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Cited by 97Exercise and Physiological ResponsesNitric Oxide and Endothelin EffectsAdipokines, Inflammation, and Metabolic Diseases

Acute physical exercise reverses S‐nitrosation of the insulin receptor, insulin receptor substrate 1 and protein kinase B/Akt in diet‐induced obese Wistar rats

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Pauli, José R., Ropelle, Eduardo R., Cintra, Dennys E., Carvalho‐Filho, Marco A., Moraes, Juliana C., De Souza, Cláudio T., Velloso, Lício A., Carvalheira, José B. C. +1 more·2008·The Journal of Physiology
DOI 10.1113/jphysiol.2007.142414PMC PMC2375587
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Abstract

Early evidence demonstrates that exogenous nitric oxide (NO) and the NO produced by inducible nitric oxide synthase (iNOS) can induce insulin resistance. Here, we investigated whether this insulin resistance, mediated by S‐nitrosation of proteins involved in early steps of the insulin signal transduction pathway, could be reversed by acute physical exercise. Rats on a high‐fat diet were subjected to swimming for two 3 h‐long bouts, separated by a 45 min rest period. Two or 16 h after the exercise protocol the rats were killed and proteins from the insulin signalling pathway were analysed by immunoprecipitation and immunoblotting. We demonstrated that a high‐fat diet led to an increase in the iNOS protein level and S‐nitrosation of insulin receptor β (IRβ), insulin receptor substrate 1 (IRS1) and Akt. Interestingly, an acute bout of exercise reduced iNOS expression and S‐nitrosation of proteins involved in the early steps of insulin action, and improved insulin sensitivity in diet‐induced obesity rats. Furthermore, administration of GSNO (NO donor) prevents this improvement in insulin action and the use of an inhibitor of iNOS (l‐N6‐(1‐iminoethyl)lysine; l‐NIL) simulates the effects of exercise on insulin action, insulin signalling and S‐nitrosation of IRβ, IRS1 and Akt. In summary, a single bout of exercise reverses insulin sensitivity in diet‐induced obese rats by improving the insulin signalling pathway, in parallel with a decrease in iNOS expression and in the S‐nitrosation of IR/IRS1/Akt. The decrease in iNOS protein expression in the muscle of diet‐induced obese rats after an acute bout of exercise was accompanied by an increase in AMP‐activated protein kinase (AMPK) activity. These results provide new insights into the mechanism by which exercise restores insulin sensitivity.

AI snapshot

Written from the paper’s full text.

TL;DR

A single acute bout of swimming reversed diet-induced insulin resistance in obese Wistar rats by reducing iNOS expression and S-nitrosation of IRβ, IRS1, and Akt, thereby improving insulin signalling. The effect was blocked by the NO donor GSNO and mimicked by the iNOS inhibitor l-NIL.

Key findings

  • High-fat feeding increased iNOS protein and S-nitrosation of IRβ, IRS1, and Akt in gastrocnemius muscle; acute exercise reduced iNOS expression and S-nitrosation at 2 h and 16 h after exercise.
  • Insulin sensitivity, measured by KITT, fell from 4.67 ± 0.14% min⁻¹ in controls to 2.4 ± 0.6% min⁻¹ in DIO rats, and was restored to 4.89 ± 0.8% min⁻¹ at 2 h and 4.72 ± 0.6% min⁻¹ at 16 h after exercise.
  • Insulin-induced IR tyrosine phosphorylation increased 6.9-fold over basal in controls versus 2.4-fold in DIO rats, and exercise restored it to 7.6-fold at 2 h and 4.8-fold at 16 h; similar improvements were seen for IRS1 phosphorylation, IRS1/PI3-K association, and Akt phosphorylation.
  • GSNO treatment prevented exercise-induced improvements in insulin sensitivity and signalling, while l-NIL improved insulin sensitivity and signalling in DIO rats with no additive effect of exercise.

