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
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“One viewpoint suggests that the inability to appropriately activate glucose oxidation in response to a meal simply reflects a secondary consequence of impaired insulin action (Galgani et al., 2008).”
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“Whereas in the advanced obese, insulin resistant state, excess nutrient supply to adipose tissue can lead to inflammation and alterations in energy metabolism [5].”
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“Metabolic load may be further exacerbated by sedentary behavior, which reduces metabolic flexibility (the ability to balance alternative fuel sources at the cellular level— (Galgani et al., 2008) and a diet high in refined carbohydrates (Taubes, 2008), each of which challenges the ongoing regulation of blood sugar con…”
BackgroundDe novo lipogenesis in metabolic homeostasis: More friend than foe?
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“DNL in metabolic homeostasis: lessons from caloric restriction and “catch-up fat” during re-feeding The transition between fasting and feeding is characterized by a remarkable metabolic flexibility consisting of a switch from glucose to lipid oxidation during fasting, and rapid induction of glucose utilization after r…”
BackgroundDostálová, I., Roubíček, T., Bártlová, M., Mráz, M., Lacinová, Z., Haluzíková, D., Kaválková, P., Matoulek, M., Kasalicky, M., & Haluzı́k, M. (2009) · European Journal of Endocrinology · doi:10.1530/eje-09-0417 · Cited by 185
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“It is also worth noting that metabolic inflexibility in insulin-resistant individuals fails to adequately oxidise fatty acids, and it diminishes the ability to switch from glucose to lipid oxidation during overnight fasting, thus leading to lipid accumulation in skeletal muscle and further impairment of insulin signal…”
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“As a consequence of absorbed excess dietary FA and increased release of FA from dysfunctional adipose tissue, lipid droplets located within myocytes are not only classified as intramyocellular lipid (IMCL), chiefly in the form of TAG, but also as lipid intermediates such as LC-CoA, DAG, sphingolipids, phospholipids, a…”
BackgroundInfluentialCoffee consumption, obesity and type 2 diabetes: a mini-review
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“A trait observed during obesity-associated insulin resistance is the development of metabolic inflexibility, which is defined as the inability to appropriately transition between different fuel sources [28].”
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“However, the role of impaired metabolic flexibility, i.e. the ability to modify fuel oxidation in response to changes in nutrient availability, in skeletal muscle IR has been intensively studied (reviewed in Galgani et al. 2008), although no clear conclusion can be made from these studies.”
BackgroundMoro, C., Galgani, J. E., Luu, L. C. T., Pasarica, M., Mairal, A., Bajpeyi, S., Schmitz, G., Langin, D., Liebisch, G., & Smith, S. R. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0053 · Cited by 162
“Alternatively, increased plasma FFA fractional extraction by the skeletal muscle during the postprandial condition and a mismatch between FFA uptake and oxidation could likely contribute to lipotoxicity and insulin resistance (8, 32).”
BackgroundSelf-citationMitochondrial response to nutrient availability and its role in metabolic disease
Gao, A. W., Cantó, C., & Houtkooper, R. H. (2014) · EMBO Molecular Medicine · doi:10.1002/emmm.201303782 · Cited by 148
“This suggests that mitochondrial dysfunction might contribute to metabolic inflexibility and insulin resistance (Galgani et al , 2008).”
InfluentialUpregulated PDK4 expression is a sensitive marker of increased fatty acid oxidation
Pettersen, I. K. N., Tusubira, D., Ashrafi, H., Dyrstad, S. E., Hansen, L., Liu, X., Nilsson, L. I. H., Løvsletten, N. G., Berge, K., Wergedahl, H., et al. (2019) · Mitochondrion · doi:10.1016/j.mito.2019.07.009 · Cited by 148
“These mechanisms regulate both the activity balance between glucose and fatty acid oxidation, and the ability to switch between these fueling pathways, a trait often referred to as metabolic flexibility (Galgani et al., 2008).”
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“Elevated levels of these by-products of β-oxidation in the fasted state in OWTrained suggest an improvement in metabolic flexibility [38].”
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“believed to play a central role in preventing ectopic fat accumulation and insulin resistance (18).”
BackgroundThe effects of a soluble activin type IIB receptor on obesity and insulin sensitivity
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“Other factors implicated in skeletal muscle insulin resistance include the accumulation of intramyocellular lipids and metabolites, such as diacylglycerol and ceramides (29, 30).”
