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Cited by 295Metabolism, Diabetes, and CancerAdipose Tissue and MetabolismNatural Antidiabetic Agents Studies

AMPK and Exercise: Glucose Uptake and Insulin Sensitivity

Open access
O'Neill, Hayley M.·2013·Diabetes & Metabolism Journal
DOI 10.4093/dmj.2013.37.1.1PMC PMC3579147
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Abstract

AMPK is an evolutionary conserved sensor of cellular energy status that is activated during exercise. Pharmacological activation of AMPK promotes glucose uptake, fatty acid oxidation, mitochondrial biogenesis, and insulin sensitivity; processes that are reduced in obesity and contribute to the development of insulin resistance. AMPK deficient mouse models have been used to provide direct genetic evidence either supporting or refuting a role for AMPK in regulating these processes. Exercise promotes glucose uptake by an insulin dependent mechanism involving AMPK. Exercise is important for improving insulin sensitivity; however, it is not known if AMPK is required for these improvements. Understanding how these metabolic processes are regulated is important for the development of new strategies that target obesity-induced insulin resistance. This review will discuss the involvement of AMPK in regulating skeletal muscle metabolism (glucose uptake, glycogen synthesis, and insulin sensitivity).

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that AMPK is activated by exercise and is important for regulating skeletal muscle glucose uptake during exercise, while its requirement for exercise-induced improvements in insulin sensitivity remains unresolved. It synthesizes genetic mouse-model and human/rodent exercise evidence on AMPK, TBC1D1/TBC1D4, glycogen synthesis, and alternative insulin-sensitizing mechanisms.

Key findings

  • AMPK is activated during exercise in an intensity-dependent manner: α2 activity increases from 40% VO2max, whereas α1 activity increases during high-intensity contractions equivalent to >100% VO2max.
  • Muscle-specific AMPK β1β2 KO mice have undetectable AMPK activity and show reduced voluntary wheel activity (75%), maximal exercise capacity (95%), mitochondrial content (30%), and exercise-mediated skeletal muscle glucose uptake (55% to 70%); young mice have normal insulin sensitivity.
  • TBC1D1 and TBC1D4 are implicated in contraction/exercise glucose uptake: TBC1D1 4P mutants reduce contraction-mediated glucose uptake by 25% to 30%, TBC1D4 4P mutant inhibits insulin-stimulated glucose uptake in vivo by ~50%, and TBC1D1 expression is reduced by ~50% in skeletal muscle of AMPK α2 KO, α2 KD, α2iTg, and β1β2 M-KO mice.
  • Exercise improves insulin sensitivity, but whether AMPK is required is not known; proposed mechanisms include TBC1D4, TBC1D1, IL-6 (which can increase ~100-fold with exercise), adiponectin, glycogen synthesis/levels, and mTOR/p70 S6K signaling.

Methods

  • Narrative review; the abstract states it will discuss AMPK involvement in skeletal muscle metabolism (glucose uptake, glycogen synthesis, insulin sensitivity).
  • Synthesizes studies using whole-body and muscle-specific AMPK mouse models (α1, α2, β1, β2, γ3 KO; β1β2 M-KO; α2 KD/α2iTg; LKB1-MKO) plus human and rodent exercise/contraction studies.
  • Main analysis is qualitative synthesis of cited literature; no systematic search, meta-analysis, or primary data collection is described.

Limitations

  • The paper states that it is not known if AMPK is required for exercise-induced improvements in insulin sensitivity and that further studies are required to fully define the role of AMPK in mediating these effects.
  • The paper notes inconsistent observations and unresolved mechanisms, including TBC1D4/TBC1D1 phosphorylation, IL-6 effects, and glycogen/AMPK relationships.
  • Evident from the text: this is a narrative review without systematic methods or new data, so conclusions depend on the cited models and may be affected by isoform compensation, mouse strain/background differences, and reliance on pharmacological or supraphysiological stimuli.

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

Integrity signals

Registry

Crossref · 10.4093/dmj.2013.37.1.1

Cites

179 of 179 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 191 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    AMPK β1β2M-KO mice have undetectable levels of AMPK activity at rest or during exercise.

    “As anticipated, AMPK β1β2M-KO mice have undetectable levels of AMPK activity at rest or during exercise [30].”
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    • cites [30] O'Neill, 2011, Proc Natl Acad Sci U S A source

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  • Findingcitation

    Whole-body and skeletal muscle specific insulin sensitivity is similar in young AMPK β1β2M-KO mice compared to wild-type littermates.

