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Cited by 742Mitochondrial Function and PathologyMetabolism, Diabetes, and CancerAdipose Tissue and Metabolism

Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities

Open access
Sivitz, William I., Yorek, Mark A.·2010·Antioxidants & Redox Signaling
DOI 10.1089/ars.2009.2531PMC PMC2824521
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Abstract

Given their essential function in aerobic metabolism, mitochondria are intuitively of interest in regard to the pathophysiology of diabetes. Qualitative, quantitative, and functional perturbations in mitochondria have been identified and affect the cause and complications of diabetes. Moreover, as a consequence of fuel oxidation, mitochondria generate considerable reactive oxygen species (ROS). Evidence is accumulating that these radicals per se are important in the pathophysiology of diabetes and its complications. In this review, we first present basic concepts underlying mitochondrial physiology. We then address mitochondrial function and ROS as related to diabetes. We consider different forms of diabetes and address both insulin secretion and insulin sensitivity. We also address the role of mitochondrial uncoupling and coenzyme Q. Finally, we address the potential for targeting mitochondria in the therapy of diabetes. Antioxid. Redox Signal. 12, 537–577.

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Written from the paper’s full text.

TL;DR

This narrative review argues that mitochondria contribute to diabetes pathophysiology through defects in insulin secretion, insulin sensitivity, and long-term complications, with mitochondrial reactive oxygen species (ROS) as a central mediator. It also evaluates uncoupling proteins, coenzyme Q, and mitochondria-targeted therapies, while emphasizing unresolved controversies about causation and optimal treatment.

Key findings

  • Diabetes affects approximately 7% of the U.S. population, with ∼90–95% type 2 diabetes; type 2 diabetes involves both impaired insulin action and impaired insulin release, and mitochondria appear important in both processes.
  • Mitochondrial ROS are implicated in β-cell dysfunction, insulin resistance, and diabetic complications; under state 4 conditions in liver or heart mitochondria, ROS production has been estimated to account for as much as 2% of oxygen consumed.
  • Mitochondrial uncoupling and coenzyme Q are linked to diabetes: UCP2 regulates insulin release, UCP3 expression is reportedly reduced by approximately half in type 2 diabetes, and CoQ content is reduced in diabetic states, including an ∼75% reduction in heart mitochondria of 8-week streptozotocin-diabetic rats.
  • Therapeutic strategies targeting mitochondrial metabolism or ROS include lifestyle modification, metformin, thiazolidinediones, angiotensin-receptor blockers, resveratrol, mitochondria-targeted antioxidants such as mitoQ, and SOD mimetics; however, clinical antioxidant trials have been disappointing, and mitoQ can have prooxidant and metabolic effects.

Methods

  • Narrative review; no primary experimental cohort or systematic review/meta-analysis is described.
  • Synthesizes basic mitochondrial physiology, methods for assessing mitochondrial function, and evidence from human, rodent, and cell studies relevant to type 1, type 2, and mitochondrial diabetes.
  • Main analysis is qualitative synthesis of cited literature, including discussion of ROS production, uncoupling, coenzyme Q, and therapeutic implications.

Limitations

  • Stated: the review explicitly addresses controversial topics, including whether diabetes results from perturbed mitochondria or vice versa, the importance of mitochondrial dysfunction versus altered mitochondrial number, sites of mitochondrial ROS production, the role of ROS in diabetes and complications, the role of membrane potential in regulating ROS, and the merits of mitochondria-directed therapy.
  • Stated: an important open question remains whether oxidative damage to islets and insulin-sensitive tissues is responsible for the progressive nature of human type 2 diabetes; human studies are limited by tissue availability and difficulty studying untreated type 1 diabetes.
  • Evident from the text: findings across cited studies are often inconsistent across models and methods, some data are described as unpublished, and no formal systematic search or quantitative synthesis is reported.

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Integrity signals

Registry

Crossref · 10.1089/ars.2009.2531

Cites

Statistics

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Claims the paper makes

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  • Findingcitation
    § C. ROS production by isolated mitochondria

    Stigmatellin markedly reduced the EPR signal.

    “Further, stigmatellin, which blocks electron entry to the complex III Q-cycle, markedly reduced the EPR signal.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [241] O'Malley Y. Fink BD. Ross NC. Prisinzano TE. Sivitz WI. Reactive oxygen and targeted antioxidant administration in endothelial cell mitochondria. J Biol Chem. 2006;281:39766–39775. doi: 10.1074/jbc.M608268200. [DOI] [PubMed] [Google Scholar] source

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  • Findingown data
    § 7. Mitochondrial function in insulin-deficient diabetes

    Proton conductance of muscle mitochondria from STZ-diabetic rats is reduced compared with nondiabetic controls.

    “Based on the kinetic relation between hydrogen transfer and membrane potential, our data indicated that the proton conductance of muscle mitochondria of the diabetic rats was reduced compared with nondiabetic controls (curve shifted down and to the right; that is, opposite to what would be expected if diabetic muscle mitochondria were uncoupled).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Herlein JA. Fink BD. O'Malley Y. Sivitz WI. Superoxide and respiratory coupling in mitochondria of insulin-deficient diabetic rats. Endocrinology. 2009;150:46–55. doi: 10.1210/en.2008-0404. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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  • Findingown data
    § 9. Mitochondria and cell-fuel selectivity

    A mitochondria-targeted coenzyme Q analogue designed as an antioxidant alters intact-cell fuel selectivity, favoring glucose use over fatty acid oxidation.

    “We recently reported data showing that a mitochondria-targeted coenzyme Q analogue, designed as an antioxidant, altered intact-cell fuel selectivity, favoring glucose use over fatty acid oxidation.”
    Quote in the paperNot a substantial claim
  • Findingown data
    § 7. Mitochondrial function in insulin-deficient diabetes

    The reductions in maximally uncoupled respiration in heart and gastrocnemius muscle mitochondria from STZ-diabetic rats are more pronounced at 8 weeks than at 2 weeks of diabetes.

    “These findings were more pronounced in 8-week than in 2-week diabetic rats.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Herlein JA. Fink BD. O'Malley Y. Sivitz WI. Superoxide and respiratory coupling in mitochondria of insulin-deficient diabetic rats. Endocrinology. 2009;150:46–55. doi: 10.1210/en.2008-0404. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Findingcitation
    § 2. ROS and oxidative damage in insulin-sensitive target tissues

    In liver mitochondria of insulin-deficient STZ-diabetic rats, GSH content is reduced.

