Exercise training increases mitochondrial content and ex vivo mitochondrial function similarly in patients with type 2 diabetes and in control individuals
Open accessAbstract
AIMS/HYPOTHESIS: We previously showed that type 2 diabetic patients are characterised by compromised intrinsic mitochondrial function. Here, we examined if exercise training could increase intrinsic mitochondrial function in diabetic patients compared with control individuals. METHODS: Fifteen male type 2 diabetic patients and 14 male control individuals matched for age, BMI and VO(2max) enrolled in a 12 week exercise intervention programme. Ex vivo mitochondrial function was assessed by high-resolution respirometry in permeabilised muscle fibres from vastus lateralis muscle. Before and after training, insulin-stimulated glucose disposal was examined during a hyperinsulinaemic-euglycaemic clamp. RESULTS: Diabetic patients had intrinsically lower ADP-stimulated state 3 respiration and lower carbonyl cyanide 4-(trifluoro-methoxy)phenylhydrazone (FCCP)-induced maximal oxidative respiration, both on glutamate and on glutamate and succinate, and in the presence of palmitoyl-carnitine (p < 0.05). After training, diabetic patients and control individuals showed increased state 3 respiration on the previously mentioned substrates (p < 0.05); however, an increase in FCCP-induced maximal oxidative respiration was observed only in diabetic patients (p < 0.05). The increase in mitochondrial respiration was accompanied by a 30% increase in mitochondrial content upon training (p < 0.01). After adjustment for mitochondrial density, state 3 and FCCP-induced maximal oxidative respiration were similar between groups after training. Improvements in mitochondrial respiration were paralleled by improvements in insulin-stimulated glucose disposal in diabetic patients, with a tendency for this in control individuals. CONCLUSIONS/INTERPRETATION: We confirmed lower intrinsic mitochondrial function in diabetic patients compared with control individuals. Diabetic patients increased their mitochondrial content to the same extent as control individuals and had similar intrinsic mitochondrial function, which occurred parallel with improved insulin sensitivity.
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Written from the paper’s full text.
TL;DR
In a 12-week supervised combined endurance and resistance training programme, men with type 2 diabetes and matched control individuals both increased skeletal muscle mitochondrial content and ex vivo mitochondrial respiration, with diabetic patients improving insulin-stimulated glucose disposal but not restoring it to control levels. The training-induced improvement in mitochondrial respiration was largely explained by increased mitochondrial density, and intrinsic mitochondrial function became similar between groups after training.
Key findings
- Before training, diabetic patients had lower intrinsic mitochondrial function than controls: lower ADP-stimulated state 3 respiration on glutamate (MG3 17.2 ± 1.4 vs 22.5 ± 2.0 pmol mg−1 s−1, p < 0.05) and glutamate + succinate (MGS3 28.1 ± 2.0 vs 33.8 ± 2.0 pmol mg−1 s−1, p = 0.05), and lower FCCP-induced maximal respiration on glutamate + succinate (41.2 ± 2.8 vs 53.3 ± 3.1 pmol mg−1 s−1, p < 0.05) and with palmitoyl-carnitine (44.8 ± 3.1 vs 55.8 ± 3.1 pmol mg−1 s−1, p < 0.05); differences largely remained after normalisation to mtDNA copy number.
- Training increased mitochondrial content by about 30%: mtDNA copy number rose from 2.0 ± 0.14 × 10⁶ to 2.7 ± 0.14 × 10⁶ AU in diabetic patients and from 1.8 ± 0.12 × 10⁶ to 2.7 ± 0.13 × 10⁶ AU in controls (both p < 0.01).
- Training increased state 3 respiration in both groups (diabetic patients: MG3 +34%, MGS3 +33%, p < 0.01; controls: MG3 +26%, p < 0.05, MGS3 +28%, p < 0.01), but FCCP-induced maximal respiration increased only in diabetic patients (e.g. +33% on glutamate + succinate and +27% with palmitoyl-carnitine, p < 0.05). After adjustment for mitochondrial density, state 3 and FCCP-induced maximal respiration were similar between groups after training.
- Insulin-stimulated glucose disposal (ΔRd) was lower in diabetic patients before training (8.1 ± 1.4 vs 16.0 ± 2.3 μmol kg−1 min−1, p < 0.01), increased in diabetic patients to 12.0 ± 1.9 μmol kg−1 min−1 (p < 0.05), showed a tendency to increase in controls (18.2 ± 2.5 μmol kg−1 min−1, p = 0.09), and remained lower in diabetic patients after training (p < 0.05). No correlations were found between ex vivo mitochondrial function and insulin-stimulated glucose disposal.
Methods
- Fifteen male type 2 diabetic patients and 14 male normoglycaemic control individuals, matched for age, BMI and maximal aerobic capacity, completed a 12-week supervised combined endurance and resistance exercise training programme. Diabetic patients had well-controlled type 2 diabetes (HbA1c 7.1 ± 0.2%) and were on metformin only or metformin plus sulfonylurea.
- Ex vivo mitochondrial function was measured by high-resolution respirometry in permeabilised vastus lateralis muscle fibres using multiple substrate combinations (glutamate, succinate, palmitoyl-carnitine, FCCP, oligomycin); mtDNA copy number was used as a marker of mitochondrial density. Insulin sensitivity was assessed with a 3 h hyperinsulinaemic–euglycaemic clamp combined with [6,6-²H₂]glucose infusion.
- Data are means ± SE; between-group differences were tested with independent Student’s t tests, and within-group training effects with repeated-measures ANOVA; significance was set at p < 0.05.
Limitations
- Stated: the study cannot determine whether the training-induced increase in mitochondrial content and oxidative function is responsible for improved insulin sensitivity; no correlation was found between changes in insulin sensitivity and mitochondrial function, suggesting they may be parallel rather than causally related.
- Stated: substrate competition may differ between the ex vivo condition, where substrates were provided in excess, and the in vivo situation; it could not be deduced whether CPT1 or other substrate transporters are altered by training. The exact meaning of the finding that controls did not enhance FCCP-driven maximal respiratory capacity after training cannot be deduced from this study.
- Evident from the text: the sample was small and included only men, limiting generalisability; one control individual was a non-responder for insulin sensitivity, and the figure legend reports 17 control individuals while the Methods report 14, indicating a possible inconsistency in reporting.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
- Findingown data
Type 2 diabetic patients had similar intrinsic mitochondrial function compared with control individuals after training.
“Diabetic patients increased their mitochondrial content to the same extent as control individuals and had similar intrinsic mitochondrial function, which occurred parallel with improved insulin sensitivity.”
- Also stated in: § Discussion · plain
“Importantly, type 2 diabetic patients had similar intrinsic mitochondrial function compared with control individuals, paralleled by an improvement, but not restoration, of insulin sensitivity.”
Quote in the paperSubstantial claim- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
- Also stated in: § Discussion · plain
- Findingown data
Before training, mitochondrial density (mtDNA copy number) was not different between diabetic patients and control individuals.
“Mitochondrial density measured as mtDNA copy number was not different between diabetic patients and control individuals before training (2.0 ± 0.14 × 106 vs 1.8 ± 0.12 × 106 AU).”
Quote in the paperNot a substantial claim - Findingown data
After training, mtDNA copy number was not significantly different between control individuals and diabetic patients.
“After training, mtDNA copy number was not significantly different between control individuals and diabetic patients.”
Quote in the paperSubstantial claim- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
- Findingown data
After training, state 4 respiration increased in diabetic patients.
“Also, state 4 respiration and maximal respiratory capacity (FCCP-driven state u) levels increased by 28% (p < 0.01) and 33% (p < 0.01), respectively.”
Quote in the paperNot a substantial claim- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
- Findingown data
The insulin-stimulated change in R a (ΔR a) was significantly lower in type 2 diabetic patients compared with control individuals before training.