    “Interestingly, young (9 to 12 weeks) AMPK β1β2M-KO mice have similar whole-body weight and adiposity, and consistent with this, whole-body and skeletal muscle specific insulin sensitivity is similar when compared to wild-type littermates [30].”
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    • cites [30] O'Neill, 2011, Proc Natl Acad Sci U S A source

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  • Premisecitation

    GLUT4 translocation during exercise is normal in skeletal muscle of type 2 diabetics.

    “Importantly, GLUT4 translocation during exercise is normal in skeletal muscle of type 2 diabetics [64], and exercise also improves insulin sensitivity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Kennedy, 1999, Diabetes source

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  • Premisecitation

    AMPK is activated during exercise in both rodents and humans.

    “Consistent with this, AMPK is activated during exercise in both rodents and humans [51-60], in an intensity-dependent manner [57,59-61].”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [51] Hayashi, 1998, Diabetes source

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    • cites [52] Hutber, 1997, Am J Physiol

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    • cites [53] Ihlemann, 1999, Am J Physiol

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    • cites [54] Rasmussen, 1998, J Appl Physiol source

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    • cites [55] Rasmussen, 1997, J Appl Physiol source

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    • cites [56] Vavvas, 1997, J Biol Chem source

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    • cites [57] Wojtaszewski, 2000, J Physiol source

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    • cites [58] Chen, 2003, Diabetes source

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    • cites [59] Fujii, 2000, Biochem Biophys Res Commun source

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    • cites [60] Winder, 1996, Am J Physiol

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  • Premisecitation

    Skeletal muscle is responsible for around 80% of insulin-stimulated glucose disposal.

    “Skeletal muscle is responsible for around 80% of insulin-stimulated glucose disposal [23-25]; therefore, responsiveness to insulin in this tissue is important for regulating whole-body insulin sensitivity.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] DeFronzo, 2009, Diabetes Care source

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    • cites [24] DeFronzo, 1981, J Clin Invest source

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    • cites [25] Thiebaud, 1982, Diabetes source

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  • Classified as probably not a substantial claim. 4

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    Findingcitation

    AMPK β1β2M-KO mice have dramatically reduced voluntary wheel activity (75%), maximal exercise capacity (95%), mitochondrial content (30%) and exercise-mediated glucose uptake in skeletal muscle (55% to 70%).

    “Their phenotype is more dramatic compared to whole-body AMPK β2 KO mice [28] and is characterized by dramatically reduced voluntary wheel activity (75%), maximal exercise capacity (95%), mitochondrial content (30%) and exercise-mediated glucose uptake in skeletal muscle (55% to 70%) [30].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] O'Neill, 2011, Proc Natl Acad Sci U S A source

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    Findingcitation

    Young AMPK β1β2M-KO mice have similar whole-body weight and adiposity compared to wild-type littermates.

    “Interestingly, young (9 to 12 weeks) AMPK β1β2M-KO mice have similar whole-body weight and adiposity, and consistent with this, whole-body and skeletal muscle specific insulin sensitivity is similar when compared to wild-type littermates [30].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] O'Neill, 2011, Proc Natl Acad Sci U S A source

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    Premisereasoning

    AMPK α2 activity is increased at low intensity exercise starting at 40% VO2 Max and increases progressively with exercise intensity.

    “In contrast, α2 activity is increased at low intensity exercise starting at 40% VO2 Max and increases progressively with exercise intensity.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Transgenic mice harboring the R225Q mutation in AMPK γ3 subunit have higher AMPK activity and glycogen levels and are protected from diet-induced insulin resistance.

    “Interestingly, transgenic mice harboring the R225Q mutation in AMPK γ3 subunit have higher AMPK activity and glycogen levels and are protected from diet-induced insulin resistance [4], which is a likely effect of increased fatty acid oxidation and subsequent reduction in skeletal muscle lipids.”
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    • cites [4] Barnes, 2004, J Biol Chem source

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    Premisecitation

    Whole-body AMPK α2 KO mice have reduced insulin secretion and whole-body insulin-stimulated glucose utilization due to elevated catecholamine levels and a hyperactive sympathetic nervous system.

