Metabolic flexibility to lipid availability during exercise is enhanced in individuals with high insulin sensitivity
Open accessAbstract
Metabolic flexibility to lipid (MetFlex-lip) is the capacity to adapt lipid oxidation to lipid availability. Hypothetically, impaired MetFlex-lip in skeletal muscle induces accumulation of lipid metabolites that interfere with insulin signaling. Our aim was to compare MetFlex-lip during exercise in subjects with low (Low_IS) vs. high (High_IS) insulin sensitivity. Twenty healthy men were designated as Low_IS or High_IS on the basis of the median of the homeostatic model assessment of insulin resistance index. Groups had similar age, body mass index, and maximum oxygen uptake (V̇o2max). Subjects cycled at 50% V̇o2max until expending 650 kcal. Adaptation in lipid oxidation was calculated as the drop in respiratory quotient (RQ) at the end of exercise vs. the maximum RQ (ΔRQ). Lipid availability was calculated as the increase in circulating nonesterified fatty acids (NEFA) at the end of exercise vs. the minimum NEFA (ΔNEFA). ΔRQ as a function of ΔNEFA was used to determine MetFlex-lip. On average, RQ and circulating NEFA changed similarly in both groups. However, ΔRQ correlated with ΔNEFA in High_IS ( r = −0.83, P < 0.01) but not in Low_IS ( r = −0.25, P = 0.48) subjects. Thus the slope of the ΔRQ vs. ΔNEFA relationship was steeper in High_IS vs. Low_IS subjects (−0.139 ± 0.03 vs. −0.025 ± 0.03 RQ·mmol−1·l−1, respectively; P < 0.05), with similar intercepts. We conclude that in subjects with High_IS lipid-to-carbohydrate oxidation ratio adapts to the increased circulating NEFA availability during exercise. Such MetFlex-lip appears impaired in subjects with Low_IS. Whether a cause-effect relationship exists between impaired MetFlex-lip and low insulin sensitivity remains to be determined.
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- Findingown data
Exercise duration was similar in low and high insulin sensitivity groups (84.1 vs 79.1 min, P=0.37).
“Exercise lasted 84.1 Ϯ 14.3 and 79.1 Ϯ 9.6 min in Low_IS and High_IS subjects, respectively (P ϭ 0.37).”
Quote in the paperNot a substantial claim - Findingown data
Glucose, lactate, NEFA, epinephrine, and norepinephrine responses to exercise were similar in low and high insulin sensitivity groups.
“Circulating concentrations of glucose (Fig. 1A), lactate (Fig. 1B), NEFA (Fig. 1C), epinephrine (Fig. 1E), and norepinephrine (Fig. 1F) responded similarly to exercise in Low_IS and High_IS subjects.”
Quote in the paperNot a substantial claim - Findingown data
When all subjects were analyzed, the RQ-change-to-NEFA-change ratio was not associated with HOMA-IR (r=-0.33, P=0.15, n=20).
“No association was found when all subjects were considered (r ϭ Ϫ0.33, P ϭ 0.15, n ϭ 20).”
Quote in the paperNot a substantial claim - Findingown data
Insulin levels during exercise were higher in low insulin sensitivity than high insulin sensitivity subjects, except at the end of exercise.
“As expected, insulinemia during exercise was higher in Low_IS vs. High_IS subjects, except at the end of exercise (Fig. 1D).”
Quote in the paperNot a substantial claim - Findingown data
Intramyocellular lipid levels tended to be higher in low insulin sensitivity than high insulin sensitivity subjects (P=0.095).
“IMCL levels tended (P ϭ 0.095) to be higher in Low_IS than High_IS subjects (Fig. 2F).”
Quote in the paperNot a substantial claim
- Findingown data
In high insulin sensitivity subjects, RQ change correlated inversely with NEFA change (r=-0.83, P<0.01).
“The inverse correlation between ⌬RQ and ⌬NEFA became stronger in High_IS (r ϭ Ϫ0.83, P Ͻ 0.01) but disappeared in Low_IS (r ϭ Ϫ0.25, P ϭ 0.48) subjects.”
- Also stated in: § Abstract · plain
“However, ⌬RQ correlated with ⌬NEFA in High_IS (r ϭ Ϫ0.83, P Ͻ 0.01) but not in Low_IS (r ϭ Ϫ0.25, P ϭ 0.48) subjects.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
In low insulin sensitivity subjects, RQ change did not correlate with NEFA change (r=-0.25, P=0.48).