Methods

  • Male Wistar rats were divided into control, diet-induced obese (DIO) fed a high-fat diet for 3 months, and DIO plus acute exercise groups; n = 8 per group.
  • Exercise consisted of swimming for two 3 h bouts separated by 45 min rest, with water at ∼34°C; rats were killed 2 h or 16 h after exercise.
  • Insulin signalling proteins were analysed by immunoprecipitation and immunoblotting, S-nitrosation by the biotin-switch method, and insulin sensitivity by insulin tolerance test (KITT); GSNO and l-NIL treatments were also tested. Statistical comparisons used one-way ANOVA with Bonferroni post hoc tests.

Limitations

  • The paper states that iNOS is normally not expressed in muscle and is induced only in insulin resistance, whereas exercise can improve insulin action in healthy muscle; therefore this mechanism may not provide a universal explanation and is probably only one of several factors.
  • The paper notes that some results differ from other acute-exercise studies, possibly due to methodological differences such as in vivo versus in vitro insulin stimulation and use of DIO versus control rats.
  • Evident from the text: the study used only male Wistar rats, a single acute exercise protocol rather than training, and some low-dose GSNO data were not shown; at 16 h after exercise, insulin sensitivity was normal but insulin signalling was only partially restored.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1113/jphysiol.2007.142414

Cites

47 of 47 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 54 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Abstract

    A high-fat diet led to an increase in iNOS protein level in the muscle of diet-induced obese Wistar rats.

    “We demonstrated that a high-fat diet led to an increase in the iNOS protein level”
    • Also stated in: § Results · plain
      “In the muscle of DIO rats an enhanced expression of iNOS was found (Fig. 2B).”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    Acute physical exercise reduced iNOS expression in the muscle of diet-induced obese rats.

    “an acute bout of exercise reduced iNOS expression”
    • Also stated in: § Results · plain
      “2 h after exercise there is greater decrease in iNOS protein expression and that after 16 h this expression is still decreased compared to controls”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    A high-fat diet led to S-nitrosation of IRβ, IRS1 and Akt in the muscle of diet-induced obese Wistar rats.

    “We demonstrated that a high-fat diet led to an increase in the iNOS protein level and S-nitrosation of insulin receptor β (IRβ), insulin receptor substrate 1 (IRS1) and Akt.”
    • Also stated in: § Results · boosted
      “We demonstrated an enhanced S-nitrosation of IRβ, IRS1, and Akt in the muscle of DIO rats”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    The administration of l-NIL for 10 days improved insulin sensitivity in DIO rats, as measured by the glucose disappearance rate during the insulin tolerance test, KITT.

    “The administration of l-NIL for 10 days improved insulin sensitivity in DIO rats, as measured by the glucose disappearance rate during the insulin tolerance test, KITT”
    Quote in the paperSubstantial claim
    • Rests on an assumption: l-NIL inhibits iNOS activity.
  • Findingown data
    § Results

    Nitrosation of IRβ, IRS1, and Akt was not reduced after exercise in GSNO-treated rats.

    “nitrosation of IRβ, IRS1, and Akt was not reduced after exercise in GSNO-treated rats (Fig. 4F–H).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 27
  • May combine two claims. 38

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data
    § Results

    There was not a clear increase in TNF-α after a bout of exercise.

    “there was not a clear increase in this cytokine after a bout of exercise.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data
    § Results

    Plasma FFA levels were higher in obese rats.

    “the plasma FFA levels were higher in obese rats”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Rats fed a high-fat diet for 12 weeks had higher body weight, epididymal fat and fasting serum insulin than age-matched controls.

    “Rats fed on the high-fat diet for 12 weeks had a higher body weight, epididymal fat and fasting serum insulin than age-matched controls (C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Insulin increased IRS1 tyrosine phosphorylation and IRS1/PI3-K association by 7.1-fold and 7.5-fold and 5.3-fold and 5.8-fold in the muscle from DIO + EXE-2 h and DIO + EXE-16 h rats, respectively, over basal.

    “Insulin increased IRS1 tyrosine phosphorylation and IRS1/PI3–K association by 7.1-fold and 7.5-fold and 5.3-fold and 5.8-fold in the muscle from DIO + EXE-2 h and DIO + EXE-16 h rats, respectively, over basal”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Two hours after exercise, in obese animals, in parallel with an increase in AMPK phosphorylation there was also an important increase in ACC phosphorylation.