Sedentary behaviour is a key determinant of metabolic inflexibility
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Glucose metabolism and metabolic flexibility in blood platelets
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“Metabolism of glucose, fatty acids and amino acids converge in mitochondria, where fuel oxidation can be modified in response to changes in the availability of nutrients and the energy demand of the cell under various conditions (41).”
BackgroundIndirect calorimetry: an indispensable tool to understand and predict obesity
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“This improvement of metabolic flexibility correlated with changes in body weight, adiposity and glycaemic control in accordance with the notion that metabolic flexibility is closely associated with insulin sensitivity [2, 32] and that impaired flexibility represents an early defect in the development of type 2 diabete…”
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Fat in flames: influence of cytokines and pattern recognition receptors on adipocyte lipolysis
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The Impact of Dietary Methionine Restriction on Biomarkers of Metabolic Health
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“…the maintenance of physiologic insulin secretion is predicated on the cell’s ability to select substrates for mitochondrial oxidative phosphorylation among glucose, lipids, and amino acids (Prentki and Madiraju, 2012), a concept known as metabolic flexibility (Figure 3D) (Galgani et al., 2008).”
Muscle-generated BDNF is a sexually dimorphic myokine that controls metabolic flexibility
Yang, X., Brobst, D., Chan, W. S., Tse, M. C. L., Herlea-Pana, O., Ahuja, P., Bi, X., Zaw, A. M., Kwong, Z. S. W., Jia, W.-H., et al. (2019) · Science Signaling · doi:10.1126/scisignal.aau1468 · Cited by 99
“Thus, it is not unexpected to find that metabolic inflexibility in muscles is a dominant cause of various metabolic disorders (36).”
BackgroundCellular and Molecular Mechanisms of Insulin Resistance
Chandrasekaran, P., & Weiskirchen, R. (2024) · Current Tissue Microenvironment Reports · doi:10.1007/s43152-024-00056-3 · Cited by 137
“…phenomenon known as “metabolic inflex-ibility” in isolated and whole-body muscle mitochondria demonstrates that obesity causes impaired switching from fatty acid to carbohydrate substrates during the fasting-fed transition and a decrease in several tricarboxylic acid cycle intermediates [78].”
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“(Galgani et al., 2008), with a meaningful translation to experimental settings, it is nonetheless only a partial measure of the functional decline that occurs with aging.”
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Metabolic Determinants of Weight Gain in Humans
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“So-called metabolic flexibility (62-66), or the individualized ability to switch substrate for oxidation in response to changes in energy intake to match macronutrient availability in the diet, was also tested as a metabolic predictor of weight change.”
BackgroundWhen Two Pandemics Meet: Why Is Obesity Associated with Increased COVID-19 Mortality?
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“The ability of mitochondria to switch efficiently between these fuels in the 2 prandial states represents efficient mitochondrial function (12, 13, 26, 27).”
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“is referred to as metabolic flexibility [82].”
Pathophysiological role of metabolic flexibility on metabolic health
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“In an earlier publication, we highlighted the influence of baseline RQ on δRQ using a theoretical example.(84) A and B are two individuals”
BackgroundMethodSelf-citationHarnessing Muscle–Liver Crosstalk to Treat Nonalcoholic Steatohepatitis
Chakravarthy, M. V., Siddiqui, M. S., Forsgren, M. F., & Sanyal, A. J. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.592373 · Cited by 96
“, FAs during fasting and carbohydrate in fed states) for energy generation is referred to as metabolic flexibility (109).”
BackgroundThe metabolic basis of nonalcoholic steatohepatitis
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Aging, Resistance Training, and Diabetes Prevention
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“Based on the 2007-2008 National Health and Nutrition Examination Survey (NHANES), 78.4% of men and 68.6% of woman ≥60 years were considered overweight or obese (BMI ≥ 25 kg/m2).”
MethodInfluentialJácome-Sosa, M., Borthwick, F., Mangat, R., Uwiera, R. R. E., Reaney, M. J. T., Shen, J., Quiroga, A. D., Jacobs, R. L., Lehner, R. S., & Proctor, S. D. (2014) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2014.02.011 · Cited by 87
“The lipid centric hypothesis of obesity proposes that insulin resistance is causally related to peripheral ectopic fat accumulation and subsequent lipid toxicity [32].”
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“Lipid “spillover” that occurs as a result leads to lipid deposition in visceral fat and, subsequently, the liver (2,3).”