“The inverse correlation between ⌬RQ and ⌬NEFA became stronger in High_IS (r ϭ Ϫ0.83, P Ͻ 0.01) but disappeared in Low_IS (r ϭ Ϫ0.25, P ϭ 0.48) subjects.”
- Also stated in: § Abstract · plain
“However, ⌬RQ correlated with ⌬NEFA in High_IS (r ϭ Ϫ0.83, P Ͻ 0.01) but not in Low_IS (r ϭ Ϫ0.25, P ϭ 0.48) subjects.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
No between-group differences were detected in muscle lipase mRNA content.
“Regarding mRNA content of muscle lipases, no differences were detected between groups (Fig. 4C).”
Quote in the paperNot a substantial claim - Findingown data
The slope of the RQ-change versus NEFA-change relationship was steeper in high insulin sensitivity than low insulin sensitivity subjects (-0.139 vs -0.025 RQ·mmol−1·l−1, P<0.05), with similar intercepts.
“Consistently, the slope of the ⌬RQ vs. ⌬NEFA relationship was steeper in High_IS vs. Low_IS subjects (Ϫ0.139Ϯ 0.03 vs. Ϫ0.025Ϯ 0.03 RQ•mmol Ϫ1 •l Ϫ1 , respectively), while intercepts were similar (Fig. 3D).”
- Also stated in: § Abstract · plain
“Thus the slope of the ⌬RQ vs. ⌬NEFA relationship was steeper in High_IS vs. Low_IS subjects (Ϫ0.139Ϯ 0.03 vs. Ϫ0.025Ϯ 0.03 RQ•mmol Ϫ1 •l Ϫ1 , respectively; P Ͻ 0.05), with similar intercepts.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
Among subjects with NEFA change above 0.45 mmol/l, the RQ-change-to-NEFA-change ratio correlated directly with HOMA-IR (r=0.79, P<0.05, n=7).
“In those subjects, ⌬RQ/⌬NEFA correlated directly with HOMA-IR [r ϭ 0.79, P Ͻ 0.05, n ϭ 7 (4 Low_IS ϩ 3 High_IS); Fig. 3G].”
Quote in the paperSubstantial claim - Findingown data
High insulin sensitivity subjects had higher mRNA levels of Fabp3 and Fatp1 than low insulin sensitivity subjects.
“However, High_IS subjects expressed lipid transport-related genes at a higher extent than Low_IS subjects, specifically fatty acid binding protein-3 (Fabp3) and fatty acid transport protein-1 (Fatp1) (Fig. 4D).”
Quote in the paperSubstantial claim - Findingown data
The sum of squares residuals of the RQ-change versus NEFA-change relationship was 2.4-fold higher in low insulin sensitivity than high insulin sensitivity subjects.
“The sum of squares residuals was 2.4-fold higher in Low_IS than in High_IS subjects (Fig. 3E).”
Quote in the paperSubstantial claim - Findingown data
Exercise did not change intramyocellular lipid levels.
“Exercise decreased muscle glycogen content similarly in Low_IS and High_IS subjects (Fig. 2E) but had no effect on IMCL levels (Fig. 2F).”
Quote in the paperNot a substantial claim - Findingown data
The residuals of the RQ-change versus NEFA-change relationship were similar in low and high insulin sensitivity groups (0.0018 vs -0.0018 RQ, P=0.77).
“The residuals of the ⌬RQ vs. ⌬NEFA relationship were similar in Low_IS and High_IS groups [0.0018 (SD 0.031) and Ϫ0.0018 (SD 0.025) RQ, respectively, P ϭ 0.77; Fig. 3B].”
Quote in the paperNot a substantial claim - Findingown data
Exercise reduced muscle glycogen content similarly in both groups.
“Exercise decreased muscle glycogen content similarly in Low_IS and High_IS subjects (Fig. 2E) but had no effect on IMCL levels (Fig. 2F).”
Quote in the paperNot a substantial claim - Findingown data
NEFA change correlated strongly with NEFA concentration at the end of exercise (r=0.92, P<0.0001).