“The insulin-stimulated change in R a (ΔR a) was significant lower in type 2 diabetic patients compared with control individuals (ΔR a 9.1 ± 1.3 vs 18.6 ± 2.8 μmol kg−1 min−1; p < 0.05).”
Quote in the paperNot a substantial claim- Rests on an assumption: The 1-week discontinuation of glucose-lowering medication before testing is sufficient to eliminate medication effects on mitochondrial function and insulin sensitivity.
- Findingown data
Before and after training, no correlations were found between ex vivo mitochondrial function and insulin-stimulated glucose disposal, even after normalization for mitochondrial content.
“Before and after training, no correlations were found between ex vivo mitochondrial function and insulin-stimulated glucose disposal. Also, when ex vivo mitochondrial function was normalised for mitochondrial content, no correlations with markers of insulin sensitivity were found.”
Quote in the paperNot a substantial claim- Rests on an assumption: The 1-week discontinuation of glucose-lowering medication before testing is sufficient to eliminate medication effects on mitochondrial function and insulin sensitivity.
- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
- Findingown data
After training, insulin-mediated glucose disposal remained significantly lower in diabetic patients compared with control individuals.
“After training, insulin-mediated glucose disposal in type 2 diabetic patients remained significantly lower compared with control individuals (p < 0.05).”
Quote in the paperNot a substantial claim- Rests on an assumption: The 1-week discontinuation of glucose-lowering medication before testing is sufficient to eliminate medication effects on mitochondrial function and insulin sensitivity.
- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
- Findingown data
In control individuals, O4 respiration on MGS3 increased after training.
“O4 respiration on MGS3 increased by 32% (p < 0.01) after training; however, FCCP-driven maximal respiratory capacity in the presence of glutamate and succinate was similar before and after training.”
Quote in the paperNot a substantial claim- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
- Findingown data
Before training, state 3 respiration on palmitoyl-carnitine, glutamate and succinate (MPGS3) tended to be lower in diabetic patients compared with control individuals.
“When palmitoyl-carnitine was added as a substrate, state 3 respiration on a combination of palmitoyl-carnitine, glutamate and succinate (MPGS3) tended to be lower in diabetic patients compared with control individuals (31.2 ± 2.1 vs 39.1 ± 3.9 pmol mg−1 s−1; p = 0.08).”
Quote in the paperNot a substantial claim - Findingown data
Before training, type 2 diabetic patients had lower intrinsic FCCP-induced maximal oxidative respiration on glutamate plus succinate and in the presence of palmitoyl-carnitine compared with control individuals.
“Diabetic patients had intrinsically lower ADP-stimulated state 3 respiration and lower carbonyl cyanide 4-(trifluoro-methoxy)phenylhydrazone (FCCP)-induced maximal oxidative respiration, both on glutamate and on glutamate and succinate, and in the presence of palmitoyl-carnitine (p < 0.05).”
- Also stated in: § Ex vivo mitochondrial respirometry before training · plain
“Maximal respiratory capacity (FCCP-driven state u) in the presence of glutamate and succinate was significantly lower in diabetic patients compared with control individuals (41.2 ± 2.8 vs 53.3 ± 3.1 pmol mg−1 s−1; p < 0.05).”
- Also stated in: § Ex vivo mitochondrial respirometry before training · plain
“The maximal respiratory capacity (FCCP-driven state u) in the presence of palmitoyl-carnitine, glutamate and succinate was significantly lower in diabetic patients compared with control individuals (44.8 ± 3.1 vs 55.8 ± 3.1 pmol mg−1 s−1; p < 0.05).”
Quote in the paperSubstantial claim - Also stated in: § Ex vivo mitochondrial respirometry before training · plain
- Findingown data
Type 2 diabetic patients increased their mitochondrial content to the same extent as control individuals.
“Diabetic patients increased their mitochondrial content to the same extent as control individuals and had similar intrinsic mitochondrial function, which occurred parallel with improved insulin sensitivity.”
- Also stated in: § Discussion · boosted
“Furthermore, we showed that the 12 week exercise training intervention increased mitochondrial content to a similar extent in diabetic patients as in control individuals, with a concomitant improvement of oxidative capacity as determined with ex vivo respiratory measurements in muscle biopsies taken from the vastus lateralis muscle.”
Quote in the paperSubstantial claim- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
- Also stated in: § Discussion · boosted
- Findingown data
After adjustment for mitochondrial density, state 3 and FCCP-induced maximal oxidative respiration were similar between diabetic patients and control individuals after training.
“After adjustment for mitochondrial density, state 3 and FCCP-induced maximal oxidative respiration were similar between groups after training.”
- Also stated in: § Discussion · plain
“Importantly, after exercise training, ADP-stimulated state 3 and state u respiration were not significantly different between type 2 diabetic patients and control individuals, irrespectively of correction for mtDNA copy number.”
Quote in the paperSubstantial claim- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
- Also stated in: § Discussion · plain
- Findingown data
After 12 weeks of exercise training, both diabetic patients and control individuals increased non-normalized state 3 respiration on glutamate and glutamate plus succinate and in the presence of palmitoyl-carnitine.
“After training, diabetic patients and control individuals showed increased state 3 respiration on the previously mentioned substrates (p < 0.05); however, an increase in FCCP-induced maximal oxidative respiration was observed only in diabetic patients (p < 0.05).”
- Also stated in: § Ex vivo mitochondrial respirometry: effect of training · plain
“After 12 weeks of exercise training, state 3 respiration on MG3 increased by 34% in diabetic patients (p < 0.01) and respiration on MGS3 increased by 33% (p < 0.01).”
- Also stated in: § Ex vivo mitochondrial respirometry: effect of training · plain
“Also, in control individuals, training improved state 3 respiration on MG3 by 26% (p < 0.05) and state 3 respiration on MGS3 increased by 28% (p < 0.01).”
Quote in the paperSubstantial claim- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
- Also stated in: § Ex vivo mitochondrial respirometry: effect of training · plain
- Findingown data
Before training, insulin-mediated glucose disposal was significantly lower in diabetic patients compared with control individuals.
“Insulin-mediated glucose disposal was significantly lower in diabetic patients compared with control individuals before training (ΔR d: 8.1 ± 1.4 vs 16.0 ± 2.3 μmol kg−1 min−1; p < 0.01)”
Quote in the paperNot a substantial claim- Rests on an assumption: The 1-week discontinuation of glucose-lowering medication before testing is sufficient to eliminate medication effects on mitochondrial function and insulin sensitivity.
- Findingown data
Before training, O4 respiration on oligomycin was not different between diabetic patients and control individuals.
“No differences were found for O4 on oligomycin between groups (13.3 ± 0.8 vs 14.9 ± 1.2 pmol mg−1 s−1).”
- Also stated in: § Ex vivo mitochondrial respirometry before training · plain
“O4 after the addition of oligomycin on MPGS3 was not different between diabetic patients and control individuals (20.4 ± 1.2 vs 22.2 ± 1.8 pmol mg−1 s−1).”
Quote in the paperNot a substantial claim - Also stated in: § Ex vivo mitochondrial respirometry before training · plain
- Findingown data
After training, O4 on MPGS3 increased in diabetic patients.
“O4 on MPGS3 significantly increased after training by 21% (p < 0.05) and FCCP-induced maximal respiration increased by 27% (p < 0.05).”
Quote in the paperNot a substantial claim- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
- Interpretationown data
Insulin sensitivity and mitochondrial function are two effects of exercise training that are not necessarily causally related.
“These results might suggest that insulin sensitivity and mitochondrial function are two effects of exercise training that are not necessarily causally related.”
Quote in the paperSubstantial claim- Rests on an assumption: The 1-week discontinuation of glucose-lowering medication before testing is sufficient to eliminate medication effects on mitochondrial function and insulin sensitivity.
- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
- Study design and conductown data
Groups were matched for age, BMI and maximal aerobic capacity.
“Groups were matched for age, BMI and maximal aerobic capacity.”
- Also stated in: § Methods · plain
“all matched for age, BMI and (age: 59.5 ± 1.2 and 58.2 ± 1.1 years; BMI: 30.0 ± 0.9 and 30.2 ± 0.9 kg/m2; : 28.2 ± 1.4 and 29.2 ± 1.2 ml kg−1 min−1; p > 0.05 for all variables).”
Quote in the paperSubstantial claim - Also stated in: § Methods · plain
- Study design and conductown data
Clamped plasma glucose concentrations were not different between type 2 diabetic patients and control individuals before and after training.
“Clamped plasma glucose concentrations were not different between type 2 diabetic patients and control individuals before the exercise training (5.7 ± 0.2 vs 5.7 ± 0.1 mmol/l) and after training (5.6 ± 0.2 vs 5.3 ± 0.1 mmol/l).”
Quote in the paperNot a substantial claim - Interpretationreasoning
Improved mitochondrial function alone was not sufficient to restore insulin sensitivity in type 2 diabetic patients.
“This may suggest that improved mitochondrial function alone was not sufficient to restore insulin sensitivity, and that additional exercise-related factors could be responsible for the training-increased insulin sensitivity.”
Quote in the paperSubstantial claim- Rests on an assumption: The 1-week discontinuation of glucose-lowering medication before testing is sufficient to eliminate medication effects on mitochondrial function and insulin sensitivity.
- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
- Interpretationreasoning
The increase in respiratory states after exercise training in both groups is based at the level of the electron transport chain or the upstream dehydrogenases.
“From these results, it may be concluded that the increase of the respiratory states after exercise training in control individuals and type 2 diabetic patients is based at the level of the ETC or the upstream dehydrogenases.”
Quote in the paperSubstantial claim- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
- May combine two claims. 9
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 2
May combine two claims.
Findingown dataΔR a increased upon exercise training in both diabetic patients and control individuals, but remained significantly lower in diabetic patients.
“The ΔR a upon exercise training increased to 12.3 ± 1.5 (p < 0.05) in diabetic patients and to 21.2 ± 3.0 μmol kg−1 min−1 (p < 0.05) in control individuals, with ΔR a remaining significantly lower in diabetic patients compared with control individuals.”
Quote in the paperNot a substantial claim- Rests on an assumption: The 1-week discontinuation of glucose-lowering medication before testing is sufficient to eliminate medication effects on mitochondrial function and insulin sensitivity.
- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
May combine two claims.
Findingown dataAfter exercise training, insulin-mediated glucose disposal increased significantly in diabetic patients and tended to increase in control individuals.
“and increased significantly after exercise training in diabetic patients to 12.0 ± 1.9 μmol kg−1 min−1 (p < 0.05) with a tendency for increase in control individuals (ΔR d 18.2 ± 2.5 μmol kg−1 min−1; p = 0.09).”
Quote in the paperNot a substantial claim- Rests on an assumption: The 1-week discontinuation of glucose-lowering medication before testing is sufficient to eliminate medication effects on mitochondrial function and insulin sensitivity.
- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
May combine two claims.
Findingown dataBefore training, type 2 diabetic patients had lower intrinsic ADP-stimulated state 3 respiration on glutamate and on glutamate plus succinate, and in the presence of palmitoyl-carnitine, compared with control individuals.
“Diabetic patients had intrinsically lower ADP-stimulated state 3 respiration and lower carbonyl cyanide 4-(trifluoro-methoxy)phenylhydrazone (FCCP)-induced maximal oxidative respiration, both on glutamate and on glutamate and succinate, and in the presence of palmitoyl-carnitine (p < 0.05).”
- Also stated in: § Ex vivo mitochondrial respirometry before training · plain
“State 3 respiration on MG3 and on MGS3 was significantly lower in diabetic patients compared with control individuals (MG3: 17.2 ± 1.4 vs 22.5 ± 2.0 pmol mg−1 s−1, p < 0.05 and MGS3: 28.1 ± 2.0 vs 33.8 ± 2.0 pmol mg−1 s−1, p = 0.05).”
- Also stated in: § Discussion · plain
“In agreement with earlier results [5], we showed a ∼25% lower state 3 respiration and a ∼31% lower FCCP-induced maximal oxidative capacity in type 2 diabetic patients compared with control individuals, even when normalised to mitochondrial content.”
Quote in the paperSubstantial claim- Also stated in: § Ex vivo mitochondrial respirometry before training · plain
May combine two claims.
Findingown dataIn control individuals, MPG3 and MPGS3 increased upon training.
“Similarly, upon the addition of palmitoyl-carnitine, MPG3 increased upon exercise training by 38% (p < 0.01), MPGS3 by 34% (p < 0.01) and O4 upon MPGS3 increased by 17% (p < 0.05).”
Quote in the paperNot a substantial claim- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
The quote only partly states this claim.
Findingown dataExercise training increased mitochondrial content (mtDNA copy number) by about 30% in both diabetic patients and control individuals.
“The increase in mitochondrial respiration was accompanied by a 30% increase in mitochondrial content upon training (p < 0.01).”
- Also stated in: § Mitochondrial density · plain
“After training, mtDNA copy number increased significantly to 2.7 ± 0.14 × 106 AU in diabetic patients (p < 0.01) and to 2.7 ± 0.13 × 106 AU (p < 0.01) in control individuals.”
Quote in the paperSubstantial claim- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
- Also stated in: § Mitochondrial density · plain
May combine two claims.
Findingown dataAfter 12 weeks of exercise training, FCCP-induced maximal oxidative respiration increased in diabetic patients but not significantly in control individuals.
“After training, diabetic patients and control individuals showed increased state 3 respiration on the previously mentioned substrates (p < 0.05); however, an increase in FCCP-induced maximal oxidative respiration was observed only in diabetic patients (p < 0.05).”
- Also stated in: § Ex vivo mitochondrial respirometry: effect of training · plain
“Also, state 4 respiration and maximal respiratory capacity (FCCP-driven state u) levels increased by 28% (p < 0.01) and 33% (p < 0.01), respectively.”
- Also stated in: § Ex vivo mitochondrial respirometry: effect of training · plain
“O4 respiration on MGS3 increased by 32% (p < 0.01) after training; however, FCCP-driven maximal respiratory capacity in the presence of glutamate and succinate was similar before and after training.”
Quote in the paperNot a substantial claim- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
- Also stated in: § Ex vivo mitochondrial respirometry: effect of training · plain
May combine two claims.
Findingown dataImprovements in mitochondrial respiration were paralleled by improvements in insulin-stimulated glucose disposal in diabetic patients, with a tendency for this in control individuals.
“Improvements in mitochondrial respiration were paralleled by improvements in insulin-stimulated glucose disposal in diabetic patients, with a tendency for this in control individuals.”
- Also stated in: § Discussion · plain
“These improvements were paralleled by improved insulin-stimulated glucose disposal in type 2 diabetic patients and control individuals.”
Quote in the paperSubstantial claim- Rests on an assumption: The 1-week discontinuation of glucose-lowering medication before testing is sufficient to eliminate medication effects on mitochondrial function and insulin sensitivity.
- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
- Also stated in: § Discussion · plain
Classified as probably not a substantial claim.
Study design and conductnone givenAll substrates were added in excess to ensure respiratory measurements were not limited by substrate availability.
“All substrates were added in excess to ensure that respiratory measurements were not limited by substrate availability influencing oxygen flux.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataIn diabetic patients, the training-induced increase in mitochondrial respiration was mainly accounted for by an increase in mitochondrial content; after normalization to mtDNA, the significant differences in respiration before and after training no longer persisted.