    “GSH content also is reduced in liver mitochondria of insulin-deficient STZ-diabetic rats, as we and others observed (21, 134).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Bastar I. Seckin S. Uysal M. Aykac-Toker G. Effect of streptozotocin on glutathione and lipid peroxide levels in various tissues of rats. Res Commun Mol Pathol Pharmacol. 1998;102:265–272. [PubMed] [Google Scholar]

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    • cites [134] Herlein JA. Fink BD. O'Malley Y. Sivitz WI. Superoxide and respiratory coupling in mitochondria of insulin-deficient diabetic rats. Endocrinology. 2009;150:46–55. doi: 10.1210/en.2008-0404. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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  • May combine two claims. 134
  • Classified as probably not a substantial claim. 35

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    Findingcitation
    § C. ROS production by isolated mitochondria

    In substrate and inhibitor studies of reactive oxygen species production by isolated bovine aortic endothelial cell mitochondria, rotenone markedly decreased succinate-driven reactive oxygen species production detected by fluorescence but had no effect on succinate-driven superoxide production detected by EPR spectroscopy.

    “These experiments showed (241) that the complex I inhibitor, rotenone, markedly decreased succinate-driven ROS production (reverse transport through complex I), as detected with fluorescence, but had no effect on succinate-driven superoxide production with EPR spectroscopy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [241] O'Malley Y. Fink BD. Ross NC. Prisinzano TE. Sivitz WI. Reactive oxygen and targeted antioxidant administration in endothelial cell mitochondria. J Biol Chem. 2006;281:39766–39775. doi: 10.1074/jbc.M608268200. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

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    Findingcitation
    § C. ROS production by isolated mitochondria

    Antimycin markedly increased succinate-driven superoxide by EPR spectroscopy but decreased reactive oxygen species by fluorescent detection.

    “Moreover, antimycin (active in complex III to increase ROS by its effect on the Q-cycle to prolong the half-life of the semiquinone) markedly increased succinate-driven superoxide by EPR, but decreased ROS by fluorescent detection.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [241] O'Malley Y. Fink BD. Ross NC. Prisinzano TE. Sivitz WI. Reactive oxygen and targeted antioxidant administration in endothelial cell mitochondria. J Biol Chem. 2006;281:39766–39775. doi: 10.1074/jbc.M608268200. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

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    Findingcitation
    § 7. Mitochondrial function in insulin-deficient diabetes

    In heart and gastrocnemius muscle mitochondria isolated from STZ-diabetic rats, maximally uncoupled respiration on FCCP is reduced, without significant difference in state 3 respiration, ADP/O ratio, or ATP-production rate.

    “We recently reported that heart and gastrocnemius muscle mitochondria isolated from STZ-diabetic rats manifest reduced maximally uncoupled respiration on FCCP but without a significant difference in state 3 respiration, ADP/O ratio, or ATP-production rate (134).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Herlein JA. Fink BD. O'Malley Y. Sivitz WI. Superoxide and respiratory coupling in mitochondria of insulin-deficient diabetic rats. Endocrinology. 2009;150:46–55. doi: 10.1210/en.2008-0404. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

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    Findingown data
    § 7. Mitochondrial function in insulin-deficient diabetes

    In liver mitochondria of STZ-diabetic rats, no significant perturbations in respiration, respiratory coupling, or proton-leak kinetics are observed, with a strong trend toward reduced respiration.

    “We also examined liver mitochondria of the STZ-diabetic rats and observed no significant perturbations in respiration, respiratory coupling, or proton-leak kinetics, although a strong trend was noted toward reduced respiration.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Herlein JA. Fink BD. O'Malley Y. Sivitz WI. Superoxide and respiratory coupling in mitochondria of insulin-deficient diabetic rats. Endocrinology. 2009;150:46–55. doi: 10.1210/en.2008-0404. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

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    Findingcitation
    § 2. ROS and oxidative damage in insulin-sensitive target tissues

    In heart, gastrocnemius muscle, and liver mitochondria of STZ-diabetic insulin-deficient rats, ROS production is not increased or is decreased, measured as H2O2 release and superoxide by EPR.

    “We also noted no increase (or an actual decrease) in ROS production measured both as fluorescent H2O2 release and as superoxide with EPR from mitochondria of heart, gastrocnemius muscle, and liver of insulin-deficient rats made diabetic with streptozotocin (134).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Herlein JA. Fink BD. O'Malley Y. Sivitz WI. Superoxide and respiratory coupling in mitochondria of insulin-deficient diabetic rats. Endocrinology. 2009;150:46–55. doi: 10.1210/en.2008-0404. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Findingown data
    § 2. ROS and oxidative damage in insulin-sensitive target tissues

    In mitochondria from muscle and heart of rats with high-fat feeding plus low-dose streptozotocin, no excess superoxide production was observed, indicating no intrinsic alteration to generate excess ROS.

    “Our results did not show excess superoxide production, indicating that the mitochondria, incubated in vitro, were not intrinsically altered to generate excess ROS.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § 2. ROS and oxidative damage in insulin-sensitive target tissues

    The reduction in GSH in liver mitochondria of STZ-diabetic rats is associated with increased GPx expression, apparently compensating for oxidative stress.

    “In our work, the reduction in GSH was associated with an increase in GPx expression, apparently in compensation for oxidative stress.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Herlein JA. Fink BD. O'Malley Y. Sivitz WI. Superoxide and respiratory coupling in mitochondria of insulin-deficient diabetic rats. Endocrinology. 2009;150:46–55. doi: 10.1210/en.2008-0404. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

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    Findingown data
    § 2. ROS and oxidative damage in insulin-sensitive target tissues

    The lack of increased ROS in STZ-diabetic rats is associated with upregulation of MnSOD and UCP3, cytoplasmic catalase in heart and muscle, and increased GPx in liver mitochondria.

