The DOI matches its Crossref record; 68 of the 68 references it cites were found in a registry or an index; 9 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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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
44 Not checked yet · 30 Own interpretation · 5 Partly supported · 5 No basis given · 1 Supported so far · 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)
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In the paper
“Further support for these findings comes from studies in which glucose disposal rates were matched by increasing the glucose or insulin infusion rates ([27](#r27), [66](#r66)).”
§ Metabolic flexibility and insulin resistance > Abstract > Determinant Factors of Metabolic Flexibility
What the sources say
- Supportedcites [27] source
The Introduction describes studies that used hyperglycemia to match glucose disposal in people with NIDDM and controls. The Discussion says this paper likewise achieved comparable systemic glucose uptake by studying participants with NIDDM at their fasting hyperglycemia while controls remained euglycemic. This supports the glucose-based example; the sentence also cites another study for the insulin-based alternative. (LLM, conf=0.89)
- Not checked yetcites [66] source
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In the paper
“Furthermore, the mitochondrial capacity to oxidize acetyl-CoA coming from glucose is conserved in insulin-resistant subjects even if mitochondrial defects have been reported in those individuals ([3](#r3), [25](#r25), [36](#r36), [37](#r37), [40](#r40), [42](#r42), [43](#r43), [48](#r48), [59](#r59)).”
§ Metabolic flexibility and insulin resistance > Abstract > Conclusions
What the sources say
- Partly supportedcites [3] sourceExperimental — accuracy not yet measured
The Discussion (page not provided) reports impaired mitochondrial function in insulin-resistant offspring, supporting the sentence’s reference to mitochondrial defects. It does not establish that their capacity to oxidize glucose-derived acetyl-CoA is conserved; instead, it reports about 30% lower total muscle substrate oxidation measured using labeled acetate. The glucose-specific part of the claim is therefore unsupported by this paper. (LLM, conf=0.86)
- Not checked yetcites [25] source
- Partly supportedcites [36] sourceExperimental — accuracy not yet measured
The Results report mitochondrial defects in obese patients with type 2 diabetes, supporting that part of the sentence. But they report significantly reduced maximal respiration with pyruvate plus malate compared with obese nondiabetic subjects, not conserved capacity for respiration using a glucose-derived substrate. The study also does not establish that result for insulin-resistant subjects generally. (LLM, conf=0.86)
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In the paper
“However, fasting RQ is not a reliable indicator of lipid oxidation capacity, since RQ under fasting conditions is mostly influenced by energy balance and dietary macronutrient composition ([22](#r22), [34](#r34), [54](#r54)).”
§ Metabolic flexibility and insulin resistance > Abstract > Conclusions
What the sources say
- Partly supportedcites [22] sourceExperimental — accuracy not yet measured
The Energy balance section reports that RQ measured after a 12-hour postabsorptive period was higher after the high-carbohydrate, low-fat diet than after the mixed diet. The Discussion likewise says dietary effects persisted in the postabsorptive state. The paper does not establish that fasting RQ is mostly influenced by energy balance or directly assess whether it reliably indicates lipid oxidation capacity; both diets produced a negative energy balance. (LLM, conf=0.83)
- Not checked yetcites [34] McNeill G , Bruce AC, Ralph A, James WP. Inter-individual differences in fasting nutrient oxidation and the influence of diet composition. Int J Obes 12 : 455–463, 1988.
- Not checked yetcites [54] Schutz Y . The adjustment of energy expenditure and oxidation to energy intake: the role of carbohydrate and fat balance. Int J Obes Relat Metab Disord 17 , Suppl 3: S23–S27; discussion S41–S42, 1993.
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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
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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
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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
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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
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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
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- It may state two separate claims as one. 16
- Probably not a substantial claim. 2
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The cited sources support only part of this claim — read each source’s verdict below.
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
- Supportedcites [14] source
The CONCLUSIONS section says insulin-resistant subjects have shown a blunted respiratory-quotient response during a hyperinsulinemic clamp. The RESULTS and DISCUSSION sections report lower insulin-stimulated nonoxidative glucose disposal—a measure that includes glucose storage—in the type 2 diabetes group. The paper also notes that both differences disappear after adjustment for glucose disposal rate; the claim describes the reported unadjusted findings. (LLM, conf=0.91)
- Not checked yetcites [24] source
- Partly supportedcites [61] sourceExperimental — accuracy not yet measured
The Introduction says insulin-resistant muscle does not switch to carbohydrate oxidation in response to insulin, and the results section reports that metabolic flexibility during a hyperinsulinemic clamp correlates with insulin sensitivity. The cited paper does not report impaired glucose storage during the clamp; its clamp measures glucose disposal and fuel switching, not storage. Page numbers are unavailable in our copy. (LLM, conf=0.87)
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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
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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
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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
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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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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
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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
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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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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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.