“However, when respiration values were normalised to mtDNA copy number, significant differences reported for all states before and after training in diabetic patients no longer persisted (Fig. 2a,b), illustrating that the major part of the improvement in mitochondrial function was because of an increase in mitochondrial content.”
Quote in the paperSubstantial claim- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
May combine two claims.
Interpretationown dataIn control individuals, the training-induced increase in mitochondrial respiration was mainly accounted for by an increase in mitochondrial density; no significant increase in intrinsic mitochondrial respiration was observed after adjustment for mtDNA copy number.
“Again, as in diabetic patients, the increase in mitochondrial respiration (with or without the addition of palmitoyl-carnitine) upon training was mainly accounted for by an increase in mitochondrial density, as no significant increase in intrinsic mitochondrial respiration was observed after adjustment for mtDNA copy number upon exercise training (Fig. 2a,b).”
Quote in the paperSubstantial claim- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe final exercise bout was performed at least 2 days before the clamp.
“The final exercise bout of the training programme was performed at least 2 days before the clamp.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningIn control individuals only, exercise training did not enhance FCCP-driven maximal respiratory capacity, whereas it did in type 2 diabetic patients; as a result, FCCP-driven maximal respiratory capacity per mitochondrion was lower after training in controls.
“Remarkably, in control individuals only, exercise training did not enhance FCCP-driven maximal respiratory capacity, as occurred in type 2 diabetic patients. As a result of the increase in mitochondrial content, FCCP-driven maximal respiratory capacity per mitochondrion was actually lower after training.”
Quote in the paperNot a substantial claim- Rests on an assumption: The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
The paper relies on this without support.
The 1-week discontinuation of glucose-lowering medication before testing is sufficient to eliminate medication effects on mitochondrial function and insulin sensitivity.
“Glucose-lowering medication was continued throughout the study except for the week preceding the actual tests and sampling of the biopsy.”
“Diabetic patients discontinued their glucose-lowering medication 1 week prior to the clamp, but restarted the use of medication after the test days.”
The paper relies on this without support.
The final exercise bout at least 2 days before the clamp is sufficient to avoid acute exercise effects on mitochondrial function and insulin sensitivity.
“The final exercise bout of the training programme was performed at least 2 days before the clamp.”
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 humans, physical exercise increases total mitochondrial mass and uncoupling in skeletal muscular cells.
“In humans, physical exercise increases total mitochondrial mass and uncoupling in skeletal muscular cells [192].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [192]
In patients with type 2 diabetes, walking and ergometer cycling increase mitochondrial muscle respiration, mitochondrial content and density, and oxidative enzyme activity.
“In patients with T2DM, walking and ergometer cycling exercise increased mitochondrial muscle respiration and mitochondrial content and density, as well as the activity of oxidative enzymes214,215.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [215]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Figure 1 lists more controls than were enrolled
MinorThe paper says 14 control individuals were included, but the Figure 1 caption says it shows 17 control individuals.
“In this study, 15 male type 2 diabetic patients and 14 normoglycaemic control individuals were included”
“Figure: Fig. 1 Intrinsic mitochondrial respiration ([pmol mg−1 s−1]/[mtDNA copy number × 106]) in 17 control individuals (white bars) vs 15 diabetic patients (black bars) before training.”
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Dysfunction of Mitochondria in Human Skeletal Muscle in Type 2 Diabetes
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Effective exercise modality to reduce insulin resistance in women with type 2 diabetes
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Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle
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Phielix, E., Schrauwen-Hinderling, V. B., Mensink, M., Lenaers, E., Meex, R., Hoeks, J., Kooi, M. E., Moonen-Kornips, E., Sels, J.-P., Hesselink, M. K. C., et al. (2008) · Diabetes · doi:10.2337/db08-0391 · Cited by 359 · see citing works
Self-citationMeex, R. C. R., Schrauwen-Hinderling, V. B., Moonen-Kornips, E., Schaart, G., Mensink, M., Phielix, E., van de Weijer, T., Sels, J.-P., Schrauwen, P., & Hesselink, M. K. C. (2010) · Diabetes · doi:10.2337/db09-1322 · Cited by 355 · see citing works
Self-citationToledo, F. G. S., Menshikova, E. V., Ritov, V. B., Azuma, K., Radikova, Z., DeLany, J., & Kelley, D. E. (2007) · Diabetes · doi:10.2337/db07-0141 · Cited by 321 · see citing works
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Exercise for the management of type 2 diabetes: a review of the evidence
Zanuso, S., Jiménez, A., Pugliese, G., Corigliano, G., & Balducci, S. (2009) · Acta Diabetologica · doi:10.1007/s00592-009-0126-3 · Cited by 283 · see citing works
Muscle Mitochondrial ATP Synthesis and Glucose Transport/Phosphorylation in Type 2 Diabetes
Szendroedi, J., Schmid, A. I., Chmelik, M., Toth, C., Brehm, A., Krssak, M., Nowotny, P., Wolzt, M., Waldhausl, W., & Roden, M. (2007) · PLoS Medicine · doi:10.1371/journal.pmed.0040154 · Cited by 243 · see citing works
Toledo, F. G. S., Menshikova, E. V., Azuma, K., Radiková, Z., Kelley, C. A., Ritov, V. B., & Kelley, D. E. (2008) · Diabetes · doi:10.2337/db07-1429 · Cited by 218 · see citing works
Muscle mitochondrial changes with aging and exercise
Lanza, I. R., & Nair, K. S. (2008) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2008.26717d · Cited by 152 · see citing works
Larsen, S., Ara, I., Rabøl, R., Andersen, J. L., Boushel, R., Dela, F., & Helge, J. W. (2009) · Diabetologia · doi:10.1007/s00125-009-1353-4 · Cited by 90 · see citing works
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Muscular mitochondrial dysfunction and type 2 diabetes mellitus
Schrauwen‐Hinderling, V. B., Roden, M., Kooi, M. E., Hesselink, M. K. C., & Schrauwen, P. (2007) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e3282f0eca9 · Cited by 56 · see citing works
Self-citationConversion of insulin units to SI units
Vølund, A. (1993) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/58.5.714 · Cited by 49 · see citing works
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Bhatti, J. S., Bhatti, G. K., & Reddy, P. H. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.11.010 · Cited by 1,655 · see citing works
Type 2 diabetes and cardiovascular disease: Have all risk factors the same strength?
Timon, I. M. (2014) · World Journal of Diabetes · doi:10.4239/wjd.v5.i4.444 · Cited by 982 · see citing works
Mitochondrial and metabolic dysfunction in ageing and age-related diseases
Amorim, J. A., Coppotelli, G., Rolo, A. P., Palmeira, C. M., Ross, J. M., & Sinclair, D. A. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00626-7 · Cited by 990 · see citing works
KANALEY, J. A., COLBERG, S. R., CORCORAN, M. H., MALIN, S. K., RODRIGUEZ, N. R., CRESPO, C. J., KIRWAN, J. P., & ZIERATH, J. R. (2022) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000002800 · Cited by 931 · see citing works
Update on the treatment of type 2 diabetes mellitus
Marín-Peñalver, J. J., Martín-Timón, I., Sevillano-Collantes, C., & Cañizo-Gómez, F. J. D. (2016) · World Journal of Diabetes · doi:10.4239/wjd.v7.i17.354 · Cited by 647 · see citing works
“…within a specific plan, provides in general terms multiple benefits: Increased insulin sensitivity in tissues, improvement of glycaemic control [44] , benefits in lipid profile and blood pressure, maintenance or weight loss, cardiovascular benefits, better quality of life, psychological…”
BackgroundThe role of mitochondria in insulin resistance and type 2 diabetes mellitus
Szendroedi, J., Phielix, E., & Roden, M. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2011.138 · Cited by 600 · see citing works
“In vivo submaximal ADP-stimulated oxidative phosphorylation and mitochondrial content were restored to values seen in control individuals upon a 12-week exercise intervention in patients with T2DM”
BackgroundMitochondrial dysfunction and insulin resistance: an update
Montgomery, M. K., & Turner, N. A. (2014) · Endocrine Connections · doi:10.1530/ec-14-0092 · Cited by 530 · see citing works
Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases
Demine, S., Renard, P., & Arnould, T. (2019) · Cells · doi:10.3390/cells8080795 · Cited by 476 · see citing works
“In humans, physical exercise increases total mitochondrial mass and uncoupling in skeletal muscular cells [192].”