    “Our findings were associated with an upregulation of MnSOD and UCP3, as well as cytoplasmic catalase in heart and muscle and an increase in glutathione peroxidase in liver mitochondria.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Herlein JA. Fink BD. O'Malley Y. Sivitz WI. Superoxide and respiratory coupling in mitochondria of insulin-deficient diabetic rats. Endocrinology. 2009;150:46–55. doi: 10.1210/en.2008-0404. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

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    Findingcitation
    § 2. Pharmacologic intervention

    CoQ10 in either the ubiquinol or ubiquinone redox state does not appear to have direct effects on mitochondrial ROS and may not easily enter mitochondria.

    “However, in our experience, CoQ10 in either the ubiquinol or ubiquinone redox state does not appear to have direct effects on mitochondrial ROS (104, 241) and may not easily enter mitochondria.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [104] Fink BD. O'Malley Y. Dake BL. Ross NC. Prisinzano TE. Sivitz WI. Mitochondrial targeted coenzyme Q, superoxide, and fuel selectivity in endothelial cells. PLoS ONE. 2009;4:e4250. doi: 10.1371/journal.pone.0004250. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [241] O'Malley Y. Fink BD. Ross NC. Prisinzano TE. Sivitz WI. Reactive oxygen and targeted antioxidant administration in endothelial cell mitochondria. J Biol Chem. 2006;281:39766–39775. doi: 10.1074/jbc.M608268200. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Mitochondrial ROS measured by lucigenin fluorescence, dichlorodihydrofluorescein fluorescence, or EPR in isolated mitochondria or cells reflects pathologically relevant ROS in vivo.

  • May combine two claims.

    Findingcitation
    § C. Mitochondria-targeted antioxidants

    Mitoquinone increased respiration by isolated mitochondria, but only on complex I substrates.

    “Subsequently, we found that mitoquinone increased respiration by isolated mitochondria, but only on complex I substrates (104).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Fink BD. O'Malley Y. Dake BL. Ross NC. Prisinzano TE. Sivitz WI. Mitochondrial targeted coenzyme Q, superoxide, and fuel selectivity in endothelial cells. PLoS ONE. 2009;4:e4250. doi: 10.1371/journal.pone.0004250. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

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    Findingown data
    § C. Mitochondria-targeted antioxidants

    MitoQ exposure caused a substantial increase in glucose use and a decrease in fat oxidation in BAE cells as well as C2C12 mouse myocytes.

    “We observed a substantial increase in glucose use and a decrease in fat oxidation in BAE cells (104) as well as C2C12 mouse myocytes (Fig. 15) exposed to mitoQ.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Fink BD. O'Malley Y. Dake BL. Ross NC. Prisinzano TE. Sivitz WI. Mitochondrial targeted coenzyme Q, superoxide, and fuel selectivity in endothelial cells. PLoS ONE. 2009;4:e4250. doi: 10.1371/journal.pone.0004250. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

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    Findingcitation
    § C. Mitochondria-targeted antioxidants

    In BAE cell mitochondria, mitoQ (either as mitoquinone or mitoquinol) had prooxidant as well as antioxidant effects and metabolic effects.

    “We recently reported that, in BAE cell mitochondria, mitoQ (either as mitoquinone or mitoquinol) had prooxidant as well as antioxidant effects (241) and metabolic effects (104).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [241] O'Malley Y. Fink BD. Ross NC. Prisinzano TE. Sivitz WI. Reactive oxygen and targeted antioxidant administration in endothelial cell mitochondria. J Biol Chem. 2006;281:39766–39775. doi: 10.1074/jbc.M608268200. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [104] Fink BD. O'Malley Y. Dake BL. Ross NC. Prisinzano TE. Sivitz WI. Mitochondrial targeted coenzyme Q, superoxide, and fuel selectivity in endothelial cells. PLoS ONE. 2009;4:e4250. doi: 10.1371/journal.pone.0004250. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

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    Findingcitation
    § C. Mitochondria-targeted antioxidants

    DecylTPP did not affect fuel selectivity despite a greater reduction in membrane potential than that with mitoquinone.

    “Moreover, decylTPP (which differs from mitoQ only in the absence of the Q moiety) (Fig. 14), did not affect fuel selectivity despite a greater reduction in membrane potential than that with mitoquinone (104).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Fink BD. O'Malley Y. Dake BL. Ross NC. Prisinzano TE. Sivitz WI. Mitochondrial targeted coenzyme Q, superoxide, and fuel selectivity in endothelial cells. PLoS ONE. 2009;4:e4250. doi: 10.1371/journal.pone.0004250. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

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

    Premisecitation
    § II. Basic Physiology

    A physiologic or mild uncoupling of oxidative phosphorylation reduces superoxide generation by reducing mitochondrial membrane potential.

    “One putative mechanism is a physiologic or “mild” uncoupling of oxidative phosphorylation, which would reduce superoxide generation by reducing mitochondrial membrane potential (295).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [295] Skulachev VP. Uncoupling: new approaches to an old problem of bioenergetics. Biochim Biophys Acta. 1998;1363:100–124. doi: 10.1016/s0005-2728(97)00091-1. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § C. Mitochondrial nitric oxide

    Superoxide reacts rapidly with nitric oxide, generating peroxynitrite, which can impair proteins involved in electron transport.

    “Moreover, superoxide is known to react very rapidly with NO (107), generating a damaging peroxynitrite (ONOO−) radical (98, 144, 246), which can impair proteins involved in electron transport (261).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
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      Not checked in the free run.

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

    Premisecitation
    § II. Basic Physiology

    Complex III superoxide is generated during the Q cycle, wherein coenzyme Q undergoes redox cycling through a reactive semiquinone species.

    “Complex III superoxide is generated during the Q cycle, wherein coenzyme Q undergoes redox cycling through a reactive semiquinone species (Fig. 2) (295).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [295] Skulachev VP. Uncoupling: new approaches to an old problem of bioenergetics. Biochim Biophys Acta. 1998;1363:100–124. doi: 10.1016/s0005-2728(97)00091-1. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § II. Basic Physiology

    Complex I superoxide is released nearly exclusively to the matrix side of the inner membrane, whereas complex III likely generates superoxide to both the matrix and outward to the intermembrane and extramitochondrial space.

    “Complex I superoxide is released nearly exclusively to the matrix side of the inner membrane, whereas complex III likely generates superoxide to both the matrix and outward to the intermembrane and extramitochondrial space (128, 299).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation
    § II. Basic Physiology

    Complex I superoxide arises from bound flavin reduced to FMNH2 by NADH, and electrons may be passed by FMNH2 or the partially reduced flavosemiquinone to oxygen-generating superoxide.