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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
Cites
Mootha, V. K., Lindgren, C. M., Eriksson, K.-F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstråle, M., Laurila, E., et al. (2003) · Nature Genetics · doi:10.1038/ng1180 · Cited by 10,197
Dysfunction of Mitochondria in Human Skeletal Muscle in Type 2 Diabetes
Kelley, D. E., He, J., Menshikova, E. V., & Ritov, V. B. (2002) · Diabetes · doi:10.2337/diabetes.51.10.2944 · Cited by 2,321
Impaired Mitochondrial Activity in the Insulin-Resistant Offspring of Patients with Type 2 Diabetes
Petersen, K. F., Dufour, S., Befroy, D., Garcia, R., & Shulman, G. I. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa031314 · Cited by 2,193
Koves, T. R., Ussher, J. R., Noland, R. C., Slentz, D., Mosedale, M., Ilkayeva, O., Bain, J., Stevens, R., Dyck, J. R. B., Newgard, C. B., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.013 · Cited by 1,990
Patti, M. E., Butte, A. J., Crunkhorn, S., Cusi, K., Berria, R., Kashyap, S., Miyazaki, Y., Kohane, I., Costello, M., Saccone, R., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1032913100 · Cited by 1,952
Dresner, A., Laurent, D., Marcucci, M., Griffin, M. E., Dufour, S., Cline, G. W., Slezak, L. A., Andersen, D. K., Hundal, R. S., Rothman, D. L., et al. (1999) · Journal of Clinical Investigation · doi:10.1172/jci5001 · Cited by 1,311
Krssak, M., Falk Petersen, K., Dresner, A., DiPietro, L., Vogel, S. M., Rothman, D. L., Shulman, G. I., & Roden, M. (1999) · Diabetologia · doi:10.1007/s001250051123 · Cited by 1,264
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
Cited by
Sorted by citations
Items 201–300 of 528
Long noncoding RNA ZFP36L2-AS functions as a metabolic modulator to regulate muscle development
Cai, B., Ma, M., Zhang, J., Kong, S., Zhou, Z., Li, Z., Abdalla, B. A., Xu, H., Zhang, X., Lawal, R. A., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04772-2 · Cited by 28
“Metabolic inflexibility in muscles is a dominant cause of various metabolic disorders [5].”
BackgroundZhang, S., McMillan, R. P., Hulver, M. W., Siegel, P. B., Sumners, L. H., Zhang, W., Cline, M. A., & Gilbert, E. R. (2014) · International Journal of Obesity · doi:10.1038/ijo.2014.8 · Cited by 26
Vaitheesvaran, B., Hartil, K., Navare, A., Zheng, C., Broin, P. Ó., Golden, A., Guha, C., Lee, W. N., Kurland, I. J., & Bruce, J. E. (2014) · Metabolomics · doi:10.1007/s11306-014-0639-9 · Cited by 25
“Impaired mitochondrial function may be a primary cause for metabolic inflexibility (van de Weijer et al. 2013; Galgani et al. 2008).”
BackgroundReactive oxygen species: role in obesity and mitochondrial energy efficiency
Corkey, B. E. (2023) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2022.0210 · Cited by 30
“Regulation occurs through alterations in food input, exercise and energy efficiency [12].”
BackgroundA review of standardized metabolic phenotyping of animal models
Rozman, J., Klingenspor, M., & de Angelis, M. H. (2014) · Mammalian Genome · doi:10.1007/s00335-014-9532-0 · Cited by 25
Fechner, E., Bilet, L., Peters, H. P. F., Hiemstra, H., Jacobs, D. M., Eyndt, C. O. ‘., Moonen‐Kornips, E., Mensink, R. P., & Schrauwen, P. (2019) · Clinical Nutrition · doi:10.1016/j.clnu.2019.12.010 · Cited by 27
“Typically, metabolic flexibility is expressed as the change in respiratory quotient (DRQ) from fasting to insulin-stimulated or postprandial conditions and can be measured by indirect calorimetry [3,4].”
Backgroundde Castro, C. A., da Silva, K. A., Rocha, M. C., Sene‐Fiorese, M., Nonaka, K. O., Malavazi, I., Aníbal, F. D. F., & Duarte, A. C. G. D. O. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2018.01881 · Cited by 24
“Studies have considered the hypothesis that dysfunction in peripheral tissues, such as skeletal muscle and adipose tissue, represent the etiology of the development of metabolic inflexibility (Saltiel and Kahn, 2001) due to the inability of increasing glucose oxidation during insulin stimulation (Galgani et al., 2008;…”
BackgroundAssociation between sleep quality and time with energy metabolism in sedentary adults
Jurado‐Fasoli, L., Mochón-Benguigui, S., Castillo, M. J., & Amaro‐Gahete, F. J. (2020) · Scientific Reports · doi:10.1038/s41598-020-61493-2 · Cited by 25
The Na/K‐ATPase α1/Src interaction regulates metabolic reserve and Western diet intolerance
Kutz, L. C., Cui, X., Xie, J. X., Mukherji, S. T., Terrell, K. C., Huang, M., Wang, X., Wang, J., Martin, A. J., Pessoa, M. T., et al. (2021) · Acta Physiologica · doi:10.1111/apha.13652 · Cited by 24
Hénin, G., Lanthier, N., & Dahlqvist, G. (2022) · Acta gastro-enterologica belgica · doi:10.51821/85.4.10899 · Cited by 26
Taurine and Regulation of Mitochondrial Metabolism
Hansen, S. H., Birkedal, H., Wibrand, F., & Grunnet, N. (2015) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-15126-7_30 · Cited by 25
Role of Skeletal Muscle Mitochondrial Density on Exercise‐Stimulated Lipid Oxidation
Galgani, J. E., Johannsen, N. M., Bajpeyi, S., Costford, S. R., Zhang, Z., Gupta, A., & Ravussin, É. (2011) · Obesity · doi:10.1038/oby.2011.166 · Cited by 27
“As discussed elsewhere (40), RQ is mostly affected by energy balance and diet composition.”