“It is worth mentioning that ⌬NEFA correlated strongly with NEFA concentration at the end of exercise (r ϭ 0.92, P Ͻ 0.0001); thus subjects with the highest ⌬NEFA had also the highest circulating NEFA concentrations at the end of exercise.”
Quote in the paperNot a substantial claim - Findingown data
Visual inspection suggested that RQ-change residuals became more negative in high insulin sensitivity than low insulin sensitivity subjects when NEFA change exceeded 0.45 mmol/l.
“However, visual inspection of ⌬RQ residuals vs. ⌬NEFA revealed that the residuals became more negative in High_IS than Low_IS at ⌬NEFA concentrations Ͼ 0.45 mmol/l (Fig. 3C).”
Quote in the paperNot a substantial claim - Findingown data
Across all subjects, the exercise-induced drop in RQ correlated inversely with the exercise-induced rise in NEFA (r=-0.48, P<0.05).
“Considering all subjects, ⌬RQ correlated inversely with ⌬NEFA (r ϭ Ϫ0.48, P Ͻ 0.05; Fig. 3A).”
Quote in the paperNot a substantial claim - Findingown data
The variance of the mean RQ-change-to-NEFA-change ratio was higher in low insulin sensitivity than high insulin sensitivity subjects (0.049 vs 0.004 RQ·mmol−1·l−1).
“The variance was higher in Low_IS than in High_IS subjects (0.049 vs. 0.004 RQ•mmol Ϫ1 •l Ϫ1 , respectively; Fig. 3F).”
Quote in the paperSubstantial claim - Findingown data
Total lipid and carbohydrate oxidation were similar between groups.
“Total oxidation of lipid and CHO were similar in both groups (Fig. 2D).”
Quote in the paperNot a substantial claim - Findingown data
In subjects with ΔNEFA >0.45 mmol/l, ΔRQ/ΔNEFA was related to HOMA-IR.
“This idea is supported by the relationship between ⌬RQ/ ⌬NEFA and HOMA-IR at ⌬NEFA Ͼ 0.45 mmol/l.”
- Also stated in: § DISCUSSION · plain
“G: ⌬RQ/⌬NEFA vs. homeostatic model assessment of insulin resistance (HOMA-IR) index in subjects with ⌬NEFA Ͼ 0.45 mmol/l (n ϭ 7).”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Findingown data
In Low_IS subjects, mRNA levels of the lipid transport genes Fabp3 and Fatp1 were lower.
“The expression of genes related to lipid transport (Fabp3, Fatp1) was also reduced in Low_IS subjects”
- Also stated in: § DISCUSSION · plain
“C-E: mRNA levels of genes related to lipid oxidation (n ϭ 5-8; C), lipid transport (n ϭ 3-10; D), and regulation of lipid metabolism (n ϭ 3-10; E) in preexercise skeletal muscle.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Findingown data
Ex vivo palmitate oxidation was similar in Low_IS and High_IS subjects.
“Low_IS and High_IS subjects had similar palmitate oxidation ex vivo, an assay that depends on the beta-oxidation (-Ox) and the tricarboxylic acid (TCA) cycle.”
Quote in the paperSubstantial claim - Findingown data
In Low_IS subjects, expression of the lipid-oxidation-inhibiting gene Acc2 was higher.
“Specifically, Low_IS subjects had decreased expression of OXPHOS complexes and of genes that promote lipid oxidation (Adipor1, Adipor2), and had increased expression of genes that inhibit lipid oxidation (Acc2).”
Quote in the paperSubstantial claim - Findingown data
In Low_IS subjects, the ΔRQ vs ΔNEFA relationship had greater variability.
“This dissociation manifested as 1) a lack of correlation between the variables and 2) a larger variability in the ⌬RQ vs. ⌬NEFA relationship.”
- Also stated in: § DISCUSSION · plain
“***P Ͻ 0.001 for comparison of variance (n ϭ 10 per group).”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Findingown data
In the study data, total exercise duration was directly related to end-exercise NEFA concentration (r=0.56, P<0.05, n=20).
“Indeed, total exercise time correlated directly with NEFA concentration at the end of exercise in our data (r ϭ 0.56, P Ͻ 0.05, n ϭ 20).”
Quote in the paperNot a substantial claim - Findingown data
Low_IS and High_IS subjects differed in expression of some markers downstream of TCA and upstream of beta-oxidation.