BackgroundPharmacological approaches to restore mitochondrial function
Andreux, P. A., Houtkooper, R. H., & Auwerx, J. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4023 · Cited by 383 · see citing works
A Prospective Study of Frailty in Nephrology-Referred Patients With CKD
Roshanravan, B., Khatri, M., Robinson-Cohen, C., Levin, G. P., Patel, K., de Boer, I. D., Seliger, S., Ruzinski, J., Himmelfarb, J., & Kestenbaum, B. (2012) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2012.05.017 · Cited by 315 · see citing works
“Antidepressant 110 (33) 89 (31) 21 (45)”
Vanweert, F., Schrauwen, P., & Phielix, E. (2022) · Nutrition and Diabetes · doi:10.1038/s41387-022-00213-3 · Cited by 316 · see citing works
“Dysfunctional mitochondrial BCAA catabolism We as well as others have repeatedly reported that people with insulin resistance and patients with T2D feature low muscle mitochondrial oxidative capacity [13, 148, 149].”
BackgroundSelf-citationEnhanced Respiratory Chain Supercomplex Formation in Response to Exercise in Human Skeletal Muscle
Greggio, C., Jha, P., Kulkarni, S. S., Lagarrigue, S., Broskey, N. T., Boutant, M., Wang, X., Conde Alonso, S., Ofori, E., Auwerx, J., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2016.11.004 · Cited by 286 · see citing works
San-Millán, I., & Brooks, G. A. (2018) · Sports Medicine · doi:10.1007/s40279-017-0751-x · Cited by 264 · see citing works
A Novel MitoTimer Reporter Gene for Mitochondrial Content, Structure, Stress, and Damage in Vivo
Laker, R. C., Xu, P., Ryall, K. A., Sujkowski, A. L., Kenwood, B. M., Chain, K. H., Zhang, M., Royal, M. A., Hoehn, K. L., Driscoll, M., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.530527 · Cited by 254 · see citing works
Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus
Hesselink, M. K. C., Schrauwen-Hinderling, V., & Schrauwen, P. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.104 · Cited by 242 · see citing works
Self-citationDemonstration of a day-night rhythm in human skeletal muscle oxidative capacity
van Moorsel, D., Hansen, J., Havekes, B., Scheer, F. A. J. L., Jörgensen, J. A., Hoeks, J., Schrauwen-Hinderling, V. B., Duez, H., Lefebvre, P., Schaper, N. C., et al. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.06.012 · Cited by 218 · see citing works
Self-citationRichards, J. C., Johnson, T. K., Kuzma, J. N., Lonac, M. C., Schweder, M. M., Voyles, W. F., & Bell, C. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.189886 · Cited by 187 · see citing works
“Journal compilation C© 2010 The Physiological Society training has been shown to induce similar mitochondrial adaptations in adults with type II diabetes compared with healthy controls (Phielix et al. 2010).”
BackgroundCoen, P. M., Menshikova, E. V., Distéfano, G., Zheng, D., Tanner, C., Standley, R., Helbling, N., Dubis, G. S., Ritov, V., Xie, H., et al. (2015) · Diabetes · doi:10.2337/db15-0809 · Cited by 155 · see citing works
“Although these effects have been previously reported for exercise (29,33), the present report is the first in obese patients following bariatric surgery.”
BackgroundPesta, D. H., Hoppel, F., Macek, C., Messner, H., Faulhaber, M., Kobel, C., Parson, W., Burtscher, M., Schocke, M. F. H., & Gnaiger, E. (2011) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00285.2011 · Cited by 181 · see citing works
“Aerobic exercise is known as an effective preventive measure to counteract these maladies (26, 36, 49).”
BackgroundInsulin Resistance and Mitochondrial Dysfunction
González-Franquesa, A., & Patti, M. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-55330-6_25 · Cited by 154 · see citing works
Gaesser, G. A., Angadi, S. S., & Sawyer, B. J. (2011) · The Physician and Sportsmedicine · doi:10.3810/psm.2011.05.1898 · Cited by 139 · see citing works
Espino-González, E., Dalbram, E., Mounier, R., Gondin, J., Farup, J., Jessen, N., & Treebak, J. T. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.02.014 · Cited by 132 · see citing works
Sparks, L. M., Johannsen, N. M., Church, T. S., Earnest, C. P., Moonen-Kornips, E., Moro, C., Hesselink, M. K. C., Smith, S. R., & Schrauwen, P. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3874 · Cited by 123 · see citing works
Self-citationHigh Oxidative Capacity Due to Chronic Exercise Training Attenuates Lipid-Induced Insulin Resistance
Phielix, E., Meex, R., Ouwens, D. M., Sparks, L., Hoeks, J., Schaart, G., Moonen-Kornips, E., Hesselink, M. K. C., & Schrauwen, P. (2012) · Diabetes · doi:10.2337/db11-1832 · Cited by 99 · see citing works
“increased mitochondrial mass rather than intrinsic mitochondrial function (32).”
BackgroundSelf-citationTargeting NAD+ in Metabolic Disease: New Insights Into an Old Molecule
Elhassan, Y., Philp, A., & Lavery, G. G. (2017) · Journal of the Endocrine Society · doi:10.1210/js.2017-00092 · Cited by 92 · see citing works
Muscle mitochondria and insulin resistance: a human perspective
Hoeks, J., & Schrauwen, P. (2012) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2012.05.007 · Cited by 94 · see citing works
Self-citationKarstoft, K., Winding, K. M., Knudsen, S. H., James, N. G., Scheel, M. M., Olesen, J., Holst, J. J., Pedersen, B. K., & Solomon, T. P. J. (2014) · Diabetologia · doi:10.1007/s00125-014-3334-5 · Cited by 91 · see citing works
“Mitochondrial content and function have been linked to insulin sensitivity, and changes in mitochondrial markers have been seen along with improvements in glycaemic control and insulin sensitivity [49, 50].”
BackgroundResistance to type 2 diabetes mellitus: a matter of hormesis?
Kolb, H., & Eizirik, D. L. (2011) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2011.158 · Cited by 86 · see citing works
“The small exercise-induced improvement in insulin sensitivity observed in patients with T2DM is not sufficient to normalize insulin action in skeletal muscle cells”
BackgroundVanweert, F., Neinast, M. D., Erazo‐Tapia, E., van de Weijer, T., Joris Hoeks, J., Schrauwen‐Hinderling, V. B., Blair, M. C., Bornstein, M. R., Hesselink, M. K. C., Schrauwen, P., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31249-9 · Cited by 87 · see citing works
Self-citationPardo, R., Enguix, N., Lasheras, J., Felíu, J. E., Kralli, A., & Villena, J. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026989 · Cited by 85 · see citing works
“thiazolidinediones) that enhance oxidative metabolism are also effective in ameliorating whole body insulin sensitivity, an effect that has been associated with the capacity of such treatments to induce mitochondrial biogenesis [12,13,14,15].”
BackgroundToledo, F. G. S., & Goodpaster, B. H. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.06.018 · Cited by 82 · see citing works
“Subjects with T2DM also display the greatest degrees of derangements in insulin sensitivity in SkM and the greatest IMCL lipid accumulation.”