BackgroundLactate homeostasis is maintained through regulation of glycolysis and lipolysis
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Measuring mitochondrial respiration in intact single muscle fibers
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“Metabolic flexibility is defined as the ability of a cell to adjust fuel oxidation to fuel availability (10).”
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Potential role of skeletal muscle glucose metabolism on the regulation of insulin secretion
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“We observed that during a euglycaemic–hyperinsulinaemic clamp, both impaired intracellular oxidative and non-oxidative glucose disposal were mostly consequence of insulin resistance (48,50).”
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“This reduced capacity of some tissues to adjust lipid oxidation leads to lipid accumulation in tissues and lipotoxicity which, in turn, impair insulin signaling [47].”
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“Assessment of metabolic flexibility using postabsorptive NPRER has also been questioned because this value is influenced by acute energy balance and dietary macronutrient consumption (20).”
BackgroundBrugnara, L., Vinaixa, M., Murillo, S., Samino, S., Rodriguez, M. A., Beltran, A., Lerín, C., Davison, G. W., Correig, X., & Novials, A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040600 · Cited by 84
“Thus, the phenomena of metabolic inflexibility mainly described in T2D and other insulinresistant states could explain some of the alterations occurring in the machinery of lipid and glucose metabolism [41,42].”
BackgroundRespiratory Quotient Predicts Fat Mass Gain in Premenopausal Women
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“Insulin is an anabolic hormone that acts to decrease fat oxidation and increase lipid storage (13).”
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The Structural and Functional Coordination of Glycolytic Enzymes in Muscle: Evidence of a Metabolon?
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“and is specifically linked to impaired glucose uptake and usage [52].”
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Battaglia, G. M., Zheng, D., Hickner, R. C., & Houmard, J. A. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00355.2012 · Cited by 74
“The ability to adjust FAO appropriately in response to excursions in dietary lipid is a critical component of metabolic health because inflexibility may lead to positive fat balance (11), ectopic lipid accumulation (29), and weight gain (21).”
BackgroundPreston, R. S., Philp, A., Claessens, T., Gijezen, L., Dydensborg, A. B., Dunlop, E. A., Harper, K., Brinkhuizen, T., Menko, F. H., Davies, D. M., et al. (2010) · Oncogene · doi:10.1038/onc.2010.497 · Cited by 72
“This inability to shift fuel oxidation to match availability is known as a loss of ‘metabolic flexibility’ (Galgani et al., 2008).”
BackgroundImpaired Metabolic Flexibility to High-Fat Overfeeding Predicts Future Weight Gain in Healthy Adults
Begaye, B., Vinales, K. L., Hollstein, T., Ando, T., Walter, M., Bogardus, C., Krakoff, J., & Piaggi, P. (2020) · Diabetes · doi:10.2337/db19-0719 · Cited by 73
“These studies showed that Rd is a determinant of glucose inflexibility (25) and that greater metabolic flexibility to glucose during the clamp is associated with decreased metabolic flexibility to lipids during fasting (26).”
BackgroundMitochondrial involvement in skeletal muscle insulin resistance: A case of imbalanced bioenergetics
Affourtit, C. (2016) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2016.07.008 · Cited by 67
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“Previous studies suggested that oxidative (slow) muscle fibers could be important for metabolic flexibility [36,49].”
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Chen, D., Liess, C., Poljak, A., Xu, A., Zhang, J.-L., Thoma, C., Trenell, M. I., Milner, B., Jenkins, A. B., Chisholm, D. J., et al. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2712 · Cited by 73
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“Impairments to insulin signal transduction are strongly associated with impaired carbohydrate and lipid metabolism in skeletal muscle (6, 10, 13).”
BackgroundBeneficial Effects of Intermittent Fasting: A Narrative Review
Song, D.-K., & Kim, Y.-W. (2023) · Journal of Yeungnam Medical Science · doi:10.12701/jyms.2022.00010 · Cited by 69
“Fasting, especially repetitive fasting, induces organisms to shift their metabolic phase, which improves metabolic conditions and extends health expectancy [18]. de Cabo and Mattson [25] reported that fasting optimizes cellular use of fuel sources, favoring ketone bodies and fatty acids over glucose, which ameliorates…”
BackgroundInfluentialTirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation
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Self-citationIntrinsic aerobic capacity impacts susceptibility to acute high-fat diet-induced hepatic steatosis
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“Metabolic inflexibility profoundly impacts storage of excess energy (13, 14) and is a hallmark feature of obesity and the metabolic syndrome (9).”