“In contrast, we did find differences between our groups in some steps downstream of TCA and upstream of -Ox.”
Quote in the paperSubstantial claim - Findingown data
The study subjects had a narrow HOMA-IR range (0.39-1.65).
“The subjects in the present study had a narrow range of HOMA-IR index (0.39 -1.65).”
Quote in the paperSubstantial claim - Findingown data
The level of insulin sensitivity distinguished distinct MetFlex-lip patterns during exercise.
“Nevertheless, we did find that insulin sensitivity level discriminated different patterns of MetFlex-lip during exercise.”
Quote in the paperSubstantial claim - Findingown data
In Low_IS subjects, ΔRQ and ΔNEFA were not correlated.
“This dissociation manifested as 1) a lack of correlation between the variables and 2) a larger variability in the ⌬RQ vs. ⌬NEFA relationship.”
Quote in the paperSubstantial claim - Findingown data
During exercise, average lipid oxidation (RQ) and lipid availability (NEFA) responses were similar between Low_IS and High_IS groups.
“Although the average responses of lipid oxidation (RQ) and availability (NEFA) during exercise were similar in Low_IS and High_IS subjects”
Quote in the paperSubstantial claim - Findingown data
Low_IS subjects had decreased expression of OXPHOS complexes.
“Specifically, Low_IS subjects had decreased expression of OXPHOS complexes and of genes that promote lipid oxidation (Adipor1, Adipor2), and had increased expression of genes that inhibit lipid oxidation (Acc2).”
- Also stated in: § DISCUSSION · plain
“F: protein level of mitochondrial oxidative phosphorylation (OXPHOS) complexes in preexercise skeletal muscle (n ϭ 10 per group).”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Findingown data
The ΔRQ-ΔNEFA slope was steeper for High_IS than for Low_IS subjects.
“The ⌬RQ vs. ⌬NEFA relationship also showed a steeper slope in High_IS subjects than in Low_IS subjects.”
Quote in the paperSubstantial claim - Findingown data
Low_IS subjects showed a tendency toward higher IMCL content.
“Accordingly, IMCL content tended to be elevated in Low_IS subjects”
Quote in the paperSubstantial claim - Findingown data
In Low_IS subjects, expression of lipid-oxidation-promoting genes Adipor1 and Adipor2 was lower.
“Specifically, Low_IS subjects had decreased expression of OXPHOS complexes and of genes that promote lipid oxidation (Adipor1, Adipor2), and had increased expression of genes that inhibit lipid oxidation (Acc2).”
- Also stated in: § DISCUSSION · plain
“C-E: mRNA levels of genes related to lipid oxidation (n ϭ 5-8; C), lipid transport (n ϭ 3-10; D), and regulation of lipid metabolism (n ϭ 3-10; E) in preexercise skeletal muscle.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Interpretationown data
The RQ-change versus NEFA-change relationship showed greater variability in low insulin sensitivity than high insulin sensitivity subjects.
“These two indexes demonstrate a larger variability in the ⌬RQ vs. ⌬NEFA relationship in Low_IS than in High_IS subjects.”
Quote in the paperSubstantial claim - Premisecitation
Lipotoxicity involves accumulation of lipid metabolites such as ceramides and diacylglycerol that interfere with insulin signaling and impair insulin action.
“Lipotoxicity is characterized by the accumulation of lipid metabolites (ceramides and diacylglycerol) that interfere with insulin signaling, thus impairing insulin action (26,28).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
A larger exercise-induced increase in circulating NEFA was associated with a larger increase in lipid oxidation relative to carbohydrate oxidation.
“Thus the higher the exercise-induced increase in circulating NEFA concentration, the higher the increase in lipid oxidation relative to CHO (i.e., drop in RQ).”
Quote in the paperSubstantial claim - Interpretationown data
In high insulin sensitivity subjects, the lipid-to-carbohydrate oxidation ratio adapts to increased circulating NEFA availability during exercise.
“We conclude that in subjects with High_IS lipid-to-carbohydrate oxidation ratio adapts to the increased circulating NEFA availability during exercise.”
Quote in the paperSubstantial claim - Interpretationown data
At high NEFA increments, metabolic flexibility to lipid during exercise was impaired in subjects with low insulin sensitivity.