    “Whole-body AMPK α2 KO mice have reduced insulin secretion and whole-body insulin-stimulated glucose utilization due to elevated catecholamine levels and a hyperactive sympathetic nervous system [33].”
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    • cites [33] Viollet, 2003, J Clin Invest source

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    Premisecitation

    AMPK β2 KO mice have reduced AMPK activity in skeletal muscle but not liver or adipose.

    “In contrast, AMPK β2 KO mice have reduced AMPK activity in skeletal muscle but not liver or adipose, and have a compensatory increase in AMPK β1 protein expression and maintained α1 expression in skeletal muscle [28].”
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    • cites [28] Steinberg, 2010, J Biol Chem source

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    Premisecitation

    Muscle-specific KD AMPKα2 B157A mutation (α2iTg) mice on FVB background are glucose intolerant and develop exacerbated skeletal muscle insulin resistance when fed a high-fat diet for 30 weeks.

    “However, an alternative muscle-specific mouse model on a model FVB background, rather than a C57Bl6 background, overexpressing a muscle-specific KD AMPKα2 B157A mutation (α2iTg), are glucose intolerant and develop exacerbated skeletal muscle insulin resistance when fed a high-fat diet for 30 weeks, which occurs independently of an increase in muscle lipids [37].”
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    • cites [37] Fujii, 2008, Diabetes source

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    Premisecitation

    AMPK β2 KO mice have reduced exercise capacity and increased susceptibility to develop insulin resistance on a high-fat diet.

    “AMPK β2 KO mice are characterized by reduced exercise capacity and increased susceptibility to develop insulin resistance on a high-fat diet possibly due to greater ceramide accumulation in skeletal muscle [28].”
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    • cites [28] Steinberg, 2010, J Biol Chem source

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    Premisecitation

    Whole-body γ3 KO mice have normal insulin sensitivity under basal conditions and glucose uptake during exercise.

    “Whole-body γ3 KO mice have reduced AMPK activity at rest, during exercise and in response to fasting, but normal insulin sensitivity under basal conditions and glucose uptake during exercise [4,41].”
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    • cites [4] Barnes, 2004, J Biol Chem source

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    • cites [41] Canto, 2010, Cell Metab source

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  • May combine two claims.

    Interpretationown data

    AMPK plays an important role in regulating exercise capacity, mitochondrial content and glucose uptake during exercise, but not insulin sensitivity.

    “These studies highlight an important role for AMPK in regulating exercise capacity, mitochondrial content and glucose uptake during exercise, but not insulin sensitivity.”
    Quote in the paperSubstantial claim

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    Premisecitation

    AMPK β1 KO mice have reduced AMPK activity in liver but not skeletal muscle.

    “AMPK β1 KO mice have reduced AMPK activity in liver but not skeletal muscle, are hyperphagic and as a result have lower body weight, adiposity and hepatic lipid accumulation, and are protected from high-fat diet induced insulin resistance [27].”
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    • cites [27] Dzamko, 2010, J Biol Chem source

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    Premisecitation

    Contraction does not promote IRS-1 autophosphorylation or increase PI3 kinase activity.

    “1) PI3 kinase inhibitor wortmannin inhibits insulin but not contraction-stimulated glucose uptake. Contraction does not promote IRS-1 autophosphorylation or increase PI3 kinase activity [103-106].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [103] Yeh, 1995, J Biol Chem source

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    • cites [104] Whitehead, 2000, Biochem J source

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    • cites [105] Lund, 1995, Proc Natl Acad Sci U S A source

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    • cites [106] Brozinick, 1998, J Biol Chem source

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    Premisecitation

    PI3 kinase inhibitor wortmannin inhibits insulin but not contraction-stimulated glucose uptake.

    “1) PI3 kinase inhibitor wortmannin inhibits insulin but not contraction-stimulated glucose uptake. Contraction does not promote IRS-1 autophosphorylation or increase PI3 kinase activity [103-106].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [103] Yeh, 1995, J Biol Chem source

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    • cites [104] Whitehead, 2000, Biochem J source

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    • cites [105] Lund, 1995, Proc Natl Acad Sci U S A source

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    • cites [106] Brozinick, 1998, J Biol Chem source

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    Premisecitation

    Whole-body mutation of S642 to alanine (TBC1D4 T649A KI) reduces whole-body glucose and insulin intolerance and impairs insulin-stimulated glucose uptake and GLUT4 translocation in muscle.