BackgroundSelf-citationGreen, C., Bunprajun, T., Pedersen, B. K., & Schéele, C. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.251421 · Cited by 27
“Therefore, type 2 diabetes is known as a ‘lifestyle’ disease and has been associated with metabolic inflexibility: a reduced capacity to increase fatty acid oxidation upon increased fatty acid availability and to switch between fuel sources following a meal (Kelley et al. 2002; Galgani et al. 2008).”
BackgroundInfluentialGabriel, B. M., Al-Tarrah, M., Alhindi, Y. Z., Kilikevičius, A., Venckūnas, T., Gray, S. R., Lionikas, A., & Ratkevičius, A. (2017) · PLoS ONE · doi:10.1371/journal.pone.0185789 · Cited by 24
Metabolic inflexibility in women with PCOS is similar to women with type 2 diabetes
Broskey, N. T., Tam, C. S., Sutton, E. F., Altazan, A. D., Burton, J. H., Ravussin, É., & Redman, L. M. (2018) · Nutrition & Metabolism · doi:10.1186/s12986-018-0312-9 · Cited by 25
Self-citationImportance of Adipose Tissue NAD+ Biology in Regulating Metabolic Flexibility
Franczyk, M. P., Qi, N., Stromsdorfer, K. L., Li, C., Yamaguchi, S., Itoh, H., Yoshino, M., Sasaki, Y., Brookheart, R. T., Finck, B. N., et al. (2021) · Endocrinology · doi:10.1210/endocr/bqab006 · Cited by 23
Dietary Macronutrient Management to Treat Mitochondrial Dysfunction in Parkinson’s Disease
Bajracharya, R., Youngson, N. A., & Ballard, J. W. O. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20081850 · Cited by 24
“Metabolic flexibility is the capacity of an organism to modify energy oxidation in response to nutrient availability, thus allowing it to adapt to a variety of physiological conditions [105].”
BackgroundTowards precision medicine in non-alcoholic fatty liver disease
Francque, S. (2023) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-023-09820-6 · Cited by 25
“Impaired metabolic flexibility or adaptation, which develop with age and weight gain, have been associated with further weight gain [54] and ectopic fat deposition [55, 56], insulin resistance [57, 58], type 2 diabetes mellitus [58] and NAFLD [59].”
BackgroundCasazza, K., Hanks, L. J., Beasley, T. M., & Fernández, J. R. (2011) · American Journal of Physical Anthropology · doi:10.1002/ajpa.21483 · Cited by 18
“Physical activity has consistently demonstrated to influence fat mass accrual as well as fat oxidative capacity (Chakravarthy and Booth, 2004; Galgani et al., 2008b; Weyer et al., 2000).”
BackgroundTaylor, H., Wu, C.-L., Chen, Y., Wang, P.-G., Gonzalez, J. T., & Betts, J. A. (2018) · Nutrients · doi:10.3390/nu10020123 · Cited by 23
“It has been suggested that impaired metabolic flexibility may be an early cause of insulin resistance via lipid accumulation [8,9], although the direction of the relationship between metabolic flexibility and insulin sensitivity remains unclear.”
BackgroundMetabolic responses to intermittent hypoxia are regulated by sex and estradiol in mice
Marcouiller, F., Jochmans‐Lemoine, A., Ganouna‐Cohen, G., Mouchiroud, M., Laplante, M., Marette, A., Bairam, A., & Joseph, V. (2020) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00272.2020 · Cited by 23
Wallenius, K., Kjellstedt, A., Thalén, P., Löfgren, L., & Oakes, N. D. (2013) · PPAR Research · doi:10.1155/2013/305347 · Cited by 22
“…August 2013 Academic Editor: Brian Finck Copyright © 2013 Kristina Wallenius et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.”
MethodInfluentialRynders, C. A., Bergouignan, A., Kealey, E. H., & Bessesen, D. H. (2017) · Obesity · doi:10.1002/oby.21807 · Cited by 23
“resistance, low leptin, and reduced sympathetic nervous system activity (5-8).”
Palmer, N. D., Okut, H., Hsu, F., Ng, M. C. Y., Chen, Y. I., Goodarzi, M. O., Taylor, K. D., Norris, J. M., Lorenzo, C., Rotter, J. I., et al. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-02203 · Cited by 22
Eelderink, C., Rietsema, S., van Vliet, I. M. Y., Loef, L. C., Boer, T. S., Koehorst, M., Nolte, I. M., Westerhuis, R., Singh‐Povel, C. M., Geurts, J. M. W., et al. (2019) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqz017 · Cited by 22
“Metabolic flexibility, the ability to switch back and forth between the 2 major energy substrates—(glucose and fat)—based on availability and need, forms a hallmark example of such a homeostatic system (19).”