“Here we showed that at high NEFA increments MetFlex-lip during exercise was impaired in subjects with low insulin sensitivity.”
- Also stated in: § Abstract · hedged
“Such Met-Flex-lip appears impaired in subjects with Low_IS.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · hedged
- Premisecitation
A mismatch between lipid availability and lipid oxidation may induce ectopic fat deposition and lipotoxicity.
“A mismatch between availability and oxidation of lipids might induce ectopic fat deposition and lipotoxicity (17,24).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
Subjects with the largest NEFA change also had the highest circulating NEFA at the end of exercise.
“It is worth mentioning that ⌬NEFA correlated strongly with NEFA concentration at the end of exercise (r ϭ 0.92, P Ͻ 0.0001); thus subjects with the highest ⌬NEFA had also the highest circulating NEFA concentrations at the end of exercise.”
Quote in the paperNot a substantial claim - Interpretationown data
Impaired metabolic flexibility to lipid may promote the development of insulin resistance in skeletal muscle.
“This finding agrees with the idea that impaired MetFlex-lip may promote the development of insulin resistance in skeletal muscle.”
Quote in the paperSubstantial claim - Premisecitation
Circulating NEFA concentration is the main determinant of muscle lipid uptake at rest (5).
“Here we used circulating NEFA concentration as an index of lipid availability, because circulating NEFA concentration has been shown to be the main determinant of muscle lipid uptake at rest (5).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] Capaldo B, 1994, J Clin Endocrinol Metab
Not checked in the free run.
- Interpretationreasoning
This oversight makes conclusions about the influence of metabolic flexibility on metabolic homeostasis uncertain.
“Such an oversight makes uncertain the conclusions regarding the putative influence of MetFlex on metabolic homeostasis.”
Quote in the paperNot a substantial claim - Interpretationown data
With larger ΔNEFA, High_IS subjects showed a more pronounced rise in lipid oxidation than Low_IS subjects.
“However, at larger ⌬NEFA, the switch to lipid oxidation was more pronounced in High_IS subjects compared with Low_IS.”
Quote in the paperSubstantial claim - Interpretationown data
People with high insulin sensitivity show greater lipid oxidation when lipid availability rises, indicating enhanced MetFlex-lip.
“Subjects with high insulin sensitivity would thus have enhanced lipid oxidation in response to elevated lipid availability, i.e. enhanced MetFlex-lip.”
- Also stated in: § DISCUSSION · boosted
“Using a new approach, we showed that MetFlex to elevated lipid availability during endurance exercise is enhanced in subjects with high insulin sensitivity.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · boosted
- Interpretationreasoning
Circulating NEFA concentration can be considered a valid marker of muscle lipid availability.
“Circulating NEFA concentration could thus be considered a valid marker of muscle lipid availability.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Likewise, healthy individuals with a family history of T2D had normal NEFA increases but lower lipid oxidation (15).
“Similarly, healthy subjects with a family history of T2D showed normal increases in circulating NEFA but reduced lipid oxidation (15).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] source
Not checked in the free run.
- Interpretationreasoning
The data suggest that impaired MetFlex-lip contributes to early insulin resistance development.
“Our data therefore point to a role of impaired MetFlex-lip in early stages of insulin resistance development.”
Quote in the paperSubstantial claim - Interpretationcitation
Insulin-resistant and insulin-sensitive individuals may have similar metabolic flexibility to glucose when tissue glucose availability is considered.
“Insulin-resistant vs. -sensitive individuals may thus have similar MetFlex-glu when tissue glucose availability is considered (10).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] source
Not checked in the free run.
- Interpretationown data
These pathways therefore do not account for the in vivo lipid oxidation difference between the two groups.
“These processes would thus not explain the difference in lipid oxidation in vivo between Low_IS and High_IS subjects.”
Quote in the paperSubstantial claim - Premisecitation
Previous work considered exercise-induced lipid oxidation as metabolic flexibility to lipid without accounting for lipid availability.
“MetFlex-lip during exercise has been considered previously as the level of exercise-induced lipid oxidation, without considering lipid availability (13).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] source
Not checked in the free run.
- Premisecitation
Tissue glucose availability explained about half of the increase in glucose oxidation during euglycemic-hyperinsulinemic clamps.