    “In mice, whole-body mutation of S642 (S649 in mouse) to alanine (TBC1D4 T649A KI) reduces whole-body glucose and insulin intolerance and impairs insulin-stimulated glucose uptake and GLUT4 translocation in muscle [75].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Chen, 2011, Cell Metab source

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  • May combine two claims.

    Interpretationreasoning

    Targeting AMPK may enhance exercise performance and be protective against insulin resistance disease development in obesity.

    “These studies suggest that targeting AMPK may enhance exercise performance and be protective against insulin resistance disease development in obesity.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Phosphorylation of TBC1D1 at S237 appears to be the predominant site phosphorylated by AMPK; however, TBC1D1 PAS phosphorylation does not appear to correlate well with S237 phosphorylation.

    “Phosphorylation of TBC1D1 at S237 appears to be the predominant site phosphorylated by AMPK; however, TBC1D1 PAS phosphorylation does not appear to correlate well with S237 phosphorylation [74].”
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    • cites [74] Pehmoller, 2009, Am J Physiol Endocrinol Metab source

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    Premisecitation

    3 hours of cycling increased 14-3-3 binding to TBC1D4 immediately following exercise, but this had returned to baseline despite maintained TBC1D4 phosphorylation 3 hours postexercise.

    “Similarly, Howlett et al. [124] found that although 3 hours of cycling increased 14-3-3 binding to TBC1D4 immediately following exercise, this had returned to baseline despite maintained TBC1D4 phosphorylation 3 hours postexercise.”
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    • cites [124] Howlett, 2008, Am J Physiol Endocrinol Metab source

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    Premisecitation

    TBC1D1 phosphorylation is enhanced immediately following exercise but returns to basal levels 3-4 and 27 hours post-exercise in rats.

    “TBC1D1 phosphorylation is enhanced immediately following exercise but returns to basal levels 3-4 and 27 hours post-exercise in rats, suggesting that the involvement of TBC1D1 in the insulin sensitizing effects of exercise are different from that of TBC1D4.”
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    • cites [74] Pehmoller, 2009, Am J Physiol Endocrinol Metab source

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    • cites [117] Frosig, 2010, J Physiol source

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    Premisecitation

    TBC1D1 PAS phosphorylation is slightly increased in α2iTg and α2KO mice but unresponsive in AMPK KD and β1β2 M-KO mice following contractions.

    “TBC1D1 PAS phosphorylation is slightly increased in α2iTg and α2KO mice but unresponsive in AMPK KD and β1β2 M-KO mice following contractions [30,74], suggesting that AMPK is important for PAS phosphorylation in response to contraction.”
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    • cites [30] O'Neill, 2011, Proc Natl Acad Sci U S A source

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    • cites [74] Pehmoller, 2009, Am J Physiol Endocrinol Metab source

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    Premisecitation

    TBC1D1 T590 is predominantly phosphorylated in response to muscle contractions, but this has not been observed in all studies.

    “TBC1D1 T590 is also predominately phosphorylated in response to muscle contractions [74]; however, this has not been observed in all studies [102].”
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    • cites [74] Pehmoller, 2009, Am J Physiol Endocrinol Metab source

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    • cites [102] Vichaiwong, 2010, Biochem J source

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    Premisecitation

    TBC1D4 T642 and PAS phosphorylation is increased immediately after exercise and 3 hours postexercise, consistent with enhanced insulin-stimulated glucose uptake; following in vitro contractions TBC1D4 phosphorylation returned to resting levels 3 hours postexercise despite having an additive effect on glucose uptake in response to insulin.

    “These studies have found that whilst TBC1D4 T642 and PAS phosphorylation is increased immediately after exercise and 3 hours postexercise consistent with enhanced insulin-stimulated glucose uptake; following in vitro contractions TBC1D4 phosphorylation had returned to resting levels 3 hours postexercise despite having an additive effect on glucose uptake in response to insulin [123].”
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    • cites [123] Funai, 2010, Am J Physiol Endocrinol Metab source

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    Premisecitation

    Only when AMPK activity is completely abolished, as in β1β2 M-KO mice, are more dramatic reductions in glucose uptake observed, similar to LKB1-MKO mice.

    “It appears that only when AMPK activity is completely abolished, as in β1β2 M-KO mice, that more dramatic reductions in glucose uptake are observed [30], which are similar to that observed in LKB1-MKO mice [18].”
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    • cites [30] O'Neill, 2011, Proc Natl Acad Sci U S A source

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    • cites [18] Sakamoto, 2005, EMBO J source

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    Premisecitation

    AMPK activation increased with exercise intensity, but there were not greater improvements in insulin sensitivity when HIT was compared to LIT exercise groups.