    “Two hours after exercise, in obese animals, in parallel with an increase in AMPK phosphorylation there was also an important increase in ACC phosphorylation”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Physical exercise stimulated AMPK phosphorylation, which peaked at 1 h and then decreased, but phosphorylation at 16 h was still higher than basal.

    “Physical exercise stimulated AMPK phosphorylation, which peaked at 1 h and then decreased, but phosphorylation at 16 h was still higher than basal (Fig. 3A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    There was no difference in basal levels of IRS1 tyrosine phosphorylation or in IRS1 protein levels between the groups.

    “There was no difference in basal levels of IRS1 tyrosine phosphorylation or in IRS1 protein levels between the groups”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    There was no difference in basal levels of IR tyrosine phosphorylation or in IR protein levels between the groups.

    “There was no difference in basal levels of IR tyrosine phosphorylation or in IR protein levels between the groups”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    IRS1 tyrosine phosphorylation and IRS1/PI3-K association increased in control animals by 8.0-fold and 8.6-fold over basal following insulin administration, respectively, compared with 2.4-fold and 1.9-fold increases in the muscle of DIO rats over basal.

    “IRS1 tyrosine phosphorylation and IRS1/PI3–K association were observed to increase in control animals by 8.0-fold and 8.6-fold over basal following insulin administration, respectively, compared with 2.4-fold and 1.9-fold increases in the muscle of DIO rats over basal.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    GSNO induces insulin resistance and impairs exercise-induced improvement in insulin action, but does not affect JNK phosphorylation, PTP1B expression or IRS1 serine phosphorylation.

    “However, the present data show that GSNO, which induces insulin resistance and impairs exercise-induced improvement in insulin action, does not affect JNK phosphorylation, PTP1B expression or IRS1 serine phosphorylation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    Two hours after exercise there is a marked increase in FFA levels and almost no change in TNF-α levels.

    “We investigated some candidates and our data showed that 2 h after exercise there is a marked increase in FFA levels and almost no change in TNF-α levels, suggesting that these are probably not common upstream events in DIO and are not reversed by exercise.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given
    § Discussion

    l-NIL, an inhibitor of iNOS, improves insulin action and insulin signalling in DIO rats without influencing JNK phosphorylation, PTP1B expression or IRS1 serine phosphorylation.

    “In addition l-NIL, an inhibitor of iNOS improves insulin action and insulin signalling in DIO rats without influencing JNK phosphorylation, PTP1B expression or IRS1 serine phosphorylation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    In the muscle of DIO rats, an acute bout of exercise is accompanied by an increase in AMPK activation and a reduction in iNOS expression.

    “In accordance with these previous data, we show that, in the muscle of DIO rats, an acute bout of exercise is accompanied by an increase in AMPK activation and a reduction in iNOS expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    At 2 h after exercise in DIO rats, insulin sensitivity and insulin signalling were completely normalized; at 16 h after exercise, despite normal insulin sensitivity, there is only a partial restoration of insulin signalling.

    “Our data show that, at 2 h after exercise in DIO rats, insulin sensitivity and insulin signalling were completely normalized; however, at 16 h after exercise, despite the normal insulin sensitivity there is only a partial restoration of insulin signalling.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    NO can react with cysteine residues in the presence of O2 to form S-nitrosothiol, altering the activity of proteins including H-ras, the olfactory cyclic nucleotide-gated channel and glyceraldehyde-3-phosphate dehydrogenase.

    “NO can react with cysteine residues in the presence of O2 to form S-nitrosothiol (Stamler et al. 1992, 1997), altering the activity of proteins including H-ras (Lander et al. 1995), the olfactory cyclic nucleotide-gated channel (Broillet & Firestein, 1996) and glyceraldehyde-3-phosphate dehydrogenase (Molina y Vedia et al. 1992).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Stamler et al. 1992, 1997

      Not checked in the free run.

    • cites Lander et al. 1995

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    • cites Broillet & Firestein, 1996

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    Treatment with AICAR, an AMPK agonist, improves glucose homeostasis and insulin sensitivity.