BackgroundMethodInfluentialCole, C. L., Kleckner, I. R., Jatoi, A., Schwarz, E. M., & Dunne, R. F. (2018) · JCSM Clinical Reports · doi:10.17987/jcsm-cr.v3i2.65 · Cited by 84 · see citing works
“These improvements were observed in patients with diabetes mellitus [205, 206] and in elderly individuals [207].”
BackgroundHouzelle, A., Jörgensen, J. A., Schaart, G., Daemen, S., van Polanen, N., Fealy, C. E., Hesselink, M. K. C., Schrauwen, P., & Hoeks, J. (2021) · Diabetologia · doi:10.1007/s00125-020-05335-w · Cited by 83 · see citing works
Self-citationThomas, A. W., Davies, N. A., Moir, H. J., Watkeys, L. J., Ruffino, J. S., Isa, S., Butcher, L., Hughes, M. G., Morris, K., & Webb, R. (2011) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00864.2011 · Cited by 81 · see citing works
“Therefore, if individuals with T2D were to respond in a manner similar to the participants in the present study, and T2D and non-T2D cohorts have been shown to respond to a similar extent to exercise (16, 43), it is possible that the exercise-associated effects seen here could help normalize PPAR signaling and, thus,…”
BackgroundResultFujimaki, S., & Kuwabara, T. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102147 · Cited by 75 · see citing works
“Other styles of exercise training, including strength and concurrent training, have been also reported to increase the mitochondrial content in skeletal muscle of patients with T2DM [161,162].”
BackgroundSavikj, M., Stocks, B., Sato, S., Caidahl, K., Krook, A., Deshmukh, A. S., Zierath, J. R., & Wallberg‐Henriksson, H. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155268 · Cited by 74 · see citing works
Secondary muscle pathology and metabolic dysregulation in adults with cerebral palsy
Peterson, M. D., Gordon, P. M., Hurvitz, E. A., & Burant, C. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00338.2012 · Cited by 73 · see citing works
Mitochondrial Plasticity in Obesity and Diabetes Mellitus
Jeleník, T., & Roden, M. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4910 · Cited by 72 · see citing works
“However, studies successfully matching the groups for Vo2max revealed no difference in insulin sensitivity between young and elderly (14), supported by observation that insulin sensitivity as well as mitochondrial oxidative capacity improve after exercise in elderly insulin-resistant patients with T2DM and age-matched…”
BackgroundShaw, C. S., Shepherd, S. O., Wagenmakers, A. J. M., Hansen, D., Dendale, P., & van Loon, L. J. C. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00272.2012 · Cited by 72 · see citing works
Salvadego, D., Domenis, R., Lazzer, S., Porcelli, S., Rittweger, J., Rizzo, G., Mavelli, I., Šimunič, B., Pišot, R., & Grassi, B. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00883.2012 · Cited by 68 · see citing works
“In any case, the data obtained in the present study are similar to those obtained after substantially following the same protocol of the present study in the healthy control subjects of recent studies (9, 23, 30).”
ResultKenny, H. C., Rudwill, F., Breen, L., Salanova, M., Blottner, D., Heise, T., Heer, M., Blanc, S., & O’Gorman, D. J. (2017) · Diabetologia · doi:10.1007/s00125-017-4298-z · Cited by 64 · see citing works
Esther Phielix, E., Jeleník, T., Nowotny, P., Szendroedi, J., & Roden, M. (2013) · Diabetologia · doi:10.1007/s00125-013-3127-2 · Cited by 66 · see citing works
“5 h, then permeabilised using saponin, and rinsed using respiration medium as described previously [2, 3, 21].”
BackgroundMethodSelf-citationVanweert, F., de Ligt, M., Joris Hoeks, J., Hesselink, M. K. C., Schrauwen, P., & Esther Phielix, E. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa751 · Cited by 60 · see citing works
Self-citationBhatti, J. S., Kumar, S., Vijayan, M., Bhatti, G. K., & Reddy, P. H. (2017) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2016.12.012 · Cited by 60 · see citing works
Combatting type 2 diabetes by turning up the heat
Schrauwen, P., & Lichtenbelt, W. D. V. M. (2016) · Diabetologia · doi:10.1007/s00125-016-4068-3 · Cited by 59 · see citing works
“Indeed, we [68, 69] and others [70–73] have shown that in type 2 diabetes patients an exercise-induced improvement in insulin sensitivity is associated with an improvement in mitochondrial function.”
BackgroundSelf-citationAkhtar, S., & Siragy, H. M. (2019) · PLoS ONE · doi:10.1371/journal.pone.0225728 · Cited by 57 · see citing works
Insulin resistance and mitochondrial function in skeletal muscle
Dela, F., & Helge, J. W. (2012) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2012.09.019 · Cited by 53 · see citing works
“Next, in a study of 15 patients with type 2 diabetes and 14 controls subjects matched for age, BMI and VO2max internal incoherent data are reported (Phielix et al., 2010).”
BackgroundDam, A. D., Mitchell, A. S., & Quadrilatero, J. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.04.014 · Cited by 51 · see citing works
Lim, S. K., Choi, S. H., Koo, B. K., Kang, S. M., Yoon, J. W., Jang, H. C., Choi, S. M., Lee, M. G., Lee, W., Shin, H., et al. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1743 · Cited by 52 · see citing works
Impairment of Mitochondrial Respiration in Metabolic Diseases: An Overview
Avram, V. F., Merce, A. P., Hâncu, I. M., Bătrîn, A. D., Kennedy, G., Rosca, M. G., & Muntean, D. M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23168852 · Cited by 49 · see citing works
“These changes in mitochondrial respiration are similar to thosse reported in skeletal muscle [90,93,96].”
BackgroundResultAre Alterations in Skeletal Muscle Mitochondria a Cause or Consequence of Insulin Resistance?
Genders, A. J., Holloway, G. P., & Bishop, D. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186948 · Cited by 51 · see citing works
“Exercise interventions that increase mitochondrial respiratory function have also been shown to improve insulin resistance [8,9].”
BackgroundMethodInfluentialKruse, R., Pedersen, A. J. T., Kristensen, J. M., Petersson, S. J., Wojtaszewski, J. F. P., & Højlund, K. (2016) · Clinical Science · doi:10.1042/cs20160736 · Cited by 48 · see citing works
Mitochondrial Function and Insulin Resistance during Aging – A Mini-Review
Phielix, E., Szendroedi, J., & Roden, M. (2011) · Gerontology · doi:10.1159/000317691 · Cited by 47 · see citing works
Broskey, N. T., Daraspe, J., Humbel, B. M., & Amati, F. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00063.2013 · Cited by 45 · see citing works
“This is particularly true in exercise science research (4, 21), obesity (2, 6, 22), and diabetes (11, 15, 18).”
BackgroundStephens, N. A., Brouwers, B., Eroshkin, A. M., Yi, F., Cornnell, H. H., Meyer, C., Goodpaster, B. H., Pratley, R. E., Smith, S. R., & Sparks, L. M. (2018) · Diabetes Care · doi:10.2337/dc18-0296 · Cited by 48 · see citing works
Petersen, M. H., de Almeida, M. E., Wentorf, E. K., Jensen, K., Ørtenblad, N., & Højlund, K. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1032235 · Cited by 49 · see citing works
“The adaptations underlying the beneficial metabolic effects of exercise training, also in obesity and type 2 diabetes, include increased mitochondrial content and function and increased abundance of proteins involved in insulin-signaling to glucose uptake and glucose storage [4, 12-16].”
BackgroundNutrients, Physical Activity, and Mitochondrial Dysfunction in the Setting of Metabolic Syndrome
Lemos, G., Torrinhas, R. S., & Waitzberg, D. L. (2023) · Nutrients · doi:10.3390/nu15051217 · Cited by 46 · see citing works
Differential Changes in Exercise Performance After Massive Weight Loss Induced by Bariatric Surgery
Wilms, B., Ernst, B., Thurnheer, M., Weisser, B., & Schultes, B. (2012) · Obesity Surgery · doi:10.1007/s11695-012-0795-9 · Cited by 45 · see citing works
“Exercise training has been demonstrated to enhance mitochondrial content in obese patients with [34] and without [35] diabetes, pointing to the dynamic nature of the muscle's mitochondrial capacity.”