    “Koshinaka et al. [143] found that whilst AMPK activation increased with exercise intensity, there were not greater improvements in insulin sensitivity when HIT was compared to LIT exercise groups.”
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    • cites [143] Koshinaka, 2008, Metabolism source

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

    Premisecitation

    The AMPK β subunits contain a central domain, referred to as the carbohydrate-binding motif (CBM) or glycogen-binding domain that allows AMPK to bind to glycogen.

    “In regards to AMPK, the AMPK β subunits contain a central domain, referred to as the carbohydrate-binding motif (CBM) or glycogen-binding domain that allows AMPK to bind to glycogen [129].”
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    • cites [129] Polekhina, 2003, Curr Biol source

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    Premisecitation

    S6K phosphorylation of IRS1 at S1101 is increased in genetic and diet-induced obese mice and has shown to induce insulin resistance.

    “S6K phosphorylation of IRS1 at S1101 is increased in genetic and diet-induced obese mice and has shown to induce insulin resistance [154].”
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    • cites [154] Tremblay, 2007, Proc Natl Acad Sci U S A source

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    Premisecitation

    GS is phosphorylated on at least nine sites and insulin and contraction dephosphorylates both C- and N terminal sites.

    “GS is phosphorylated on at least nine sites and insulin and contraction dephosphorylates both C- and N terminal sites [126].”
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    • cites [126] Jensen, 2009, Arch Physiol Biochem source

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    Premisecitation

    The CBM is closely related to isoamylase domains found in glycogen and starch branching enzymes.

    “The CBM is closely related to isoamylase domains found in glycogen and starch branching enzymes [129].”
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    • cites [129] Polekhina, 2003, Curr Biol source

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    Premisecitation

    Glycogen can inhibit AMPK, suggesting that AMPK may regulate cellular energy status through glycogen sensing.

    “Glycogen can also inhibit AMPK, suggesting that AMPK may regulate cellular energy status through glycogen sensing [130].”
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    • cites [130] McBride, 2009, Cell Metab source

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    Interpretationreasoning

    Alternative pathways and measures other than glycogen levels and AMPK activity should be considered when determining the level of exercise-mediated improvements in insulin sensitivity.

    “These studies suggest that whilst AMPK may be involved in insulin sensitizing effects of exercise, alternative pathways and measures other than glycogen levels and AMPK activity should be considered when determining the level of exercise-mediated improvements in insulin sensitivity.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Acute treatment with AICAR promotes glycogen synthesis in skeletal muscle through a G6P-GS dependent pathway; an effect that is blunted in GS R582A KI mice.

    “Recently, acute treatment with AICAR was shown to promote glycogen synthesis in skeletal muscle through a G6P-GS dependent pathway; an effect that is blunted in GS R582A KI mice [137].”
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    • cites [137] Hunter, 2011, Diabetes source

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    Premisecitation

    Activation of AMPK by glucose deprivation or AICAR promotes tyrosine phosphorylation of IR and IRS-1 as well as Akt T308 and S473 phosphorylation.

    “Instead, activation of AMPK by glucose deprivation or AICAR promotes tyrosine phosphorylation of IR and IRS-1 as well as Akt T308 and S473 phosphorylation [146].”
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    • cites [146] Chopra, 2012, Diabetologia source

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    Premisecitation

    Endurance training inhibits mTOR/p70 S6K signaling and reduces IRS1 serine phosphorylation in rat skeletal muscle.

    “Endurance training has been shown to inhibit mTOR/p70 S6K signaling and reduce IRS1 serine phosphorylation in rat skeletal muscle [157], and recent studies have demonstrated that AMPK is involved in the suppression of mTOR signaling [39].”
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    • cites [157] Glynn, 2008, Appl Physiol Nutr Metab source

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    Premisecitation

    AMPK rapidly phosphorylates IRS1 on S789 in vitro and treatment with AICAR increases IRS1 S789 phosphorylation in mouse C2C12 myotubes.

    “It has been reported that AMPK rapidly phosphorylates IRS1 on S789 in vitro and treatment with AICAR increases IRS1 S789 phosphorylation in mouse C2C12 myotubes, suggesting a possible link between the potentiating effects of exercise on insulin signaling [145].”
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    • cites [145] Jakobsen, 2001, J Biol Chem source

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    Premisecitation

    Different contraction protocols altered the level of AMPK activation, but there were no differences in the level of improvement in insulin sensitivity.