    “Treatment with AICAR, an AMPK agonist, improves glucose homeostasis and insulin sensitivity (Winder, 2000; Fiedler et al. 2001).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Winder, 2000

      Not checked in the free run.

    • cites Fiedler et al. 2001

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Discussion

    Physical exercise is linked to improved glucose homeostasis and enhanced insulin sensitivity after an acute bout of exercise in humans and rodents.

    “Physical exercise has been linked to improved glucose homeostasis and enhanced insulin sensitivity after an acute bout of exercise in humans (Devlin et al. 1987; Zierath, 1995) and rodents (Richter et al. 1982; Wallberg-Henriksson, 1987; Wallberg-Henriksson et al. 1988).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Devlin et al. 1987

      Not checked in the free run.

    • cites Zierath, 1995

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    • cites Richter et al. 1982

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  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    AMPK activation can modulate NO production through down-regulation of iNOS protein expression.

    “AMPK activation can modulate NO production through down-regulation of iNOS protein expression (Pilon et al. 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pilon et al. 2004

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    The reversible regulation of protein function by S-nitrosation has led to the proposal that S-nitrosothiols function as post-translational modifiers, analogous to those created by phosphorylation or acetylation.

    “The reversible regulation of protein function by S-nitrosation has led to the proposal that S-nitrosothiols function as post-translational modifiers, analogous to those created by phosphorylation or acetylation (Stamler et al. 1997).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stamler et al. 1997

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    iNOS knockout mice are protected from muscle insulin resistance by related diet-induced obesity.

    “The iNOS knockout mice are protected from muscle insulin resistance by related diet-induced obesity (Perreault & Marette, 2001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Perreault & Marette, 2001

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Abstract

    iNOS is overexpressed in the muscle and fat of genetic and dietary models of obesity and type 2 diabetes, and this expression is associated with insulin resistance.

    “A previous study reported that inducible nitric oxide synthase (iNOS), a cytokine-inducible proinflamatory mediator in several pathological conditions, is overexpressed in the muscle and fat of genetic and dietary models of obesity and type 2 diabetes (Perreault & Marette, 2001), and that this expression is associated with insulin resistance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Perreault & Marette, 2001

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    Exercise training, even acutely, can improve insulin sensitivity in the muscle of obese rats.

    “It is well established that exercise training, even acutely, can improve insulin sensitivity in the muscle of obese rats (Betts et al. 1993; Bruce et al. 2001).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Betts et al. 1993

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    • cites Bruce et al. 2001

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    Genetic disruption of iNOS protects against obesity-linked insulin resistance, preventing impairments in PI3-K and Akt activation by insulin in muscle.

    “Perreault & Marette (2001) demonstrated that the genetic disruption of iNOS protects against obesity-linked insulin resistance, preventing impairments in PI3-K and Akt activation by insulin in muscle.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Perreault & Marette (2001)

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Discussion

    FFA and TNF-α are probably not common upstream events in DIO and are not reversed by exercise.

    “We investigated some candidates and our data showed that 2 h after exercise there is a marked increase in FFA levels and almost no change in TNF-α levels, suggesting that these are probably not common upstream events in DIO and are not reversed by exercise.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    Previous studies on acute exercise showed unchanged serine phosphorylated Akt but increased threonine phosphorylated Akt.

    “Some of our results differ from other studies on acute exercise (Chibalin et al. 2000; Arias et al. 2007), which showed unchanged serine phosphorylated Akt, but increased threonine phosphorylated Akt.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Chibalin et al. 2000

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    • cites Arias et al. 2007

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Discussion

    Exercise activates AMPK, and this is believed to contribute to its insulin-sensitizing action in situations of insulin resistance.

    “It is well known that exercise activates AMPK, and this is believed to contribute to its insulin-sensitizing action in situations of insulin resistance (Wojtaszewski et al. 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wojtaszewski et al. 2005

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  • May combine two claims.

    Interpretationown data
    § Discussion

    S-nitrosation is an important mechanism of insulin resistance, and reversal of this mechanism is sufficient to improve insulin action and signalling.

