, H. E., Fazio, S., Vaughan, D. E., & Niswender, K. D. (2014) · Metabolism · doi:10.1016/j.metabol.2014.01.004 · Cited by 34
“Importantly, enhanced oxidation should decrease vulnerability to inflammation and insulin resistance [42].”
BackgroundChildhood obesity: the impact on long-term risk of metabolic and CVD is not necessarily inevitable
McMullen, S. (2014) · Proceedings of The Nutrition Society · doi:10.1017/s0029665114000111 · Cited by 30
Terrien, J., Gaudubois, M., Champeval, D., Zaninotto, V., Roger, L., Riou, J., & Aujard, F. (2017) · International Journal of Obesity · doi:10.1038/ijo.2017.195 · Cited by 26
Liu, Y., Wang, J., Zhou, X., Cao, H., Zhang, X., Huang, K., Li, X., Yang, G., & Shi, X. (2020) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2020.09.037 · Cited by 29
“Skeletal muscle is an important organ for energy metabolism in the body.(35) Emerging evidences have indicated that lipid overflow to nonadipose tissues results in muscular fat storage, which is related to insulin resistance.”
BackgroundGilbertson, N. M., Gaitán, J. M., Osinski, V., Rexrode, E. A., Garmey, J. C., Mehaffey, J. H., Hassinger, T. E., Kranz, S., McNamara, C. A., WELTMAN, A. L., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0239130 · Cited by 29
Cormier, R. J., Strang, R., Menail, H. A., Touaibia, M., & Pichaud, N. (2021) · Insect Biochemistry and Molecular Biology · doi:10.1016/j.ibmb.2021.103556 · Cited by 32
Cellular heterogeneity in superficial and deep subcutaneous adipose tissues in overweight patients
Boulet, N., Estève, D., Bouloumié, A., et al. (2012) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-012-0225-4 · Cited by 29
“buffering capacity might lead to ectopic lipid depots in other metabolically active tissues [11].”
BackgroundGuadalupe‐Grau, A., Fernández-Elías, V. E., ORTEGA, J. F., Dela, F., Helge, J. W., & Mora‐Rodríguez, R. (2017) · Scandinavian Journal of Medicine and Science in Sports · doi:10.1111/sms.12881 · Cited by 30
Amaro‐Gahete, F. J., De‐la‐O, A., Jurado‐Fasoli, L., Sánchez‐Delgado, G., Ruiz, J. R., & Castillo, M. J. (2020) · Clinical Nutrition · doi:10.1016/j.clnu.2020.02.001 · Cited by 31
Zhao, N., Tan, H., Wang, L., Han, L., Cheng, Y., Feng, Y., Li, T., & Liu, X. (2021) · PLoS ONE · doi:10.1371/journal.pone.0243938 · Cited by 28
“This creates an overall enhanced hepatic supply of circulating FFAs and subsequently leads to ectopic fat deposition in the liver [5,6].”
BackgroundHypermetabolism and altered substrate oxidation in HIV-infected patients with lipodystrophy
Vassimon, H. S., de Paula, F. J. A., Machado, A. A., Monteiro, J. P., & Jordão, A. A. (2012) · Nutrition · doi:10.1016/j.nut.2011.12.010 · Cited by 27
“This is known as metabolic flexibility, “the capacity to switch from predominantly lipid oxidation and high rates of fatty acid uptake during fasting conditions to the suppression of lipid oxidation and increased glucose uptake, oxidation, and storage under insulin-stimulated conditions” [19,26].”
BackgroundThe RNA binding protein HuR influences skeletal muscle metabolic flexibility in rodents and humans
Mynatt, R. L., Noland, R. C., Elks, C. M., Vandanmagsar, B., Bayless, D. S., Stone, A. C., Ghosh, S., Ravussin, É., & Warfel, J. D. (2019) · Metabolism · doi:10.1016/j.metabol.2019.05.010 · Cited by 28
“Classical approaches to describing whole body and skeletal muscle metabolic flexibility have involved measurement of RER changes before and after insulin stimulation[1, 5, 33].”
BackgroundResultInfluentialSelf-citationTrinchese, G., Cavaliere, G., Cimmino, F., Catapano, A., Carta, G., Pirozzi, C., Murru, E., Lama, A., Meli, R., Bergamo, P., et al. (2020) · Cells · doi:10.3390/cells9040823 · Cited by 27
“Deteriorated insulin-mediated substrate switching is the best example of metabolic inflexibility and it has a central role in obesity and in the development of insulin resistance [5].”
BackgroundDalske, K. A., Raymond‐Pope, C. J., McFaline‐Figueroa, J., Basten, A. M., Call, J. A., & Greising, S. M. (2021) · PLoS ONE · doi:10.1371/journal.pone.0253629 · Cited by 31
Metadata
- 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
- 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
- green
- www.ncbi.nlm.nih.gov
- 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 (medical) › 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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