    “Similarly, Kim et al. [144] showed that whilst the different contraction protocols altered the level of AMPK activation, there were no differences in the level of improvement in insulin sensitivity.”
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    • cites [144] Kim, 2004, J Appl Physiol source

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    Premisecitation

    Mutations in the CBM prevent glycogen binding and reduce total AMPK activity in cell-free assays and in vivo.

    “Recently, mutations in the CBM have been shown to prevent glycogen binding and reduce total AMPK activity in cell-free assays [130] and in vivo [131].”
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    • cites [130] McBride, 2009, Cell Metab source

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    • cites [131] Bendayan, 2009, J Histochem Cytochem source

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    Premisecitation

    AMPK activation by AICAR promotes glucose uptake and increases G6P, which can be used for glycogen synthesis or metabolized through glycolysis to produce ATP.

    “Interestingly, AMPK activation by AICAR promotes glucose uptake and increases G6P, which can be used for glycogen synthesis or metabolized through glycolysis to produce ATP [127].”
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    • cites [127] Bouskila, 2010, Cell Metab source

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    Premisecitation

    The CBM is highly conserved between isoforms and across species, ranging from mammals, fruitfly, worm, yeast, and plants.

    “This domain is highly conserved between isoforms and across species, ranging from mammals, fruitfly (Drosophila melanogaster), worm (Caenorhabditis elegans), yeast (Saccharomyces cerevisiae), and plants [129].”
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    • cites [129] Polekhina, 2003, Curr Biol source

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    Premisecitation

    Chronic treatment with IL-6 induces insulin resistance via mechanisms involving protein-tyrosine phosphatase 1B, JNK activation and SOCS3-mediated inhibition of insulin signaling, while acute exposure enhances insulin-stimulated glucose uptake via the LKB1/AMPK/TBC1D4 pathway.

    “The following year, Nieto-Vazquez et al. [166] found that the differential effects of IL-6 may be due to the amount of exposure to the cytokine, whereby, chronic treatment induces insulin resistance via mechanisms involving protein-tyrosine phosphatase 1B, JNK activation and SOCS3-mediated inhibition of insulin signaling, while acute exposure enhances insulin-stimulated glucose uptake via the LKB1”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Nieto-Vazquez, 2008, Diabetes source

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    Premisecitation

    Activation of AMPK by adiponectin enhances the ability of insulin to stimulate IRS1 and Akt phosphorylation concurrently, with reduced S6K1 phosphorylation at T389 as well as IRS1 phosphorylation at S302 and S636/639.

    “Recent studies have shown that the activation of AMPK by adiponectin enhances the ability of insulin to stimulate IRS1 and Akt phosphorylation concurrently, with reduced S6K1 phosphorylation at T389 as well as IRS1 phosphorylation at S302 and S636/639 [160].”
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    • cites [160] Wang, 2007, J Biol Chem source

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    Premisecitation

    IL-6 is additive to insulin in stimulating glucose uptake, but this was not observed by all studies.

    “Their study and Geiger et al. [164] also suggested that IL-6 is additive to insulin in stimulating glucose uptake; however, this was not observed by all studies [165] who found that IL-6 regulated glucose uptake and glycogen synthesis via a PI3-dependent pathway and not AMPK; given human myotubes targeted for AMPK depletion by siRNA did not have impaired insulin sensitivity.”
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    • cites [164] Geiger, 2007, Am J Physiol Endocrinol Metab source

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    • cites [165] Al-Khalili, 2006, Mol Endocrinol source

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    Premisecitation

    AMPK γ3 expression is reduced following strength training in obese type 2 diabetic humans and endurance training in healthy men.

    “AMPK γ3 expression is reduced following strength training in obese type 2 diabetic humans and endurance training in healthy men [10,49].”
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    • cites [10] Wojtaszewski, 2005, J Physiol source

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    • cites [49] Frosig, 2004, Am J Physiol Endocrinol Metab source

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    Premisecitation

    IL-6 increases glucose disposal in humans and glucose uptake in L6 myotubes; an effect dependent on AMPK signaling.

    “Carey et al. [163] was one of the first studies to show that IL-6 increases glucose disposal in humans and glucose uptake in L6 myotubes; an effect dependent on AMPK signaling.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] Carey, 2006, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMPK was found to phosphorylate the IR in response to glucose deprivation; conditions that also suppresses mTOR activity.