    “These data suggest that S-nitrosation is an important mechanism of insulin resistance, and reversal of this mechanism is sufficient to improve insulin action and signalling.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    A regular exercise programme reduces the local expression of cytokines and iNOS in muscle biopsies.

    “In accordance, it has recently been demonstrated in muscle biopsies that a regular exercise programme reduces the local expression of cytokines and iNOS (Gielen et al. 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gielen et al. 2003

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    Exercise down-regulates TLR4 in monocytes in humans.

    “It was recently demonstrated in humans that exercise down-regulates TLR4 in monocytes (Lancaster et al. 2005), suggesting that this receptor may be a candidate for the activation of JNK, iNOS and S-nitrosation in obesity, and may be reversed by exercise.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lancaster et al. 2005

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  • May combine two claims.

    Premisecitation
    § Discussion

    Several mechanisms may be involved in insulin resistance in the muscle of DIO rats, including serine phosphorylation of IR or IRSs, increased activity or amount of enzymes that reverse insulin action such as PTP1B, and increased iNOS.

    “Several mechanisms may be involved in insulin resistance in the muscle of DIO rats, including serine phosphorylation of IR or IRSs (induced by serine kinases such as mTOR, and the stress kinases, JNK and IKKβ IAB kinase), by an increase in the activity or amount of the enzymes that normally reverse insulin action (e.g. PTP1B) or by an increase in iNOS (Hotamisligil et al. 1996; Bedard et al. 1997;”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Hotamisligil et al. 1996

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    • cites Bedard et al. 1997

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    • cites Elchebly et al. 1999

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  • May combine two claims.

    Premiseown data
    § Discussion

    In the same exercise protocol, there is reversal of JNK activation and an increase of serine phosphorylation of IRS1 in muscle of DIO rats.

    “In this same exercise protocol, we also observed the reverse of JNK activation and the increase of serine phosphorylation of IRS1 in muscle of DIO rats.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ropelle et al. 2006

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning
    § Discussion

    Common upstream events could mediate the increased activation of JNK, S-nitrosation and iNOS expression in DIO rats, and this common mechanism is reversed by exercise.

    “It is possible that common upstream events could mediate the increased activation of JNK, S-nitrosation and iNOS expression in DIO rats, and that this common mechanism is reversed by exercise.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    The effect of NO on insulin sensitivity is dose dependent and also depends on the enzyme that generates NO.

    “We can, thus, suggest that the effect of NO on insulin sensitivity is dose dependent and also depends on the enzyme that generates NO, which is expressed in different sites.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning
    § Discussion

    Methodological differences may contribute to discrepancies between the present results and other studies on acute exercise.

    “The reasons for these differences are not completely clear, but certainly methodological differences may contribute to these discrepancies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Discussion

    In previous reports, insulin signalling was investigated in isolated muscle after in vitro incubation, whereas the present results were obtained after in vivo insulin stimulation.

    “In previous reports (Chibalin et al. 2000; Arias et al. 2007), insulin signalling was investigated in isolated muscle after in vitro incubation; however, our results were obtained after in vivo insulin stimulation.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Chibalin et al. 2000

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    • cites Arias et al. 2007

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    Low doses of NO donors can increase glucose uptake and improve insulin action.

    “Previous data show that low doses of NO donors can increase glucose uptake and improve insulin action (McGrowder et al. 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites McGrowder et al. 2006

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  • May combine two claims.

    Premisecitation
    § Discussion

    Previous studies investigated control rats, while the present study investigated the effect of exercise on DIO rats.

    “In addition, these previous studies investigated control rats, while in the present study we investigated the effect of exercise on DIO rats.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Chibalin et al. 2000

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    • cites Arias et al. 2007

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    Exercise and muscle contraction enhance NO production and NOS expression in muscle.

    “Exercise and muscle contraction have been shown to enhance NO production and NOS expression in muscle (Balon & Nadler, 1997).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Balon & Nadler, 1997

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  • May combine two claims.

    Premisecitation
    § Discussion

    AMPK activation reduces iNOS induction and blunts iNOS-mediated NO production.