BackgroundProlonged Rapamycin treatment led to beneficial metabolic switch
Fang, Y., & Bartke, A. (2013) · Aging · doi:10.18632/aging.100554 · Cited by 21
Goldenshluger, A., Constantini, K., Goldstein, N., Shelef, I., Schwarzfuchs, D., Zelicha, H., Meir, A. Y., Tsaban, G., Chassidim, Y., & Gepner, Y. (2021) · Nutrients · doi:10.3390/nu13072230 · Cited by 27
“Previous studies have associated RQ and metabolic outcomes such as hypertriglyceridemia [46,47], and similarly to our results, to insulin function [21,48,49], and hepatosteatosis [50], where higher RQ may increase hepatic fat accumulation and promote liver pathogenesis due to lower fat oxidation [50].”
BackgroundMethodResultMetabolic Dysfunction in Diabetic Offspring
Russell, R., Kraemer, R. R., & Nelson, A. G. (2013) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0b013e31826909d3 · Cited by 22
“Furthermore, assessment of MF at rest may be insufficient to detect deficiencies in fat metabolism, because demand for fat oxidation at rest is minimal (16).”
BackgroundResultInfluentialKim, D. H., Sartor, M. A., Bain, J. R., Sandoval, D. A., Stevens, R. D., Medvedovic, M., Newgard, C. B., Woods, S. C., & Seeley, R. J. (2012) · Diabetes · doi:10.2337/db11-1579 · Cited by 21
Sen, I., Bozkurt, O., Aras, E., Heise, S., Brockmann, G. A., & Severcan, F. (2015) · Applied Spectroscopy · doi:10.1366/14-07443 · Cited by 21
Archer, E., Pavela, G., McDonald, S. M., Lavie, C. J., & Hill, J. O. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.01053 · Cited by 23
No Influence of Overweight/Obesity on Exercise Lipid Oxidation: A Systematic Review
Arad, A. D., Basile, A. J., Albu, J., & DiMenna, F. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21051614 · Cited by 24
“A better alternative might be to investigate lipid use during moderate-intensity exercise when metabolic activity is higher, yet lipid can still contribute significantly [20].”
BackgroundJung, Y. H., & Bu, S. Y. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2020.158678 · Cited by 21
Pesta, D. H., Anadol, E., Sarabhai, T., den Kamp, Y. J. M. O., Gancheva, S., Trinks, N., Zaharia, O., Mastrototaro, L., Lyu, K., Habets, I., et al. (2025) · Science Advances · doi:10.1126/sciadv.adr8849 · Cited by 23
Nellemann, B., Gormsen, L. C., Sørensen, L. P., Christiansen, J. S., & Nielsen, S. (2011) · Obesity · doi:10.1038/oby.2011.290 · Cited by 21
Impaired Metabolic Flexibility in the Osteoarthritis Process: A Study on Transmitochondrial Cybrids
Dalmao‐Fernández, A., Lund, J., Hermida‐Gómez, T., Vázquez-Mosquera, M. E., Rego‐Pérez, I., Blanco, F. J., & Fernández-Moreno, M. (2020) · Cells · doi:10.3390/cells9040809 · Cited by 19
“Metabolic inflexibility implies mitochondrial dysfunction and, depending on substrate availability, impaired glucose or FA oxidation which further leads to nutrient accumulation [7,8].”
BackgroundMetabolic responses to polychromatic LED and OLED light at night
Ishihara, A., Park, I., Suzuki, Y., Yajima, K., Cui, H., Yanagisawa, M., Sano, T., Kido, J., & Tokuyama, K. (2021) · Scientific Reports · doi:10.1038/s41598-021-91828-6 · Cited by 20
Stimulatory Effects of Balanced Deep Sea Water on Mitochondrial Biogenesis and Function
Ha, B. G., Park, J., Hyun-Jung, C., & Shon, Y. H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0129972 · Cited by 20
“These suggest that mitochondrial dysfunction might contribute to metabolic inflexibility and insulin resistance [29].”
Bartsch, M., Vital, M., Woltemate, S., Bouwman, F. G., Berkemeyer, S., Hahn, A., & Müller, M. (2025) · Journal of Nutrition · doi:10.1016/j.tjnut.2025.08.034 · Cited by 25
“However, such effects may require prolonged exposure or are more evident in metabolically impaired individuals, where homeostatic mechanisms are less robust [49].”