    “Recently, AMPK was found to phosphorylate the IR in response to glucose deprivation; conditions that also suppresses mTOR activity [146].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Chopra, 2012, Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A two week dietary intervention to induce weight loss improved insulin sensitivity in obese humans but did not alter TBC1D1 phosphorylation; it increased TBC1D1 S231 and 660 but not S700 or PAS phosphorylation in response to exercise.

    “Interestingly, a two week dietary intervention to induce weight loss improved insulin sensitivity in obese humans but did not alter TBC1D1 phosphorylation. Instead, the dietary intervention did increase TBC1D1 S231 and 660 but not S700 or PAS phosphorylation in response to exercise [175].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [175] Jessen, 2011, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TBC1D4 phosphorylation (S318, 341, 588, 642, and 751) is reduced in skeletal muscle from obese type 2 diabetics under basal conditions, but can be restored to comparable levels of nondiabetics by 10 weeks of endurance training.

    “TBC1D4 phosphorylation (S318, 341, 588, 642, and 751) is reduced in skeletal muscle from obese type 2 diabetics under basal conditions, but can be restored to comparable levels of nondiabetics by 10 weeks of endurance training [81].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Vind, 2011, Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aerobic training increases circulating adiponectin and adiponectin receptor mRNA in skeletal muscle.

    “Aerobic training increases circulating adiponectin and adiponectin receptor mRNA in skeletal muscle [161], further supporting a role for AMPK signaling in improving insulin sensitivity during exercise.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [161] Bluher, 2006, J Clin Endocrinol Metab source

      Not checked in the free run.

46 of 46

  • The paper relies on this without support.

    Exercise improves insulin sensitivity.

    “Importantly, GLUT4 translocation during exercise is normal in skeletal muscle of type 2 diabetics [64], and exercise also improves insulin sensitivity.”
    “Exercise improves insulin sensitivity and it was originally proposed that this may involve the direct interaction of AMPK with IRS1 [145].”

  • The paper relies on this without support.

    Obesity and type 2 diabetes are causally linked through their association with skeletal muscle insulin resistance.

    “Obesity and type 2 diabetes are casually linked through their association with skeletal muscle insulin resistance.”

  • The paper relies on this without support.

    AICAR is a specific activator of AMPK.

    “Skeletal muscle-specific deletion of LKB1 (LKB1-MKO) from mice results in greatly reduced α2 AMPK T172 phosphorylation following activation by AICAR (a cell-permeable adenosine analog that can be phosphorylated to form 5-aminoimidazoel4-carboxamide-1-d-riborfuronosil-5'monophosphate) or muscle contractions/exercise [17-19]”

  • The paper relies on this without support.

    Exercise enhances insulin-stimulated glucose uptake, an effect that can persist for hours following an acute bout of exercise.

    “Exercise enhances insulin-stimulated glucose uptake, an effect that can persist for hours following an acute bout of exercise.”

  • The paper relies on this without support.

    Glycogen synthesis is increased following exercise and during insulin stimulation, and insulin-stimulated glycogen synthesis is enhanced following exercise.

    “Glycogen synthesis is increased following exercise and during insulin stimulation, and insulin-stimulated glycogen synthesis is enhanced following exercise.”

  • The paper relies on this without support.

    Contraction and insulin promote glycogen synthesis by distinct mechanisms but both involve multisite dephosphorylation and activation of glycogen synthase (GS).

    “Contraction and insulin promote glycogen synthesis by distinct mechanisms but both involve multisite dephosphorylation and activation of glycogen synthase (GS).”

  • The paper relies on this without support.

    In the case of insulin-stimulated glycogen synthesis, insulin signaling thru Akt inactivates GSK3 by phosphorylation at S9 and 21, and this in turn activates GS.

    “In the case of insulin-stimulated glycogen synthesis, insulin signaling thru Akt inactivates GSK3 by phosphorylation at S9 and 21, and this in turn activates GS.”

  • The paper relies on this without support.

    Insulin-stimulated glucose transport enhances cellular G6P, which in turn promotes glycogen synthesis.

    “Insulin-stimulated glucose transport enhances cellular G6P, which in turn promotes glycogen synthesis.”

  • The paper relies on this without support.

    Exercise promotes glycogen resynthesis.