    “Data from different sources indicate that AMPK activation reduces iNOS induction and blunts iNOS-mediated NO production (Bedard et al. 1997; Kapur et al. 1997; Pilon et al. 2004).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bedard et al. 1997

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    • cites Kapur et al. 1997

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    • cites Pilon et al. 2004

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given
    § Discussion

    The doses of insulin used were 3-4 times higher than the dose required for maximal insulin signalling, suggesting a possibility of spare insulin signalling under these conditions.

    “It is important to mention that the doses of insulin used were 3–4 times higher than the dose required for maximal insulin signalling, suggesting a possibility of spare insulin signalling under these conditions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    Exercise improves insulin-induced glucose uptake, at least in part, as a result of haemodynamic adaptations.

    “These data are in accordance with previous data demonstrating that exercise improves insulin-induced glucose uptake, at least in part, as a result of haemodynamic adaptations.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bisquolo et al. 2005

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    In humans, 15-18 h after a single session of exercise there is protection against fatty acid-induced insulin resistance, accompanied by increased lipogenic capacity of muscle and increased partitioning of excess fatty acids toward triglyceride synthesis in muscle.

    “It has been recently demonstrated that in humans, 15–18 h after a single session of exercise there is protection against fatty acid-induced insulin resistance and that this protective effect of exercise is accompanied by an increased lipogenic capacity of muscle and a resulting increase in partitioning of excess fatty acids toward triglyceride synthesis in muscle.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schenk & Horowitz, 2007

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    Transgenic overexpression of DGAT1 in mouse skeletal muscle mitigates the detrimental effect of fatty acids and protects mice against high-fat diet-induced insulin resistance.

    “Similar results were obtained by transgenic overexpression of diacylglycerol acyltransferase (DGAT1) in mouse skeletal muscle, which mitigated the detrimental effect of fatty acids, and protected mice against high-fat diet-induced insulin resistance (Liu et al. 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liu et al. 2007

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation
    § Discussion

    TLR4 may be a candidate for the activation of JNK, iNOS and S-nitrosation in obesity, and may be reversed by exercise.

    “It was recently demonstrated in humans that exercise down-regulates TLR4 in monocytes (Lancaster et al. 2005), suggesting that this receptor may be a candidate for the activation of JNK, iNOS and S-nitrosation in obesity, and may be reversed by exercise.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation
    § Discussion

    Haemodynamic changes may contribute to the reversion of insulin resistance after exercise.

    “These haemodynamic changes may also contribute to the reversion of the insulin resistance (Bisquolo et al. 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bisquolo et al. 2005

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  • May combine two claims.

    Interpretationreasoning
    § Discussion

    The theory that exercise-induced insulin sensitization is mediated by iNOS/S-nitrosation may not provide a universal explanation and is probably only one of several factors involved in the improvement of insulin sensitivity induced by exercise in DIO.

    “Therefore, this theory may not provide a universal explanation and, hence, is probably only one of several factors involved in the improvement of insulin sensitivity induced by exercise in DIO.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Exercise can also improve insulin action in healthy muscle.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    Repartitioning of fatty acids after exercise toward intramyocellular triglyceride synthesis and oxidation reduces the accumulation of bioactive fatty acid metabolites, which increase proinflammatory pathways and induce insulin resistance.

    “This repartitioning of fatty acids after exercise toward intramyocellular triglyceride (IMTG) synthesis and oxidation reduced the accumulation of bioactive fatty acid metabolites, which are known to increase the activation of proinflammatory pathways in skeletal muscle and induce insulin resistance (Schenk & Horowitz, 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schenk & Horowitz, 2007

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Discussion

    iNOS is normally not expressed in muscle, and its expression is only induced in states of insulin resistance.

    “One limitation of the proposed theory of exercise-induced insulin sensitization in this study is that iNOS is normally not expressed in muscle (Kapur et al. 1997), and its expression is only induced in states of insulin resistance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kapur et al. 1997

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Discussion

    Complete normalization of insulin action in diet-induced obesity by acute exercise may be caused by other factors and may involve other pathways.