Ang, J.-H. C., Sun, L., Foo, S.-Y. R., Leow, M. K., Vidal‐Puig, A., Fontana, L., & Dalakoti, M. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102354 · Cited by 23
“6 This rigidity in fuel switching and utilization creates a vicious cycle, where insulin resistance and insufficient lipid utilization result in, and are mutually reinforced by, metabolic inflexibility, driving the organism toward metabolic dysfunction, particularly in the context of chronic…”
InfluentialMetabolic flexibility during sleep
Zhang, S., Tanaka, Y., Ishihara, A., Uchizawa, A., Park, I., Iwayama, K., Ogata, H., Yajima, K., Omi, N., Satoh, M., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-97301-8 · Cited by 21
Empagliflozin restores cardiac metabolic flexibility in diet-induced obese C57BL6/J mice
Xie, B., Ramirez, W., Mills, A. M., Huckestein, B. R., Anderson, M., Pangburn, M. M., Lang, E. Y., Mullett, S. J., Chuan, B. W., Guo, L., et al. (2022) · Current Research in Physiology · doi:10.1016/j.crphys.2022.05.003 · Cited by 19
“Insulin resistance plays an important role in obesity-associated metabolic inflexibility by reducing the amount of glucose transported and thus oxidized by cell types expressing the insulin-responsive glucose transporter GLUT4, such as skeletal and cardiac muscle (Galgani et al., 2008).”
BackgroundGalgani, J. E., & Castro‐Sepúlveda, M. (2017) · Obesity · doi:10.1002/oby.21981 · Cited by 19
“, ability of adapting fuel oxidation to fuel availability) is commonly assessed by the increase in RQ during a euglycemic-hyperglycemic clamp (8).”
BackgroundSelf-citationFernández‐Verdejo, R., Castro‐Sepúlveda, M., Gutiérrez‐Pino, J., Malo‐Vintimilla, L., López‐Fuenzalida, A., Olmos, P. R., Santos, J. L., & Galgani, J. E. (2020) · Obesity · doi:10.1002/oby.22783 · Cited by 19
“thus allows maintenance of metabolic homeostasis during metabolic challenges such as nutrient ingestion and fasting (1).”
BackgroundInfluentialSelf-citationNutritional Mechanisms of Cancer Cachexia
Compton, S. L. E., Heymsfield, S. B., & Brown, J. C. (2024) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-062122-015646 · Cited by 23
Novelle, M. G., Vazquez, M. J., Peinado, J. R., Martinello, K. D. B., López, M., Luckman, S. M., Tena‐Sempere, M., Malagón, M. M., Nogueiras, R., & Diéguez, C. (2017) · Scientific Reports · doi:10.1038/srep46194 · Cited by 18
Decreased complexity of glucose dynamics preceding the onset of diabetes in mice and rats
Zhang, X. D., Pechter, D., Yang, L. M., Ping, X., Yao, Z., Zhang, R., Shen, X., Li, N. X., Connick, J. H., Nawrocki, A. R., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0182810 · Cited by 18
Amaro‐Gahete, F. J., Sánchez‐Delgado, G., Helge, J. W., & Ruiz, J. R. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00909 · Cited by 18
Kumagai, H., Kim, S., Miller, B., Natsume, T., Wan, J., Kumagai, M. E., Ramírez, R., Lee, S. H., Sato, A., Mehta, H. H., et al. (2024) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00285.2023 · Cited by 20
Even, P. C. (2011) · Frontiers in Physiology · doi:10.3389/fphys.2011.00096 · Cited by 18
“…been suggested in the literature, but one possible mechanism that we consider worth further investigation may be a defective lipid oxidation located specifically in muscles which progressively leads to fat accumulation in muscle and insulin resistance if HFD is continued (Galgani et al., 2008).”
Kruppel‐like factor 15 regulates fuel switching between glucose and fatty acids in brown adipocytes
Nabatame, Y., Hosooka, T., Aoki, C., Hosokawa, Y., Imamori, M., Tamori, Y., Okamatsu‐Ogura, Y., Yoneshiro, T., Kajimura, S., Saito, M., et al. (2021) · Journal of Diabetes Investigation · doi:10.1111/jdi.13511 · Cited by 17
Apaijai, N., Chattipakorn, S. C., & Chattipakorn, N. (2014) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-014-6553-6 · Cited by 18
“However, excess FFA can increase intracellular oxidative stress [47, 49].”
BackgroundAlterations in the carnitine cycle in a mouse model of Rett syndrome
Mucerino, S., Salle, A. D., Alessio, N., Margarucci, S., Nicolai, R., Melone, M. A. B., Galderisi, U., & Peluso, G. (2017) · Scientific Reports · doi:10.1038/srep41824 · Cited by 18
Low capacity to oxidize fat and body weight
Péronnet, F., & Haman, F. (2019) · Obesity Reviews · doi:10.1111/obr.12910 · Cited by 20
Early differences in metabolic flexibility between obesity-resistant and obesity-prone mice
Bardova, K., Horakova, O., Janovska, P., Hansikova, J., Kus, V., van Schothorst, E. M., Hoevenaars, F. P. M., Uil, M., Hensler, M., Keijer, J., et al. (2016) · Biochimie · doi:10.1016/j.biochi.2015.11.014 · Cited by 17
A Novel Approach to Assess Metabolic Flexibility Overnight in a Whole‐Body Room Calorimeter
McDougal, D. H., Marlatt, K. L., Beyl, R. A., Redman, L. M., & Ravussin, É. (2020) · Obesity · doi:10.1002/oby.22982 · Cited by 17
“(2), suggesting that metabolic flexibility can be measured with significantly less participant burden compared with other paradigms that use indirect calorimetry.”