    “Complex I superoxide arises from bound flavin reduced to FMNH2 by NADH. Eventually, electrons are passed to membrane-embedded ubiquinone. In this process, electrons may be passed by FMNH2 or the partially reduced flavosemiquinone to oxygen-generating superoxide (282).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § II. Basic Physiology

    Recent studies document expression and antioxidant activity of catalase in liver mitochondria, and reports exist of catalase in heart mitochondria.

    “Conversely, recent studies document the expression and antioxidant activity in liver mitochondria (195, 280), and reports exist of catalase in heart mitochondria (262, 313).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
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    Premisecitation
    § C. Mitochondrial nitric oxide

    Nitric oxide can decrease mitochondrial respiration and potentially trigger apoptosis or cell necrosis by inhibiting cytochrome oxidase.

    “In mitochondria, this radical can decrease respiration and potentially trigger apoptosis or cell necrosis or both by inhibiting cytochrome oxidase (41).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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      Not checked in the free run.

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    Premisecitation
    § II. Basic Physiology

    Considerable reactive oxygen species derives from outside mitochondria, including peroxisomal β-oxidation, NAD(P)H oxidase, xanthine oxidase, arachidonic acid metabolism, microsomal P-450 enzymes, and prooxidant heme.

    “Although this review is concerned with mitochondrial ROS, it should be recognized that considerable ROS derives from outside this organelle, including oxygen radicals from peroxisomal β-oxidation of fatty acids (24), NAD(P)H oxidase (53), xanthine oxidase, arachidonic acid metabolism, microsomal P-450 enzymes (75), and the prooxidant heme molecule (226).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
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      Not checked in the free run.

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    Premisecitation
    § II. Basic Physiology

    Mitochondrial reactive oxygen species can serve metabolic purposes such as induction of mitochondrial uncoupling and cell signaling.

    “Although the ROS so generated may be destructive, these radicals also serve metabolic purposes such as induction of mitochondrial uncoupling (92, 93) and cell signaling (further discussed later).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisereasoning
    § IV. Mitochondrial Metabolism and Diabetes

    A3243G mitochondrial diabetes is characterized by decreased glucose-induced insulin release but not insulin resistance.

    “The A3243G form of mitochondrial diabetes is characterized by decreased glucose-induced insulin release but not insulin resistance, suggesting that the major pathology occurs within mitochondria of pancreatic β cells.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § C. Mitochondrial nitric oxide

    Calcium is taken up by mitochondria through a uniporter and through a pulsed or rapid mode dependent on pre-pulse calcium and inhibited by calcium concentration >100-150 nM.

    “Calcium is taken up by mitochondria both through a uniporter (thus, independent of other ion or molecule) and through a pulsed or rapid mode, dependent on pre-pulse calcium and inhibited by calcium concentration >100–150 nM (123).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Gunter TE. Buntinas L. Sparagna G. Eliseev R. Gunter K. Mitochondrial calcium transport: mechanisms and functions. Cell Calcium. 2000;28:285–296. doi: 10.1054/ceca.2000.0168. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § C. Mitochondrial nitric oxide

    The mitochondrial permeability transition pore is believed to be mediated by reversible opening of a protein pore in the inner membrane.

    “It is believed that the MPTP is mediated by the reversible opening of a protein pore in the inner membrane (257).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [257] Pfeiffer DR. Gunter TE. Eliseev R. Broekemeier KM. Gunter KK. Release of Ca2+ from mitochondria via the saturable mechanisms and the permeability transition. IUBMB Life. 2001;52:205–212. doi: 10.1080/15216540152846019. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § C. Mitochondrial nitric oxide

    In its dramatic form, mitochondrial permeability transition pore opening increases inner-membrane permeability, decreases ΔΨ, and leads to mitochondrial swelling, cytochrome c release, cell damage, and apoptosis.

    “In its dramatic form, the MPTP results in a marked increase in mitochondrial inner-membrane permeability, which will decrease ΔΨ and lead to mitochondrial swelling, release of cytochrome c, cell damage, and apoptosis.”
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    • cites [284] Scheffler I. Mitochondria. New York: Wiley-Liss; 1999. Mitochondrial electron transport and oxidative phosphorylation; pp. 141–245. [Google Scholar]

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    Premisecitation
    § C. ROS production by isolated mitochondria

    Rhodamine derivatives like TMRM can themselves be a source of reactive oxygen species.

    “In using rhodamine derivatives like TMRM, attention has to be paid to the capacity for these compounds themselves to be a source of ROS (255).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [255] Petrat F. Pindiur S. Kirsch M. de Groot H. NAD(P)H, a primary target of 1O2 in mitochondria of intact cells. J Biol Chem. 2003;278:3298–3307. doi: 10.1074/jbc.M204230200. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § 1. Mitochondrial number and morphology

    Type 2 diabetes and obese subjects have reduced numbers of SLM in skeletal muscle associated with reduced electron-transport activity per unit mitochondrial DNA.

    “Studies with transmission electron microscopy revealed reduced numbers of SLM in skeletal muscle of type 2 diabetes and obese subjects associated with reduced electron-transport activity per unit mitochondrial DNA, suggesting functional impairment as well (268).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [268] Ritov VB. Menshikova EV. He J. Ferrell RE. Goodpaster BH. Kelley DE. Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes. 2005;54:8–14. doi: 10.2337/diabetes.54.1.8. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § C. ROS production by isolated mitochondria

    Isoprostanes have adverse vascular effects, including mitogenesis and altered vascular reactivity.

    “Isoprostanes have adverse vascular effects, including mitogenesis and altered vascular reactivity (217).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [217] Mezzetti A. Cipollone F. Cuccurullo F. Oxidative stress and cardiovascular complications in diabetes: isoprostanes as new markers on an old paradigm. Cardiovasc Res. 2000;47:475–488. doi: 10.1016/s0008-6363(00)00118-8. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § C. Mitochondrial nitric oxide

    The composition of the mitochondrial permeability transition pore is unclear, but pore creation may involve interaction of several proteins including adenine nucleotide translocase.