    “These data suggest that the complete normalization, by acute exercise, of the insulin action in obesity induced by diet may be caused by other factors and may involve other pathways.”
    Quote in the paperSubstantial claim
49 of 49

  • The paper relies on this without support.

    l-NIL inhibits iNOS activity.

    “l-NIL inhibits iNOS activity, but our results show that l-NIL has no effect on iNOS protein expression.”

  • The paper relies on this without support.

    The molecular mechanisms involved in the improvement in insulin signalling by acute exercise are not fully understood.

    “However, the molecular mechanisms involved in this improvement in insulin signalling are not fully understood.”

  • The paper relies on this without support.

    Exercise training is associated with enhanced AMPK signalling.

    “Exercise training is also associated with enhanced AMP-activated protein kinase (AMPK) signalling.”

  • The paper relies on this without support.

    Exercise can also improve insulin action in healthy muscle.

    “However, exercise can also improve insulin action in healthy muscle.”

  • The paper relies on this without support.

    Exercise induces neuronal and endothelial nitric-oxide synthase (nNOS and eNOS) and not iNOS expression.

    “In addition, it is important to emphasize that exercise induces neuronal and endothelial nitric-oxide synthase (nNOS and eNOS, also termed NOS1 and NOS3, respectively) and not iNOS (also termed NOS2) expression.”

  • The paper relies on this without support.

    A single bout of exercise decreases sympathetic activity and increases muscle blood flow during the postexercise period.

    “It is known that a single bout of exercise decreases sympathetic activity and increases muscle blood flow during the postexercise period.”

  • The paper relies on this without support.

    During hyperinsulinaemia after a single bout of exercise, sympathetic activity is lower and muscle vasodilation is higher.

    “It is interesting that, during hyperinsulinaemia after a single bout of exercise, sympathetic activity is lower and muscle vasodilation is higher.”
7 of 7

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?

  • Nitrosative post-translational modifications of proteins in the insulin signaling pathway are responsible for NOS2-induced insulin resistance.

    “suggesting that nitrosative post-translational modifications of proteins in the insulin signaling pathway are responsible for NOS2-induced insulin resistance [347, 348]”

    From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [348]

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.

  • Fasting glucose is described as similar despite a significance marker

    Minor

    The text says fasting glucose was similar between groups, but Table 2 marks the 16-hour exercise group's glucose value with an asterisk, defined as P < 0.001 versus control.

1 of 1

Cites

1 retracted

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Related

Authors
Pauli, J. R., Ropelle, E. R., Cintra, D. E., Carvalho‐Filho, M. A., Moraes, J. C., De Souza, C. T., Velloso, L. A., Carvalheira, J. B. C., & Saad, M. J. A.
Affiliations
Universidade Estadual de Campinas (UNICAMP) (BR)
ORCID
Venue
The Journal of Physiology
Publisher
Wiley
Published
2008-01-14
Volume
586
Issue
2
Pages
659-671
ISSN
  • 0022-3751 (ISSN-L)
  • 1469-7793
DOI
10.1113/jphysiol.2007.142414
PMC
PMC2375587
OpenAlex
W1542372173
Semantic Scholar
d14f9a13eb4d5eafb78d09d5caad56575c821f1c
Cited by
97
References
47
Citations by year
2026: 2 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 2 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 3 · 2016: 4 · 2015: 12 · 2014: 12 · 2013: 7 · 2012: 7
FWCI
6.85
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The Journal of Physiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Topics
  • Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
acute exercise, S-nitrosylation, insulin resistance, insulin receptor beta, IRS-1, Akt, inducible nitric oxide synthase, nitric oxide, diet-induced obesity, high-fat diet, swimming training, S-nitrosoglutathione, L-NIL, AMPK, insulin signaling, skeletal muscle
MeSH terms
AMP-Activated Protein Kinase Kinases, Animals, Diet, Disease Models, Animal, Enzyme Inhibitors, Insulin Resistance, Lysine, Male, Obesity, Physical Conditioning, Animal, Protein Kinases, Receptor, Insulin, Signal Transduction, Rats, Wistar, Nitric Oxide Donors, S-Nitrosoglutathione, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-akt, Rats, Nitric Oxide Synthase Type II, Insulin Receptor Substrate Proteins

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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