BackgroundSelf-citationRemchak, M. E., Piersol, K. L., Bhatti, S., Spaeth, A. M., Buckman, J. F., & Malin, S. K. (2021) · Nutrients · doi:10.3390/nu13051708 · Cited by 17
“This active shift in substrate utilization from fasting fat oxidation to insulin-stimulated glucose reliance is referred to as metabolic flexibility [21].”
BackgroundBioactive compounds from Artemisia dracunculus L. activate AMPK signaling in skeletal muscle
Vandanmagsar, B., Yu, Y., Simmler, C., Dang, T. N., Kuhn, P. E., Poulev, A., Ribnicky, D., Pauli, G. F., & Floyd, Z. E. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112188 · Cited by 17
KAHL, S., Nowotny, B., Piepel, S., Nowotny, P., Straßburger, K., Herder, C., Pacini, G., & Roden, M. (2014) · Diabetologia · doi:10.1007/s00125-014-3328-3 · Cited by 18
“Metabolic flexibility, defined as the whole-body capacity to adapt fuel oxidation to fuel availability [47] and assessed by the switch from fat to carbohydrate oxidation during a hyperinsulinaemic clamp test can be impaired by high NEFA levels [47].”
BackgroundRynders, C. A., Pereira, R. I., Bergouignan, A., Kealey, E. H., & Bessesen, D. H. (2018) · Obesity · doi:10.1002/oby.22321 · Cited by 19
“The ability to switch from carbohydrate to fat oxidation when transitioning from fed to fasted states has been termed metabolic flexibility (22, 23).”
BackgroundMalin, S. K., Viskochil, R. H., Oliver, C., & Braun, B. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00084.2013 · Cited by 17
Lund, J., Tangen, D. S., Wiig, H., Stadheim, H. K., Helle, S. A., Birk, J. B., Ingemann-Hansen, T., Rustan, A. C., Thoresen, G. H., Wojtaszewski, J. F. P., et al. (2017) · Archives of Physiology and Biochemistry · doi:10.1080/13813455.2017.1369547 · Cited by 18
“Furthermore, metabolic flexibility has previously been described as the ability to adapt fuel oxidation by fuel availability and exercise intensity (Galgani et al. 2008).”
BackgroundHepatic p63 regulates glucose metabolism by repressing SIRT1
Gonzalez-Rellan, M. J., Nóvoa, E., Lima, N. D. S., Rodrı́guez, A., Veyrat‐Durebex, C., Seoane, S., Porteiro, B., Fondevila, M. F., Fernandez, U., Varela‐Rey, M., et al. (2022) · Gut · doi:10.1136/gutjnl-2021-326620 · Cited by 18
Lai, N., Fealy, C. E., Kummitha, C., Cabras, S., Kirwan, J. P., & Hoppel, C. L. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00677 · Cited by 15
“In addition, unaltered enzymatic activity of Complex I, II, III, and IV in the insulin-resistant GK muscle mitochondria (Lai et al., 2017) indicated a preservation of biochemical properties of the electron transport chain.”
BackgroundInfluentialGlaves, A., Díaz‐Castro, F., Farías, J., Ramírez-Romero, R., Galgani, J. E., & Fernández‐Verdejo, R. (2021) · Frontiers in Nutrition · doi:10.3389/fnut.2021.744187 · Cited by 15
Self-citationDutt, C., Salles, J. E. N., Joshi, S., Nair, T., Chowdhury, S., Mithal, A., Mohan, V., Kasliwal, R., Sharma, S., Tijssen, J. G. P., et al. (2022) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s333787 · Cited by 16
“The equilibrium translates into insulin’s metabolic and non-metabolic actions that profoundly influence CV physiology, including glucose uptake in skeletal muscle and adipose tissue, glycogen synthesis in skeletal muscles, suppression of gluconeogenesis, lipolysis inhibition, and modulation of vascular effects.(12) In…”
BackgroundEffectiveness of high cardiorespiratory fitness in cardiometabolic protection in prediabetic rats
Thonusin, C., Pantiya, P., Sumneang, N., Chunchai, T., Nawara, W., Arunsak, B., Siri‐Angkul, N., Sriwichaiin, S., Chattipakorn, S. C., & Chattipakorn, N. (2022) · Molecular Medicine · doi:10.1186/s10020-022-00458-9 · Cited by 16
Using mass spectrometry imaging to visualize age-related subcellular disruption
Hogan, K. A., Zeidler, J. D., Beasley, H. K., Alsaadi, A. I., Alshaheeb, A. A., Chang, Y., Tian, H., Hinton, A. O., Jr., & McReynolds, M. R. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.906606 · Cited by 16
“Loss of this adaptive capacity compromises metabolic homeostasis leading to chronic metabolic diseases (Galgani et al., 2008).”
BackgroundDalmao‐Fernández, A., Aizenshtadt, A., Bakke, H. G., Krauss, S. J. K., Rustan, A. C., Thoresen, G. H., & Kase, E. T. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1130693 · Cited by 15
“Cellular impairments caused by this loss of flexibility are also associated with reduced lipid oxidation promoting accumulation of lipids in skeletal muscle, which can interfere with insulin signaling and function (Galgani et al., 2008; Goodpaster and Sparks, 2017).”