    “The composition of the MPTP is still unclear, but creation of the pore may involve the interaction of several proteins. This includes adenine nucleotide translocase (ANT), which imports ADP and exports ATP through binding of these nucleotides on opposite sides and directing the carrier opening toward or away from the mitochondrial matrix (284).”
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    • cites [284] Scheffler I. Mitochondria. New York: Wiley-Liss; 1999. Mitochondrial electron transport and oxidative phosphorylation; pp. 141–245. [Google Scholar]

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    Premisecitation
    § C. Mitochondrial nitric oxide

    There is a lack of confirmed evidence that mitochondria contain a nitric oxide synthase and are capable of producing nitric oxide.

    “Although this implies that NO interacts with mitochondrial proteins, a lack of confirmed evidence exists to suggest that mitochondria contain a nitric oxide synthase (NOS) and are capable of actually producing the radical.”
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    • cites [183] Lacza Z. Pankotai E. Busija DW. Mitochondrial nitric oxide synthase: current concepts and controversies. Front Biosci. 2009;14:4436–4443. doi: 10.2741/3539. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    § C. ROS production by isolated mitochondria

    Peroxynitrite can cause nitration of tyrosine, forming nitrotyrosine.

    “Peroxynitrite, which results from oxygen radical interaction with nitric oxide, can cause nitration of tyrosine, resulting in a formation of the marker compound, nitrotyrosine (216).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [216] Mercuri F. Quagliaro L. Ceriello A. Oxidative stress evaluation in diabetes. Diabetes Technol Ther. 2000;2:589–600. doi: 10.1089/15209150050502014. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § 3. Mitochondrial biogenesis

    PGC-1α is reduced in muscle of patients with type 2 diabetes and in family members.

    “Muscle-biopsy studies showed that PGC-1α is reduced in patients with type 2 diabetes (215, 222, 247) as well as in family members of individuals with type 2 diabetes (247).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [215] Mensink M. Hesselink MK. Russell AP. Schaart G. Sels JP. Schrauwen P. Improved skeletal muscle oxidative enzyme activity and restoration of PGC-1 alpha and PPAR beta/delta gene expression upon rosiglitazone treatment in obese patients with type 2 diabetes mellitus. Int J Obes (Lond) 2007;31:1302–1310. doi: 10.1038/sj.ijo.0803567. [DOI] [PubMed] [Google Scholar] source

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    • cites [222] Mootha VK. Lindgren CM. Eriksson KF. Subramanian A. Sihag S. Lehar J. Puigserver P. Carlsson E. Ridderstrale M. Laurila E. Houstis N. Daly MJ. Patterson N. Mesirov JP. Golub TR. Tamayo P. Spiegelman B. Lander ES. Hirschhorn JN. Altshuler D. Groop LC. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34:267–273. doi: 10.1038/ng1180. [DOI] [PubMed] [Google Scholar] source

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    • cites [247] Patti ME. Butte AJ. Crunkhorn S. Cusi K. Berria R. Kashyap S. Miyazaki Y. Kohane I. Costello M. Saccone R. Landaker EJ. Goldfine AB. Mun E. DeFronzo R. Finlayson J. Kahn CR. Mandarino LJ. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A. 2003;100:8466–8471. doi: 10.1073/pnas.1032913100. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    Premisecitation
    § C. ROS production by isolated mitochondria

    Dihydroethidine has been criticized as nonspecific, and some advocate HPLC analysis of oxidation products to document specificity for superoxide as opposed to H2O2.

    “DHE has been criticized as nonspecific, and some advocate analysis of the oxidation products with high-pressure liquid chromatography (HPLC) to document specificity for superoxide as opposed to H2O2 (188).”
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    • cites [188] Laurindo FR. Fernandes DC. Santos CX. Assessment of superoxide production and NADPH oxidase activity by HPLC analysis of dihydroethidium oxidation products. Methods Enzymol. 2008;441:237–260. doi: 10.1016/S0076-6879(08)01213-5. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § C. Mitochondrial nitric oxide

    The major roles of calcium in mitochondria appear to be stimulation of ATP production and induction of the mitochondrial permeability transition.

    “The major roles of calcium in mitochondria appear to be to stimulation of ATP production and induction of the mitochondrial permeability transition (124).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Gunter TE. Gunter KK. Uptake of calcium by mitochondria: transport and possible function. IUBMB Life. 2001;52:197–204. doi: 10.1080/15216540152846000. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § C. ROS production by isolated mitochondria

    Mitochondrial protein can be evaluated for 4-HNE protein adducts with immunoblotting antibody, although specificity can be questioned.

    “Mitochondrial protein also can be evaluated for 4-HNE protein adducts with immunoblotting antibody (34), although specificity can be questioned.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Boudina S. Sena S. Theobald H. Sheng X. Wright JJ. Hu XX. Aziz S. Johnson JI. Bugger H. Zaha VG. Abel ED. Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes. 2007;56:2457–2466. doi: 10.2337/db07-0481. [DOI] [PubMed] [Google Scholar] source

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    Interpretationreasoning
    § 1. Mitochondrial number and morphology

    Morphologic changes in mitochondria occur in diabetic states, though data are inconsistent.

    “In summary, it is clear that morphologic changes in mitochondria occur in diabetic states, although the data are not completely consistent over different studies.”
    Quote in the paperNot a substantial claim

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    Premisenone given
    § C. ROS production by isolated mitochondria

    In obesity and diabetes, lipids accumulate near mitochondria, and products of lipid oxidation can interfere with cell signaling.

    “Moreover, in obesity and diabetes, lipids have been observed to accumulate near mitochondria, and products of lipid oxidation can interfere with cell signaling (see Section IV.C.5).”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § C. ROS production by isolated mitochondria

    Aconitase activity is a method to measure oxidative damage specifically within mitochondria; aconitase is highly sensitive to oxidative damage.

    “One method is to determine the activity of the aconitase enzyme, a protein that is highly sensitive to oxidative damage (110).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Gardner PR. Superoxide-driven aconitase FE-S center cycling. Biosci Rep. 1997;17:33–42. doi: 10.1023/a:1027383100936. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § IV. Mitochondrial Metabolism and Diabetes

    Both β-cell dysfunction and insulin resistance can be identified early and are present in nondiabetic offspring of patients with type 2 diabetes.