    “Exercise promotes glycogen resynthesis and this may be important for improving insulin sensitivity postexercise.”

  • The paper relies on this without support.

    JNK and IKK can phosphorylate serine residues on IRS1 and impair insulin signaling.

    “JNK and IKK can phosphorylate serine residues on IRS1 and impair insulin signaling; therefore, these studies may suggest that activation of AMPK during exercise may help restore insulin signaling that is impaired by these serine kinases in obesity.”

  • The paper relies on this without support.

    Circulating IL-6 levels are elevated in obesity and during exercise.

    “Circulating IL-6 levels are elevated in obesity and during exercise; however, in obesity high levels of IL-6 have been linked to insulin resistance whereas during exercise IL-6 may enhance glucose uptake via AMPK and improve insulin sensitivity given IL-6 is additive to insulin in promoting glucose uptake.”

  • The paper relies on this without support.

    Both acute exercise and AICAR activate AMPK and increase insulin sensitivity.

    “Both acute exercise and AICAR activate AMPK and increase insulin sensitivity.”
12 of 12

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?

  • Exercise activates AMPK, which enhances glucose uptake into muscle and improves insulin sensitivity, thereby offsetting negative effects of obesity, diabetes, and cardiovascular disease, reducing morbidity and improving healthspan.

    “Exercise activates AMPK, which in turn enhances glucose uptake into muscle and improves insulin sensitivity thus helping to offset the negative effects of obesity, diabetes and cardiovascular disease and thereby reducing morbidity and improving healthspan (197).”

    From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [197]

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.

  • Exercise glucose uptake is described as both insulin-dependent and insulin-independent

    Minor

    The abstract calls the exercise mechanism insulin-dependent, while the main text explicitly calls it insulin-independent.

  • TBC1D1 mutant's Akt site differs between descriptions

    Minor

    Two descriptions of the four-site mutant attributed to An et al. [95] list the same three other sites but give the Akt site as T590 and T596, respectively.

  • β1 deletion is associated with both increased and reduced appetite

    Minor

    The main text describes β1 KO mice as hyperphagic, whereas the title of its cited reference says β1 deletion reduces appetite.

  • TBC1D4 knock-in glucose intolerance is reported in opposite directions

    Minor

    The main text says the mutation reduces glucose and insulin intolerance. The title of the cited study instead says the mice are glucose intolerant and have reduced insulin sensitivity.

  • TBC1D4 mutation site is labeled both serine and threonine

    Minor

    The text identifies the human and mouse sites as T642 and T649, then calls the same sites S642 and S649 while naming a T649A mutation.

5 of 5

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 9

  1. Hutber, 1997, Am J Physiol, 272, E262
  2. Ihlemann, 1999, Am J Physiol, 277, E208
  3. Winder, 1996, Am J Physiol, 270, E299
  4. Martin, 1995, Am J Physiol, 269, E583
  5. Han, 1995, Am J Physiol, 269, R544
  6. King, 1993, Am J Physiol, 265, R447
  7. Steinberg, 2010, J Biol Chem, 285, 37198
  8. Fischer, 2006, Exerc Immunol Rev, 12, 6
  9. Friedrichsen, Mol Cell Endocrinol

Cited by

Sorted by citations

Related

Authors
O'Neill, H. M.
Affiliations
Protein Chemistry and Metabolism Unit, St. Vincent's Institute of Medical Research, Fitzroy, Australia.
Venue
Diabetes & Metabolism Journal
Publisher
Korean Diabetes Association
Published
2013
Volume
37
Issue
1
Pages
1
ISSN
  • 2233-6079 (ISSN-L)
  • 2233-6087
DOI
10.4093/dmj.2013.37.1.1
PMC
PMC3579147
OpenAlex
W2134304387
Semantic Scholar
7f2feca848d0903c0145aa7ea795eab629122e01
Cited by
295
References
179
Citations by year
2026: 26 · 2025: 21 · 2024: 23 · 2023: 23 · 2022: 24 · 2021: 24 · 2020: 20 · 2019: 17 · 2018: 31 · 2017: 17 · 2016: 13 · 2015: 25 · 2014: 22 · 2013: 7
FWCI
10.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes & Metabolism Journal (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
Keywords
AMPK, physical activity, glucose uptake, insulin sensitivity, insulin resistance, obesity, skeletal muscle metabolism, glycogen synthesis, fatty acid oxidation, mitochondrial biogenesis

About these checks

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

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

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

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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