Hursel, R., Gonnissen, H. K. J., Rutters, F., Martens, E. A. P., & Westerterp‐Plantenga, M. S. (2013) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.112.054924 · Cited by 15
“Because no relations between sleep variables and substrate oxidation remained after sleep disturbance, metabolic flexibility may have been disrupted (27).”
BackgroundJurado‐Fasoli, L., Amaro‐Gahete, F. J., Merchán-Ramírez, E., Labayen, I., & Ruiz, J. R. (2020) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2020.11.021 · Cited by 15
Fiamoncini, J., Donado-Pestana, C. M., Duarte, G. B. S., Rundle, M., Thomas, E. L., Kiselova-Kaneva, Y. D., Gundersen, T. E., Bunzel, D., Trezzi, J., Kulling, S. E., et al. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.898782 · Cited by 15
“Subjects with insulin resistance display impaired phenotypic flexibility as a consequence of a reduced capacity for insulinstimulated glucose uptake into muscle and adipose tissue and insufficient suppression of hepatic gluconeogenesis (1, 2).”
BackgroundBouwman, L. M. S., Fernández‐Calleja, J. M. S., Swarts, H. J. M., et al. (2017) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201700315 · Cited by 14
Battista, F., Belligoli, A., Neunhäeuserer, D., Gasperetti, A., Bettini, S., Compagnin, C., Marchese, R., Quinto, G., Bergamin, M., Vettor, R., et al. (2021) · Obesity Facts · doi:10.1159/000517589 · Cited by 17
Síndrome de resistencia a la insulina. estudio y manejo
Fernando Carrasco, N., Galgani, F. J. E., & Reyes, J. M. (2013) · Revista Médica Clínica Las Condes · doi:10.1016/s0716-8640(13)70230-x · Cited by 20
Komada, H., Sakaguchi, K., Hirota, Y., Sou, A., Nakamura, T., Kyotani, K., Kawamitsu, H., Sugimura, K., Okuno, Y., & Ogawa, W. (2017) · Journal of Diabetes Investigation · doi:10.1111/jdi.12720 · Cited by 14
“掲載誌・巻号・ページ Citat ion Journal of Diabetes Invest igat ion,9(3):505-511”
Thermogenesis and Related Metabolic Targets in Anti-Diabetic Therapy
Arch, J. R. S. (2011) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-17214-4_10 · Cited by 14
An Extract of Russian Tarragon Prevents Obesity‐Related Ectopic Lipid Accumulation
Yu, Y., Mendoza, T. M., Ribnicky, D., Poulev, A., Noland, R. C., Mynatt, R. L., Raskin, I., Cefalu, W. T., & Floyd, Z. E. (2018) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201700856 · Cited by 15
The Carbohydrate Sensitive Rat as a Model of Obesity
Nadkarni, N. A., Chaumontet, C., Azzout‐Marniche, D., Piedcoq, J., Fromentin, G., Tomé, D., & Even, P. C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0068436 · Cited by 18
“It has been suggested that nutrient partitioning or metabolic flexibility (meaning the capacity of the organism to adapt fuel oxidation to food composition) may be responsible for establishing different adiposity levels in the long-term [49–51].”
Morio, B., Comte, B., Martin, J., Chanséaume, E., Alligier, M., Junot, C., Lyan, B., Boirie, Y., Vidal, H., Laville, M., et al. (2014) · Metabolomics · doi:10.1007/s11306-014-0750-y · Cited by 14
“Changes mostly related to modifications in fatty acid (FA) metabolism suggest differences in metabolic flexibility, defined as the capability to modify fuel oxidation in response to variations in nutrient availability (Galgani et al. 2008), and inflammation between the lean and OW individuals.”
BackgroundKilwein, M. D., Dao, T. K., & Welte, M. A. (2023) · PLoS Genetics · doi:10.1371/journal.pgen.1010875 · Cited by 13
“Metabolic flexibility, including flexibility in substrate utilization, is a trait previously described in mature organisms in mammals and flies [44,45,46,47,48].”
BackgroundInterplay of fatty acids, insulin and exercise in vascular health
Anderson, K. C., Liu, J., & Liu, Z. (2025) · Lipids in Health and Disease · doi:10.1186/s12944-024-02421-5 · Cited by 18
“One study showed that pre-prandial fatty acid oxidation is inversely associated with insulin-stimulated glucose disposal rate during a hyper-insulinaemic-euglycaemic clamp in both healthy individuals and individuals with T2D [180].”