    “Both defects can be identified early and are present even in nondiabetic offspring of patients with type 2 diabetes (112, 122, 249).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [112] Gautier JF. Wilson C. Weyer C. Mott D. Knowler WC. Cavaghan M. Polonsky KS. Bogardus C. Pratley RE. Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes. Diabetes. 2001;50:1828–1833. doi: 10.2337/diabetes.50.8.1828. [DOI] [PubMed] [Google Scholar]

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    • cites [122] Gulli G. Ferrannini E. Stern M. Haffner S. DeFronzo RA. The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes. 1992;41:1575–1586. doi: 10.2337/diab.41.12.1575. [DOI] [PubMed] [Google Scholar] source

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    • cites [249] Perseghin G. Ghosh S. Gerow K. Shulman GI. Metabolic defects in lean nondiabetic offspring of NIDDM parents: a cross-sectional study. Diabetes. 1997;46:1001–1009. doi: 10.2337/diab.46.6.1001. [DOI] [PubMed] [Google Scholar] source

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    Premisenone given
    § IV. Mitochondrial Metabolism and Diabetes

    Type 2 diabetes etiology involves both pancreatic β-cell dysfunction and insulin resistance in insulin-sensitive tissues.

    “It is widely accepted that the etiology of type 2 diabetes involves both pancreatic β-cell dysfunction and insulin resistance in insulin-sensitive tissues, including hepatocytes, myocytes, and adipocytes.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § C. ROS production by isolated mitochondria

    Superoxide production has been effectively assessed by measuring H2O2 production in the presence and absence of added SOD in studies of the topology of muscle, heart, and liver mitochondria, although mathematical correction for fluorescent interference was required.

    “Superoxide production has been effectively assessed in this way in studies of the topology of muscle, heart, and liver mitochondria (299), although that required mathematical correction for fluorescent interference.”
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    • cites [299] St-Pierre J. Buckingham JA. Roebuck SJ. Br MD. Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem. 2002;4277:44784–44790. doi: 10.1074/jbc.M207217200. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § C. Mitochondrial nitric oxide

    Transient mitochondrial permeability transition pore opening may be physiologic, involved in voltage, redox or pH sensing, divalent cation sensing, or regulation of adenine nucleotide concentrations.

    “Conversely, transient opening may be physiologic, being involved in functions such as voltage, redox or pH sensing, divalent cation sensing, or regulation of adenine nucleotide concentrations (178).”
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    • cites [178] Kroemer G. Zamzami N. Susin SA. Mitochondrial control of apoptosis. Immunol Today. 1997;18:44–51. doi: 10.1016/s0167-5699(97)80014-x. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § C. ROS production by isolated mitochondria

    Oxidative damage can modify amino acids, change protein structure and function, and lead to cross-linking or protein breakdown.

    “Oxidative damage also can modify amino acids and, therefore, change structure and function and lead to cross-linking or protein breakdown (258).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [258] Piconi L. Quagliaro L. Ceriello A. Oxidative stress in diabetes. Clin Chem Lab Med. 2003;41:1144–1149. doi: 10.1515/CCLM.2003.177. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § 6. Mitochondrial respiratory coupling and insulin release

    In cultured pancreatic islets, fatty acid inhibition of insulin secretion is not associated with increased peroxide or nitric oxide and is not prevented by antioxidants.

    “Conversely, Moore et al. (221) found that fatty acid inhibition of insulin secretion in cultured pancreatic islets was not associated with increased peroxide or nitric oxide and was not prevented by antioxidants.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [221] Moore PC. Ugas MA. Hagman DK. Parazzoli SD. Poitout V. Evidence against the involvement of oxidative stress in fatty acid inhibition of insulin secretion. Diabetes. 2004;53:2610–2616. doi: 10.2337/diabetes.53.10.2610. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § 6. Mitochondrial respiratory coupling and insulin release

    In islets isolated from ZDF rats, adenoviral expression of UCP2 increased proinsulin and improved glucose-induced insulin secretion.

    “In contrast, Wang et al. (326) found that adenoviral expression of UCP2 in islets isolated from ZDF rats increased proinsulin and improved glucose-induced insulin secretion.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [326] Wang MY. Shimabukuro M. Lee Y. Trinh KY. Chen JL. Newgard CB. Unger RH. Adenovirus-mediated overexpression of uncoupling protein-2 in pancreatic islets of Zucker diabetic rats increases oxidative activity and improves beta-cell function. Diabetes. 1999;48:1020–1025. doi: 10.2337/diabetes.48.5.1020. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § 4. Mitochondrial function in type 2 diabetes and insulin-resistant states

    High-fat feeding is associated with insulin resistance and may lead to oversupply of fatty acids to mitochondria.

    “High-fat feeding is associated with insulin resistance (286) and may lead to oversupply of fatty acids to mitochondria.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [286] Schrauwen P. High-fat diet, muscular lipotoxicity and insulin resistance. Proc Nutr Soc. 2007;66:33–41. doi: 10.1017/S0029665107005277. [DOI] [PubMed] [Google Scholar] source

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    Premisenone given
    § 4. Mitochondrial function in type 2 diabetes and insulin-resistant states

    Insulin-resistant states are associated with mitochondrial dysfunction or decreased mitochondrial content or both.

    “As discussed in the preceding section, insulin-resistant states are associated with mitochondrial dysfunction or decreased mitochondrial content or both.”
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    Interpretationreasoning
    § 4. Mitochondrial function in type 2 diabetes and insulin-resistant states

    Mitochondria of high-fat-fed rodents are exposed to increased β-oxidation but become impaired and unable to handle high flux.

    “Hence these data imply that mitochondria of high-fat–fed rodents are exposed to increased rather than decreased rates of β oxidation but become impaired and unable to handle the high rate of flux.”
    Quote in the paperSubstantial claim

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    Interpretationcitation
    § 6. Mitochondrial respiratory coupling and insulin release

    Mitochondria, with a major role for UCP2, modulate mitochondrial respiration and membrane potential, ATP production, and therefore insulin release.

    “However, these considerations now direct attention to mitochondria with a major role for UCP2 in modulating mitochondrial respiration and membrane potential, ATP production, and therefore insulin release (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Affourtit C. Br MD. On the role of uncoupling protein-2 in pancreatic beta cells. Biochim Biophys Acta. 2008;1777:973–979. doi: 10.1016/j.bbabio.2008.03.022. [DOI] [PubMed] [Google Scholar] source

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    Interpretationcitation
    § 4. Mitochondrial function in type 2 diabetes and insulin-resistant states

    Decreased respiration in type 2 diabetes can be attributed to reduced muscle mitochondrial content if normalization parameters reflect mitochondrial numbers.