“Indeed, tissue glucose availability explained ~50% of the increase in glucose oxidation during euglycemic-hyperinsulinemic clamps (10,27).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
In Low_IS subjects, lipid oxidation and lipid availability appeared dissociated during exercise.
“oxidation and availability seemed dissociated from each other in Low_IS subjects.”
Quote in the paperSubstantial claim - Interpretationreasoning
The higher IMCL in Low_IS subjects may result from impaired MetFlex-lip.
“Accordingly, IMCL content tended to be elevated in Low_IS subjects, eventually as a result of impaired MetFlex-lip.”
Quote in the paperSubstantial claim - Premisecitation
Exogenous lipid infusions can boost lipid oxidation even during high-intensity exercise.
“Indeed, exogenous lipid infusions can boost lipid oxidation even during high-intensity exercise (22).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] source
Not checked in the free run.
- Premisecitation
Circulating NEFA are the main determinant of muscle lipid uptake.
“This relationship between circulating NEFA and lipid oxidation is explained by the fact that circulating NEFA are the main determinant of muscle lipid uptake (5).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] Capaldo B, 1994, J Clin Endocrinol Metab
Not checked in the free run.
- Premisecitation
In human myotubes, in vitro MetFlex-lip is directly correlated with the donor's in vivo insulin sensitivity (29).
“Accordingly, MetFlex-lip of human myotubes in vitro correlates directly with the donor's insulin sensitivity in vivo (29).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] source
Not checked in the free run.
- Interpretationcitation
For cellular lipid availability during exercise, muscle NEFA uptake is a better index than circulating NEFA.
“A more accurate index of cellular lipid availability during exercise is thus muscle NEFA uptake, and this should be considered in future studies.”
Quote in the paperSubstantial claim - Premisecitation
During exercise, circulating NEFA may be a suboptimal index of lipid availability, since contraction moves NEFA transporters to the sarcolemma and increases NEFA uptake (3).
“However, circulating NEFA may not be the best index of lipid availability during exercise, because muscle contraction induces translocation of NEFA transporters to the sarcolemma, thus intensifying NEFA uptake (3).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] source
Not checked in the free run.
- Interpretationreasoning
The results point to skeletal muscle as directly involved in the impaired MetFlex-lip seen in insulin-resistant states.
“Our findings thus suggest that skeletal muscle is directly implicated in the impaired MetFlex-lip characterizing insulinresistant states.”
Quote in the paperSubstantial claim- Rests on an assumption: Fat-rich meals increase oxidation in multiple tissues, while endurance exercise increases it predominantly in skeletal muscle.
- Interpretationreasoning
In the Low_IS group, changes in NEFA produced less predictable changes in RQ.
“Therefore, the change in NEFA led to less predictable changes in RQ in the Low_IS group.”
Quote in the paperSubstantial claim - Study design and conductreasoning
Sample homogeneity allowed the groups to be matched for almost every parameter.
“The advantage of this sample homogeneity is that the groups were matched for almost every parameter.”
Quote in the paperSubstantial claim - Premisecitation
Prior work indicates that in insulin-resistant states, lipid oxidation is impaired at a given circulating NEFA concentration, i.e., MetFlex-lip is impaired.
“Therefore, previous studies demonstrate that insulin-resistant states have impaired lipid oxidation for a certain circulating NEFA level, i.e., impaired MetFlex-lip.”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
MetFlex-lip during exercise may be determined by lipid uptake and/or intracellular transport.
“suggesting that lipid uptake and/or intracellular transport might determine MetFlex-lip during exercise.”
Quote in the paperSubstantial claim
- May combine two claims. 15
- Classified as probably not a substantial claim. 7
May combine two claims.
Findingown dataHigh insulin sensitivity subjects had higher Adipor1 mRNA than low insulin sensitivity subjects, with a trend for Adipor2 (P=0.051).
“High_IS subjects also had higher mRNA levels of adiponectin receptor-1 (Adipor1) than Low_IS subjects, and a similar trend (P ϭ 0.051) was observed for Adipor2 (Fig. 4E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataProtein levels of OXPHOS complexes II and III were higher in high insulin sensitivity than low insulin sensitivity subjects, with trends for complexes I and IV (P<0.06).