Influence of lipolysis and fatty acid availability on fuel selection during exercise
Moro, C., Harant, I., Badin, P.-M., Patarca, F.-X., Guilland, J.-C., Bourlier, V., Langin, D., & de Glisezinski, I. (2013) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-013-0306-z · Cited by 13
Self-citationMisconceptions in body weight regulation: Implications for the obesity pandemic
Flatt, J. P. (2012) · Critical Reviews in Clinical Laboratory Sciences · doi:10.3109/10408363.2012.712904 · Cited by 13
Characterizing skeletal muscle dysfunction in women with polycystic ovary syndrome
McDonnell, T., Cussen, L., McIlroy, M., & O’Reilly, M. (2022) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/20420188221113140 · Cited by 15
Greyslak, K. T., Hetrick, B., Bergman, B. C., Dean, T. A., Wesolowski, S. R., GANNON, M. A., Schenk, S., Sullivan, E. L., Aagaard, K. M., Kievit, P., et al. (2023) · Diabetes · doi:10.2337/db23-0289 · Cited by 11
Garthwaite, T., Sjöros, T., Laine, S., Koivumäki, M., Vähä‐Ypyä, H., Verho, T., Norha, J., Kallio, P., Saarenhovi, M., Löyttyniemi, E., et al. (2024) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00338.2023 · Cited by 15
How to interpret and apply the results of indirect calorimetry studies: A case-based tutorial
Berger, M. M., Waele, E. D., Gramlich, L. M., Jin, J., Pantet, O., Pichard, C., Roffe, A. J., Russell, L. A., Singer, P., & Wischmeyer, P. E. (2024) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2024.07.1055 · Cited by 13
Conn, M. O., Marko, D. M., & Schertzer, J. D. (2024) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00255.2024 · Cited by 13
Ramzan, F., D’Souza, R. F., Durainayagam, B. R., Milan, A. M., Roy, N. C., Kruger, M. C., Henry, C. J., Mitchell, C. J., & Cameron‐Smith, D. (2020) · Genes & Nutrition · doi:10.1186/s12263-020-0660-8 · Cited by 12
Rodríguez-López, L. A., Torre-Villalvazo, I., Alemán, G., Flores‐López, A., Guevara‐Cruz, M., Sánchez‐Tapia, M., Torre-Anaya, E. A., Martínez-López, V., Vásquez‐Reyes, S., Torres‐Villalobos, G., et al. (2021) · International Journal of Obesity · doi:10.1038/s41366-021-00921-3 · Cited by 12
Metabolic switching of human skeletal muscle cells in vitro
Thoresen, G. H., Hessvik, N. P., Bakke, S. S., Aas, V., & Rustan, A. C. (2011) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2011.04.017 · Cited by 15
“The usual way to measure metabolic flexibility to carbohydrate in vivo is to calculate the difference between steady-state respiratory quotient (RQ) at the end of hyperinsulinemic euglycemic clamp and fasting RQ (ΔRQ) [9].”
BackgroundMetabolic fuel utilization and subclinical atherosclerosis in overweight/obese subjects
Montalcini, T., Gazzaruso, C., Ferro, Y., Migliaccio, V., Rotundo, S., Castagna, A., & Pujia, A. (2012) · Endocrine · doi:10.1007/s12020-012-9845-2 · Cited by 12
“Furthermore, it is recognized that postprandial endogenous insulin can increase RQ [22].”
BackgroundResultPeterson, C. M., Zhang, B., Johannsen, D. L., & Ravussin, É. (2017) · International Journal of Obesity · doi:10.1038/ijo.2017.58 · Cited by 15
“Some studies have shown that adjusting MF for the glucose disposal rate (GDR) (9, 11, 25) or measuring MF at matched GDR (8) causes the differences to vanish between lean individuals and individuals with obesity or diabetes, which suggests that metabolic inflexibility stems mostly from lower rates of glucose transport.”
BackgroundInfluentialSelf-citationClamp, L. D., Hume, D. J., Lambert, E. V., & Kroff, J. (2018) · Journal of Nutritional Science · doi:10.1017/jns.2018.11 · Cited by 12
“Metabolic flexibility is the ability to transition between fat and carbohydrate oxidation depending on availability((25)).”
BackgroundFernández‐Calleja, J. M. S., Bouwman, L. M. S., Swarts, H. J. M., Oosting, A., Keijer, J., & van Schothorst, E. M. (2019) · Scientific Reports · doi:10.1038/s41598-019-47977-w · Cited by 12
Changes in substrate utilization rates during 40 min of walking within the Fatmax range
Özdemir, Ç., Özgünen, K., Günaştı, Ö., Eryılmaz, S. K., Kılcı, A., & Kurdak, S. S. (2019) · Physiology International · doi:10.1556/2060.106.2019.28 · Cited by 11
“” These individuals rely mainly on glucose metabolism with a blunted preference for muscle fat oxidation (17, 26, 39).”
BackgroundSleep-Disordered Breathing and Free Fatty Acid Metabolism
Stefanovski, D., Boston, R., & Punjabi, N. M. (2020) · CHEST Journal · doi:10.1016/j.chest.2020.05.600 · Cited by 12
“Metabolic inflexibility (ie, diminished insulin-mediated suppression of lipolysis and sluggish recovery) may also contribute to intramyocellular lipid accumulation and insulin resistance.(29,30)”
BackgroundRussell, R., Nelson, A. G., & Kraemer, R. R. (2014) · The Journal of Strength and Conditioning Research · doi:10.1519/jsc.0000000000000624 · Cited by 11
“Because we have observed metabolic inflexibility in young healthy FH (38), and others observed that metabolic inflexibility is directly related to fasting blood glucose (14), we chose fasting blood glucose as a marker of metabolic impact from this training program.”
MethodDiPietro, L. (2010) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01152.2010 · Cited by 11
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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