    “If these parameters actually reflect mitochondrial numbers, the implication is that the decreased respiration in type 2 diabetes can be attributed to reduced muscle mitochondrial content.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § 4. Mitochondrial function in type 2 diabetes and insulin-resistant states

    Prolonged insulin infusion increases mitochondrial ATP production in healthy controls, but type 2 diabetes subjects are resistant.

    “Prolonged insulin infusion increases mitochondrial ATP production (301) in vastus lateralis muscle and ATP synthesis (254, 303) in healthy controls, whereas subjects with type 2 diabetes were resistant to this effect of insulin.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [301] Stump CS. Short KR. Bigelow ML. Schimke JM. Nair KS. Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc Natl Acad Sci U S A. 2003;100:7996–8001. doi: 10.1073/pnas.1332551100. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    • cites [254] Petersen KF. Dufour S. Shulman GI. Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents. PLoS Med. 2005;2:e233. doi: 10.1371/journal.pmed.0020233. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    • cites [303] Szendroedi J. Schmid AI. Chmelik M. Toth C. Brehm A. Krssak M. Nowotny P. Wolzt M. Waldhausl W. Roden M. Muscle mitochondrial ATP synthesis and glucose transport/phosphorylation in type 2 diabetes. PLoS Med. 2007;4:e154. doi: 10.1371/journal.pmed.0040154. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    Premisecitation
    § 4. Mitochondrial function in type 2 diabetes and insulin-resistant states

    Boushel et al. found reduced oxygen use under ADP stimulation and maximal uncoupling in diabetic subjects, but differences resolved when normalized to mtDNA or citrate synthase.

    “These investigators found reduced oxygen use under conditions of ADP stimulation (coupled respiration) and maximal uncoupling by carbonyl cyanide p-[trifluoromethoxy]-phenyl-hydrazone (FCCP) in the diabetic subjects compared with nondiabetic controls. However, the differences were resolved when the data were normalized to mitochondrial DNA or to citrate synthase activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Boushel R. Gnaiger E. Schjerling P. Skovbro M. Kraunsoe R. Dela F. Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia. 2007;50:790–796. doi: 10.1007/s00125-007-0594-3. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    Premisecitation
    § 4. Mitochondrial function in type 2 diabetes and insulin-resistant states

    High-fat feeding overloads mitochondria with β-oxidation products, restricting complete metabolism and switch from fat to glucose oxidation.

    “Recent metabolomic studies in rodents suggest that enhanced fat metabolism seen with high-fat feeding overloads mitochondria with β-oxidation products in a way that restricts their ability to metabolize these products completely to CO2 and restricts their capacity to switch from fat to glucose oxidation (228).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [228] Muoio DM. Newgard CB. Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol. 2008;9:193–205. doi: 10.1038/nrm2327. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § 6. Mitochondrial respiratory coupling and insulin release

    UCP2 KO in ob/ob mice restored first-phase insulin release, reduced blood glucose, increased insulin.

    “UCP2 knockout (KO) in these mice restored first-phase insulin release (346). In addition, UCP2 KO reduced blood glucose and increased insulin when measured in the fed state in ob/ob mice observed over a period of 15 weeks.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [346] Zhang CY. Baffy G. Perret P. Krauss S. Peroni O. Grujic D. Hagen T. Vidal-Puig AJ. Boss O. Kim YB. Zheng XX. Wheeler MB. Shulman GI. Chan CB. Lowell BB. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes [comment] Cell. 2001;105:745–755. doi: 10.1016/s0092-8674(01)00378-6. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § 6. Mitochondrial respiratory coupling and insulin release

    Diacylglycerol reproduces fatty acid inhibition of insulin secretion in cultured pancreatic islets, suggesting an effect downstream of diacylglycerol.

    “However, the effect could be reproduced by diacylglycerol, suggesting some effect downstream of this metabolite.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [221] Moore PC. Ugas MA. Hagman DK. Parazzoli SD. Poitout V. Evidence against the involvement of oxidative stress in fatty acid inhibition of insulin secretion. Diabetes. 2004;53:2610–2616. doi: 10.2337/diabetes.53.10.2610. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § 6. Mitochondrial respiratory coupling and insulin release

    UCP2 deficient mice have higher islet ATP and increased glucose-stimulated insulin release.

    “Indeed, Zhang et al. (346) reported that mice genetically deficient in UCP2 manifest higher islet ATP levels and increased glucose-stimulated insulin release.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [346] Zhang CY. Baffy G. Perret P. Krauss S. Peroni O. Grujic D. Hagen T. Vidal-Puig AJ. Boss O. Kim YB. Zheng XX. Wheeler MB. Shulman GI. Chan CB. Lowell BB. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes [comment] Cell. 2001;105:745–755. doi: 10.1016/s0092-8674(01)00378-6. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § 7. Mitochondrial function in insulin-deficient diabetes

    In insulin-deficient diabetic rats, respiration is impaired in heart and brain mitochondria but increased in kidney mitochondria respiring on succinate or complex I substrates.

    “Overall, the results appear somewhat variable, suggesting that respiration is impaired in mitochondria isolated from heart and brain mitochondria (101, 223) but actually increased in kidney mitochondria respiring on succinate or complex I substrates (159).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [101] Ferko M. Gvozdjakova A. Kucharska J. Mujkosova J. Waczulikova I. Styk J. Ravingerova T. Ziegelhoffer-Mihalovicova B. Ziegelhoffer A. Functional remodeling of heart mitochondria in acute diabetes: interrelationships between damage, endogenous protection and adaptation. Gen Physiol Biophys. 2006;25:397–413. [PubMed] [Google Scholar]

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    • cites [223] Moreira PI. Rolo AP. Sena C. Seica R. Oliveira CR. Santos MS. Insulin attenuates diabetes-related mitochondrial alterations: a comparative study. Med Chem. 2006;2:299–308. doi: 10.2174/157340606776930754. [DOI] [PubMed] [Google Scholar]

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    • cites [159] Katyare SS. Satav JG. Effect of streptozotocin-induced diabetes on oxidative energy metabolism in rat kidney mitochondria: a comparative study of early and late effects. Diabetes Obes Metab. 2005;7:555–562. doi: 10.1111/j.1463-1326.2004.00429.x. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § 6. Mitochondrial respiratory coupling and insulin release

    Troglitazone treatment of ZDF animals depleted islet fat, induced UCP2 expression, reduced islet fat, and improved insulin secretion.