BackgroundEffect of Aerobic Exercise-induced Weight Loss on the Components of Daily Energy Expenditure
Broskey, N. T., Martin, C. K., Burton, J. H., Church, T. S., Ravussin, É., & Redman, L. M. (2021) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000002689 · Cited by 41 · see citing works
Bishop, D. J., Lee, M. J.-C., & Picard, M. A. (2024) · Annual Review of Physiology · doi:10.1146/annurev-physiol-022724-104836 · Cited by 42 · see citing works
Feng, Y., Nikolić, N., Bakke, S. S., Kase, E. T., Guderud, K., Hjelmesaeth, J. S., Aas, V., Rustan, A. C., & Thoresen, G. H. (2015) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00314.2014 · Cited by 39 · see citing works
“Although it has been shown that exercise improves both mitochondrial content and intrinsic mitochondrial function in obese and insulin-resistant subjects (43), it has also been reported that there were no changes in key regulators of mitochondrial biogenesis in skeletal muscles in diabetic men after in vivo exercise (…”
Four days of bed rest increases intrinsic mitochondrial respiratory capacity in young healthy males
Larsen, S., Lundby, A. M., Dandanell, S., Oberholzer, L., Keiser, S., Andersen, A. B., Haider, T., & Lundby, C. (2018) · Physiological Reports · doi:10.14814/phy2.13793 · Cited by 38 · see citing works
“In recent years, reduced skeletal muscle mitochondrial content and function (intrinsic mitochondrial respiratory capacity and reactive oxygen species production) has been proposed important in the development of T2D (Mogensen et al. 2007; Phielix et al. 2010) although this remains debated (Larsen et al. 2009, 2011; He…”
BackgroundRole of PGC-1α in the Mitochondrial NAD+ Pool in Metabolic Diseases
Koh, J., & Kim, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094558 · Cited by 38 · see citing works
Hao, J., Hao, C., Zhang, L., Liu, X., Zhou, X., Dun, Y., Li, H., Li, G., Zhao, X., An, Y., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0131930 · Cited by 38 · see citing works
Eghbalzadeh, K., Brixius, K., Bloch, W., & Brinkmann, C. K. (2013) · Nitric Oxide · doi:10.1016/j.niox.2013.12.009 · Cited by 38 · see citing works
Effects and potential mechanisms of exercise and physical activity on eye health and ocular diseases
Zhang, Q., Jiang, Y., Deng, C., & Wang, J. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1353624 · Cited by 38 · see citing works
Kacerovsky-Bielesz, G., Kacerovsky, M., Chmelík, M., Farukuoye, M., Ling, C., Pokan, R., Tschan, H., Szendroedi, J., Schmid, A. I., Gruber, S., et al. (2011) · Diabetes Care · doi:10.2337/dc11-1426 · Cited by 37 · see citing works
“Furthermore, fATP measures demand-driven ATP synthesis at rest, not necessarily reflecting maximal mitochondrial capacity as assessed with postexercise phosphocreatine recovery (35).”
Backgroundde Goede, P., Wüst, R. C. I., Schomakers, B. V., Denis, S. W., Vaz, F. M., Pras‐Raves, M. L., van Weeghel, M., Yi, C., Kalsbeek, A., & Houtkooper, R. H. (2022) · The FASEB Journal · doi:10.1096/fj.202100707r · Cited by 36 · see citing works
Riera-Borrull, M., Rodríguez‐Gallego, E., Hernández‐Aguilera, A., et al. (2015) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-015-1262-3 · Cited by 35 · see citing works
Dahlmans, D., Houzelle, A., Jörgensen, J. A., Esther Phielix, E., Lindeboom, L., Hesselink, M. K. C., Schrauwen, P., & Joris Hoeks, J. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00711 · Cited by 35 · see citing works
“NCT00943059 (van de Weijer et al., 2014), NCT01298375 (Vosselman et al., 2015) and NTR2002 (Phielix et al., 2010, 2012)], and all participants gave their informed written consent in accordance with the Declaration of Helsinki.”
MethodResultInfluentialSelf-citationSparks, L. M., Gemmink, A., Phielix, E., Bosma, M., Schaart, G., Moonen-Kornips, E., Jörgensen, J. A., Nascimento, E. B. M., Hesselink, M. K. C., Schrauwen, P., et al. (2016) · Diabetologia · doi:10.1007/s00125-016-3885-8 · Cited by 34 · see citing works
Self-citationOnofre, T., Carlos, R., Oliver, N., Felismino, A., Fialho, D., Corte, R. C., da Silva, E. P., de Godoy, E. P., & Bruno, S. (2017) · Obesity Surgery · doi:10.1007/s11695-017-2584-y · Cited by 34 · see citing works
Kerr, M. J., Miller, J. J. J. J., Thapa, D., Stiewe, S., Timm, K. N., Aparicio, C. N. M., Scott, I., Tyler, D. J., & Heather, L. C. (2020) · JCI Insight · doi:10.1172/jci.insight.140326 · Cited by 34 · see citing works
Zamora, M., Pardo, R., & Villena, J. A. (2015) · Biochemical Pharmacology · doi:10.1016/j.bcp.2015.06.032 · Cited by 32 · see citing works
Diabetes and Stem Cell Function
Fujimaki, S., Wakabayashi, T., Takemasa, T., Asashima, M., & Kuwabara, T. (2015) · BioMed Research International · doi:10.1155/2015/592915 · Cited by 32 · see citing works
Hoffmann, C., Schneeweiß, P., Randrianarisoa, E., Schnauder, G., Kappler, L., Machann, J., Schick, F., Fritsche, A., Heni, M., Birkenfeld, A. L., et al. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa571 · Cited by 31 · see citing works
Physical Fitness and Cardiovascular Risk Factors in Novel Diabetes Subgroups
Saatmann, N., Zaharia, O., Straßburger, K., Pesta, D. H., Burkart, V., Szendroedi, J., Gerdes, N., Kelm, M., & Roden, M. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab810 · Cited by 31 · see citing works
Exercise in the Management of Type 2 Diabetes Mellitus: What are the Benefits and how does it Work?
Duclos, M., Virally, M.-L., & Dejager, S. (2011) · The Physician and Sportsmedicine · doi:10.3810/psm.2011.05.1899 · Cited by 31 · see citing works
“Combined training increased mitochondrial content to the same extent in both patients with type 2 diabetes and control individuals, in parallel with improved insulin sensitivity.(34) In patients with type 2 diabetes, restoration of mitochondrial function is paralleled by improved insulinstimulated glucose disposal and…”
BackgroundDrug-induced mitochondrial toxicity: Risks of developing glucose handling impairments
Kuretu, A., Arineitwe, C., Mothibe, M. E., Ngubane, P. S., Khathi, A., & Sibiya, N. H. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1123928 · Cited by 30 · see citing works
“(92)found no correlation between insulin sensitivity and mitochondrial content.”
BackgroundHejazi, K., & Hackett, D. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12083011 · Cited by 29 · see citing works
“Over the past few years, NAFLD has attracted a lot of attention as a risk factor for the development of insulin resistance (IR) and type 2 diabetes mellitus (T2DM) [9,10].”