“Protein levels of the OXPHOS complexes II and III were higher in High_IS than in Low_IS subjects, and complexes I and IV presented similar trends (P Ͻ 0.06) (Fig. 4F).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataExercise raised whole-body lipid oxidation and slightly lowered whole-body carbohydrate oxidation, with no difference between groups.
“Exercise increased whole body lipid oxidation rate and slightly decreased whole body CHO oxidation rate, without differences between groups (Fig. 2, A-C).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn both groups, complete muscle palmitate oxidation ex vivo increased after exercise, while incomplete oxidation did not change.
“In both groups, complete palmitate oxidation ex vivo increased after exercise, whereas incomplete oxidation did not change (Fig. 4, A and B).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMcad mRNA was lower in high insulin sensitivity than low insulin sensitivity subjects, with a trend for Acc2 (P=0.055).
“The mRNA level of acyl-CoA dehydrogenase C-4 to C-12 straight chain (Mcad) was lower in High_IS than Low_IS subjects, and a similar trend (P ϭ 0.055) was found for acetyl-CoA carboxylase beta (Acc2) (Fig. 4E).”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataIn the studied healthy men, the low and high insulin sensitivity groups did not differ in age, body mass, BMI, body fat, fat-free mass, VO2max, physical activity level, muscle fiber type composition, or fasting glucose.
“Low_IS and High_IS groups had similar age, body mass, body mass index (BMI), body fat, fat-free mass, V ˙O2max , PAL, fiber type composition (preexercise biopsy), and fasting glycemia (Table 1).”
- Also stated in: § Abstract · plain
“Groups had similar age, body mass index, and maximum oxygen uptake (V ˙O2max).”
Quote in the paperSubstantial claim- Also stated in: § Abstract · plain
Classified as probably not a substantial claim.
Study design and conductown dataFasting insulin and HOMA-IR differed between the low and high insulin sensitivity groups by design.
“By design, fasting insulinemia and HOMA-IR were different between groups (Table 1).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIn those studies, people with T2D showed larger rises in circulating NEFA but lower lipid oxidation than controls (19).
“In that approach, subjects with T2D had higher increases in circulating NEFA levels, but lower lipid oxidation, than control subjects (19).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] source
Not checked in the free run.
May combine two claims.
Premisenone givenEndurance exercise is a metabolic challenge that increases lipid availability together with lipid oxidation.
“Here we used as a model endurance exercise, a metabolic challenge that increases lipid availability with concomitant increases in lipid oxidation.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
InterpretationreasoningEnhanced metabolic flexibility to lipid may prevent ectopic fat deposition and protect against insulin resistance.
“In this context, an enhanced capacity to adapt lipid oxidation to lipid availability, i.e., enhanced metabolic flexibility to lipid (MetFlex-lip), may prevent ectopic fat deposition and therefore protect from insulin resistance.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe strong link between BMI and insulin sensitivity means that groups differing widely in insulin sensitivity are usually difficult to match on BMI and fat mass, which complicates interpretation.
“Given the strong association between BMI and insulin sensitivity (8), groups with large differences in insulin sensitivity are generally difficult to match for BMI and fat mass, complicating data interpretation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationUnder euglycemic-hyperinsulinemic clamp conditions, insulin-resistant states are associated with impaired metabolic flexibility to glucose.
“In those studies, insulin-resistant states are clearly associated with impaired metabolic flexibility to glucose (MetFlex-glu).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Study design and conductreasoningSample homogeneity and small sample size may make differences in MetFlex-lip undetectable.
“The disadvantage of the sample homogeneity is that differences in MetFlex-lip might be undetectable, which is aggravated by our small sample size.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningAt low ΔNEFA near the intercept, the two groups increased lipid oxidation similarly, but Low_IS showed more variability.
“This last observation suggests that at small ⌬NEFA during exercise (close to the intercept), both groups switched to lipid oxidation to a similar extent (although with larger variability in Low_IS).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable).
PremisereasoningTo be consistent with the definition of metabolic flexibility, both lipid oxidation and lipid availability must be considered.
“To be consistent with the definition of MetFlex, both lipid oxidation and lipid availability must be considered.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationSimilar exercise-induced lipid oxidation has been observed in lean, obese/insulin-resistant, and type 2 diabetes subjects and in obese versus obese/type 2 diabetes subjects.