BackgroundMetabolic Evidence of Diminished Lipid Oxidation in Women With Polycystic Ovary Syndrome
Whigham, L. D., Bütz, D. E., Dashti, H., Tonelli, M., Johnson, L. K., Cook, M. E., Porter, W. P., Eghbalnia, H. R., Markley, J. L., Lindheim, S. R., et al. (2014) · Current Metabolomics · doi:10.2174/2213235x01666131203230512 · Cited by 65
“4), by which diminished utilization of lipid as an energy substrate may lead to increased fat accumulation in both adipose stores and ectopic sites, such as liver and skeletal muscle [40].”
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“Metabolic inflexibility, which reflects the inability to adapt tissuespecific substrate oxidation to whole body fuel availability, was suggested to be implicated in the development of obesity, insulin resistance, and type 2 diabetes (8, 11, 21, 36).”
BackgroundRole of Endoplasmic Reticulum-Mitochondria Communication in Type 2 Diabetes
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“As metabolic flexibility is important to avoid ectopic lipid accumulation and the development of insulin resistance (Galgani et al. 2008), the capacity of MAM to connect energy sensing to”
InfluentialEffect of contrasted levels of habitual physical activity on metabolic flexibility
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Insulin: Trigger and Target of Renal Functions
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Exercise counteracts lipotoxicity by improving lipid turnover and lipid droplet quality
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Macronutrient Determinants of Obesity, Insulin Resistance and Metabolic Health
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Giles, E. D., Jackman, M. R., Johnson, G. C., Schedin, P. J., Houser, J. L., & MacLean, P. S. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00219.2010 · Cited by 63
“Obesity is known to be associated with an impaired ability to regulate fat during metabolic stress, a characteristic that has been referred to as metabolic inflexibility (21).”
BackgroundReversal of diet-induced obesity and insulin resistance by inducible genetic ablation of GRK2
Vila‐Bedmar, R., Cruces‐Sande, M., Lucas, E., Willemen, H. L. D. M., Heijnen, C. J., Kavelaars, A., Mayor, F., & Murga, C. (2015) · Science Signaling · doi:10.1126/scisignal.aaa4374 · Cited by 62
“However, some animal models of impaired lipolysis display an overall impairment in systemic metabolic function (36).”
BackgroundShi, W., Hegeman, M. A., van Dartel, D. A. M., Tang, J., Suarez, M., Swarts, H., van der Hee, B., Arola, L., & Keijer, J. (2017) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201600878 · Cited by 62
“Because insulin resistance interacts with glucose and glucose disposal [29, 50], a causal relation exists.”
BackgroundmiR-182 Regulates Metabolic Homeostasis by Modulating Glucose Utilization in Muscle
Zhang, D., Li, Y., Yao, X., Wang, H. J., Zhao, L., Jiang, H., Yao, X., Zhang, S., Cheng, Y., Liu, W., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.06.040 · Cited by 63
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“Many T2DM patients demonstrate a reduced ability to switch between lipid and carbohydrate utilization in response to the acute metabolic demand [6,7].”
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“Additionally, a mismatch between fatty acid uptake (due to lipid overflow) and fat oxidation may be detrimental to insulin signaling by generating several lipotoxic intermediates (6).”
BackgroundThe sedentary (r)evolution: Have we lost our metabolic flexibility?
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“The increase in lipid availability reduces glucose uptake and oxidation in skeletal muscle, leading tometabolic inflexibility.(38)Todetermine if the maladaptive UPR activated in SAT in response to acute (pharmacological) and chronic (obesity-induced) ER stress associates with skeletal muscle and hepatic lipid accumula…”
BackgroundTranscriptional Cofactor TBLR1 Controls Lipid Mobilization in White Adipose Tissue
Rohm, M., Sommerfeld, A., Strzoda, D., Jones, A., Sijmonsma, T., Rudofsky, G., Wolfrum, C., Sticht, C., Gretz, N., Zeyda, M., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.02.010 · Cited by 61
“…metabolic dysfunction, maybe as a consequence of impaired WAT metabolic flexibility upon an imbalanced equilibrium between lipid storage and mobilization (Galgani et al., 2008), and/or the simultaneous dysregulation of inflammatory and adipocytokine pathways as observed upon TBLR1 deficiency.”
Plasma Lactate as a Marker for Metabolic Health
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“Being able to switch substrates also extends to lipid oxidation; for example, lean controls fed a high-fat diet (HFD) adjusted within days to a preference for fat oxidation (26).”
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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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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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