BackgroundInfluentialAl‐Rawaf, H. A., Gabr, S. A., Iqbal, A., & Alghadir, A. H. (2023) · Medicina · doi:10.3390/medicina59071320 · Cited by 30 · see citing works
Larsen, J. K., Kruse, R., Sahebekhtiari, N., Moreno‐Justicia, R., Jorba, G. G., Petersen, M. H., de Almeida, M. E., Ørtenblad, N., Deshmukh, A. S., & Højlund, K. (2023) · Science Advances · doi:10.1126/sciadv.adi7548 · Cited by 31 · see citing works
“In humans, this is accompanied by improved lipid droplet distribution and increased content of mitochondria and enzymes involved in insulin signaling to glucose transport and glycogen synthesis in skeletal muscle ( 3 , 7 – 10 ).”
Poljšak, B., Kovač, V., & Milisav, I. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/8819627 · Cited by 31 · see citing works
“Both manipulations increase the NAMPT-mediated NAD generation, activate mechanistic pathways of AMPK, and enhance the SIRT1 activity and mitochondrial function [4, 114, 177, 178].”
BackgroundRemie, C. M. E., Janssens, G. E., Bilet, L., van Weeghel, M., Duvivier, B. M. F. M., de Wit‐Verheggen, V. H. W., Connell, N. J., Jörgensen, J. A., Schomakers, B. V., Schrauwen‐Hinderling, V. B., et al. (2021) · Diabetologia · doi:10.1007/s00125-021-05558-5 · Cited by 30 · see citing works
Self-citationDahlmans, D., Houzelle, A., Andreux, P. A., Jörgensen, J. A., Wang, X., Windt, L. J. D., Schrauwen, P., Auwerx, J. H., & Joris Hoeks, J. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.08.007 · Cited by 29 · see citing works
“NCT00943059 [33], NTR2002 [34,35] and NCT01298375 [36]), and all participants gave their written informed consent prior to inclusion in the study.”
BackgroundSelf-citationHouzelle, A., Dahlmans, D., Nascimento, E. B. M., Schaart, G., Jörgensen, J. A., Moonen‐Kornips, E., Kersten, S., Wang, X., & Hoeks, J. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29797 · Cited by 28 · see citing works
“To test whether these findings are relevant in human physiology, we then selected (from previous human clinical trials performed in our facilities [Phielix et al., 2010; Phielix et al., 2012; van de Weijer et al., 2015; Vosselman et al., 2015]) four subject groups known to be characterized by…”
MethodSelf-citationLactate Levels with Chronic Metformin Use: A Narrative Review
Huang, W., Castelino, R. L., & Peterson, G. M. (2017) · Clinical Drug Investigation · doi:10.1007/s40261-017-0564-6 · Cited by 27 · see citing works
de Queiroz, K. B., Sampaio, K. H., Rossoni, J. V., Leal, D. A., Pinto, A. B. G., Becker, L. K., Evangelista, E. A., & Guerra‐Sá, R. (2017) · PLoS ONE · doi:10.1371/journal.pone.0172103 · Cited by 26 · see citing works
Strijcker, D. D., Lapauw, B., Ouwens, D. M., de Velde, D. V., Hansen, D., Petrović, M., Cuvelier, C. A., Tonoli, C., & Calders, P. (2018) · Europe PMC (PubMed Central) · Cited by 28 · see citing works
Rehabilitation of Individuals With Diabetes Mellitus: Focus on Diabetic Myopathy
Dibai, D. B., Santos‐de‐Araújo, A. D., Dibai‐Filho, A. V., de Azevedo, L. F. S., Goulart, C. D. L., Luz, G. C. P., Burke, P. R., Garcia-Araújo, A. S., & Borghi‐Silva, A. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.869921 · Cited by 28 · see citing works
Hyperlactatemia in type 2 diabetes: Can physical training help?
Brinkmann, C. K., & Brixius, K. (2015) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2015.05.018 · Cited by 26 · see citing works
Al-Jarrah, M. D., Erekat, N. S., & Alkhatib, A. J. (2014) · Neural Regeneration Research · doi:10.4103/1673-5374.130105 · Cited by 25 · see citing works
“…has been reported to promote mitochondrial biogenesis by increasing mitochondrial content, volume and number (Menshikova et al., 2006; Palmer, 2010; Phielix et al., 2010; Safdar et al., 2011) which could account for reduced reactive oxygen species and oxidative stress, and the consequent HSP90…”
BackgroundHarmsen, J., Kotte, M., Habets, I., Bosschee, F., Frenken, K. G., Jörgensen, J. A., de Kam, S. S., Moonen‐Kornips, E., Cissen, J., Doligkeit, D., et al. (2023) · The Journal of Physiology · doi:10.1113/jp285523 · Cited by 25 · see citing works
Self-citationMason, S. A., Baptista, R., Gatta, P. A. D., Yousif, A. M., Russell, A. P., & Wadley, G. D. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.09.013 · Cited by 24 · see citing works
Gavin, T. P., Ernst, J. M., Kwak, H., Caudill, S. E., Reed, M. A., Garner, R. T., Nie, Y., Weiss, J. A., Pories, W. J., Dar, M. S., et al. (2017) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-01727 · Cited by 25 · see citing works
Tam, E., Bruseghini, P., Calabria, E., Sacco, L. D., Doria, C., Grassi, B., Pietrangelo, T., Pogliaghi, S., Reggiani, C., Salvadego, D., et al. (2015) · European Journal of Applied Physiology · doi:10.1007/s00421-015-3256-z · Cited by 23 · see citing works
Can resveratrol help to maintain metabolic health?
Schrauwen, P., & Timmers, S. (2014) · Proceedings of The Nutrition Society · doi:10.1017/s0029665113003856 · Cited by 24 · see citing works
“We showed that all aspects of mitochondrial function, including in vivo mitochondrial function using phosphocreatine recovery rate, intrinsic mitochondrial function using high-resolution respirometry, and mitochondrial content, increased after the 12 weeks training((24,25)), and restored T2DM patients towards control…”
Self-citationExercise attenuates the premature cardiovascular aging effects of type 2 diabetes mellitus
Huebschmann, A. G., Kohrt, W. M., & Regensteiner, J. G. (2011) · Vascular Medicine · doi:10.1177/1358863x11419996 · Cited by 22 · see citing works
Whytock, K. L., Pino, M. F., Sun, Y., Yu, G., de Carvalho, F. G., Yeo, R. X., Vega, R. B., Parmar, G., Divoux, A., Kapoor, N., et al. (2023) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00143.2023 · Cited by 22 · see citing works
Poljšak, B., & Milisav, I. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25126321 · Cited by 22 · see citing works
“Finkel and Holbrook (2000) [202] observed that the most effective approach to boost endogenous antioxidant levels can involve exposure to oxidative stress itself, based on the classical physiological concept of hormesis.”
Background
- Authors
- Phielix, E., Meex, R., Moonen-Kornips, E., Hesselink, M. K. C., & Schrauwen, P.
- Affiliations
- Maastricht University Medical Centre (NL)
- Corresponding author
- Schrauwen, P.
- Venue
- Diabetologia
- Published
- 2010-04-27
- Volume
- 53
- Issue
- 8
- Pages
- 1714-1721
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC2892060
- OpenAlex
- W1966012125
- Cited by
- 206
- References
- 22
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 16 · 2023: 23 · 2022: 12 · 2021: 15 · 2020: 13 · 2019: 6 · 2018: 8 · 2017: 23 · 2016: 12 · 2015: 10 · 2014: 11 · 2013: 12 · 2012: 14
- FWCI
- 5.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Diabetologia (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by-nc)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Diabetes Fonds (2004.00.059)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Keywords
- type 2 diabetes, exercise training, mitochondrial function, mitochondrial content, skeletal muscle, vastus lateralis, insulin-stimulated glucose disposal, insulin sensitivity, oxidative respiration, state 3 respiration, palmitoylcarnitine, mitochondrial density
- MeSH terms
- Analysis of Variance, Blood Glucose, Diabetes Mellitus, Type 2, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Mitochondria, Oxygen Consumption, Glucose Clamp Technique, Exercise, Muscle, Skeletal
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