“On one hand, similar exerciseinduced lipid oxidation has been observed in lean, obese/ insulin-resistant, and type 2 diabetes (T2D) subjects (6) and in obese vs. obese/T2D subjects (2).”
Quote in the paperSubstantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
InterpretationreasoningPrior approaches to metabolic flexibility did not truly consider fuel availability, a key component of the concept.
“All these approaches were aimed at studying the capacity to modify fuel oxidation in response to metabolic challenges (clamp, meal, exercise), but none of them truly considered fuel availability, a key component in the MetFlex concept.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationCirculating NEFA concentration rises during endurance exercise, and this rise is essential for boosting muscle lipid oxidation.
“Circulating nonesterified fatty acid (NEFA) concentration increases during endurance exercise, and such increase is essential to boost muscle lipid oxidation (23,30).”
Quote in the paperSubstantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationLipid oxidation during exercise was higher in obese/insulin-resistant than lean subjects.
“On the other hand, lipid oxidation during exercise was higher in obese/insulin-resistant vs. lean subjects (14,16).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
InterpretationreasoningIf exercise-induced lipid oxidation were a reliable marker of metabolic flexibility to lipid, insulin resistance would be associated with normal or enhanced metabolic flexibility to lipid, which is counterintuitive.
“Hence, if exercise-induced lipid oxidation was a reliable and valid marker of MetFlex-lip, insulin resistance would be associated with a normal or even enhanced MetFlex-lip, which is counterintuitive.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Fat-rich meals increase oxidation in multiple tissues, while endurance exercise increases it predominantly in skeletal muscle.
“Notably, high-fat meals increase lipid oxidation in several tissues (liver, skeletal muscle, and others), but endurance exercise augments lipid oxidation mostly in skeletal muscle.”
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?
The extent of carbohydrate depletion during high-intensity exercise directly influences the reliance of the body on lipid metabolism during recovery.
“This suggests that the extent of carbohydrate depletion during high-intensity exercise directly influences the reliance of the body on lipid metabolism during recovery, highlighting the complementary role of these substrates in meeting energy demands [12,29,32,33,34].”
From Isocaloric High-Intensity Interval and Circuit Training Increases Excess Post-Exercise Oxygen Consumption and Lipid Oxidation Compared to Moderate-Intensity Continuous Training (2025) · cites this paper as [32]
The Results section (“Similar metabolic response to exercise in Low_IS and High_IS subjects”; page unavailable) reports decreased muscle glycogen and increased lipid oxidation during exercise. The Study design describes cycling at 50% of maximum oxygen uptake, not a high-intensity exercise test, and the copy does not establish that the extent of carbohydrate depletion directly influences lipid metabolism during recovery. (LLM, conf=0.82)
Experimental — accuracy not yet measured
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- Authors
- Fernández-Verdejo, R., Bajpeyi, S., Ravussin, E., & Galgani, J. E.
- Affiliations
- Carrera de Nutrición y Dietética, Departamento de Ciencias de la Salud, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- The University of Texas at El Paso (US)
- Human Physiology Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana
- Pontificia Universidad Católica de Chile (CL)
- Corresponding author
- Galgani, José E.
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2018-10-01
- Volume
- 315
- Issue
- 4
- Pages
- E715-E722
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC6230709
- OpenAlex
- W2807141150
- Cited by
- 34
- References
- 30
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 6 · 2023: 5 · 2022: 2 · 2021: 7 · 2020: 4 · 2019: 2 · 2018: 2
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- scholarworks - UTEP (The University of Texas at El Paso) (submittedVersion)
- Funders
- The Obesity Society (Young Scientist Award 2008)
- Clinical Nutrition Research Unit Grant (P30-DK-072476)
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01-DK-060412)
- Fondo Nacional de Desarrollo Científico y Tecnológico (National Fund for Scientific and Technological Development) (1170117)
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- metabolic flexibility, lipid oxidation, insulin sensitivity, free fatty acids, respiratory quotient, physical activity, skeletal muscle, insulin resistance, insulin signaling
- MeSH terms
- Adolescent, Adult, Glycogen, Humans, Insulin Resistance, Male, Oxygen Consumption, Exercise, Muscle, Skeletal, Muscle Fibers, Skeletal, Palmitic Acid, Lipid Metabolism, Young Adult, Real-Time Polymerase Chain Reaction, Healthy Volunteers
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