    “The in vivo depletion of islet fat as a result of troglitazone treatment of these animals induced UCP2 expression, reduced islet fat, and improved insulin secretion (291).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [291] Shimabukuro M. Zhou YT. Lee Y. Unger RH. Troglitazone lowers islet fat and restores beta cell function of Zucker diabetic fatty rats. J Biol Chem. 1998;273:3547–3550. doi: 10.1074/jbc.273.6.3547. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § 4. Mitochondrial function in type 2 diabetes and insulin-resistant states

    Skeletal muscle oxidative phosphorylation is impaired in insulin-resistant offspring of type 2 diabetes, associated with increased intramyocellular lipid.

    “These studies showed that skeletal muscle oxidative phosphorylation was impaired in insulin-resistant offspring of individuals with type 2 diabetes, associated with increased intramyocellular lipid (253).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [253] Petersen KF. Dufour S. Befroy D. Garcia R. Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. [see comment] N Engl J Med. 2004;350:664–671. doi: 10.1056/NEJMoa031314. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    Interpretationcitation
    § 4. Mitochondrial function in type 2 diabetes and insulin-resistant states

    Mitochondrial dysfunction leads to impaired fatty acid oxidation, increased fatty acyl-CoA and DAG, activation of PKC, serine phosphorylation of IRS-1, blocking insulin signaling.

    “Mitochondrial dysfunction should lead to impaired fatty acid oxidation, resulting in increased intracellular fatty acyl-CoA and diacylglycerol content, with consequent activation of protein kinase C (1, 204). This, in turn, triggers a serine kinase cascade, ultimately resulting in serine phosphorylation of insulin-receptor substrate type 1 (IRS-1). This has the consequence of blocking the tyrosine”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Abdul-Ghani MA. DeFronzo RA. Mitochondrial dysfunction, insulin resistance, and type 2 diabetes mellitus. Curr Diabetis Rep. 2008;8:173–178. doi: 10.1007/s11892-008-0030-1. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [204] Lowell BB. Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science. 2005;307:384–387. doi: 10.1126/science.1104343. [DOI] [PubMed] [Google Scholar] source

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  • May combine two claims.

    Interpretationreasoning
    § 4. Mitochondrial function in type 2 diabetes and insulin-resistant states

    Mitochondrial defects could add to hyperglycemia once insulin resistance is in place and lead to progressive worsening of diabetic state.

    “In any case, it is important to realize that even if mitochondrial dysfunction were secondary to insulin resistance, mitochondrial defects could add to hyperglycemia once the insulin resistance is in place and lead to progressive worsening of the diabetic state.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 8. Diabetes and mitochondrial function in non–insulin-sensitive tissues

    Hyperglycemia in insulin-independent tissues generates increased mitochondrial substrates for ETS and increases propensity for ROS production.

    “Hyperglycemia in these insulin-independent tissues appears to generate increased mitochondrial substrates for the ETS and to increase the propensity for ROS production (87, 237),”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [87] Du Y. Miller CM. Kern TS. Hyperglycemia increases mitochondrial superoxide in retina and retinal cells. Free Radic Biol Med. 2003;35:1491–1499. doi: 10.1016/j.freeradbiomed.2003.08.018. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [237] Nishikawa T. Edelstein D. Du XL. Yamagishi S. Matsumura T. Kaneda Y. Yorek MA. Beebe D. Oates PJ. Hammes HP. Giardino I. Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404:787–790. doi: 10.1038/35008121. [DOI] [PubMed] [Google Scholar] source

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    Interpretationreasoning
    § 7. Mitochondrial function in insulin-deficient diabetes

    Respiratory uncoupling in heart and skeletal muscle is not evident in insulin deficiency, perhaps because of proportional reduction in respiration and ATP synthesis.

    “Respiratory uncoupling in heart and skeletal muscle is not evident, perhaps because of proportional reduction in respiration and ATP synthesis.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § 7. Mitochondrial function in insulin-deficient diabetes

    In insulin-deficient diabetic rodents, UCP3 expression is increased, but proton conductance of isolated mitochondria incubated in vitro is not increased or is decreased.

    “Interestingly, UCP3 expression is increased in insulin-deficient diabetic rodents but with no associated increase (42) or an actual decrease (134) in the proton conductance (decrease in the proton leak) of isolated mitochondria incubated in vitro.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [42] Bugger H. Boudina S. Hu XX. Tuinei J. Zaha VG. Theobald HA. Yun UJ. McQueen AP. Wayment B. Litwin SE. Abel ED. Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3. Diabetes. 2008;57:2924–2932. doi: 10.2337/db08-0079. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [134] Herlein JA. Fink BD. O'Malley Y. Sivitz WI. Superoxide and respiratory coupling in mitochondria of insulin-deficient diabetic rats. Endocrinology. 2009;150:46–55. doi: 10.1210/en.2008-0404. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    Premisecitation
    § 1. Non–insulin-sensitive tissues (retina, renal, neural cells)

    Most tissues take up glucose by facilitated diffusion independent of insulin, unlike muscle, liver, and heart which depend on insulin for glucose transport and utilization.

    “As opposed to tissues such as muscle, liver, and heart, which depend on insulin for glucose transport and utilization, most tissues take up glucose by facilitated diffusion, independent of insulin (250).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [250] Pessin JE. Richardson JM. Sivitz WI. Regulation of the glucose transporter in animal models of diabetes. Adv Exp Med Biol. 1991;293:249–262. doi: 10.1007/978-1-4684-5949-4_23. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § 8. Diabetes and mitochondrial function in non–insulin-sensitive tissues

    Retinal capillary cells exposed to hyperglycemia become dysfunctional and manifest proapoptotic BAX translocation.

    “Consistent with excess ROS production, retinal capillary cells exposed to hyperglycemia become dysfunctional and manifest proapoptotic BAX translocation (171).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [171] Kowluru RA. Diabetic retinopathy: mitochondrial dysfunction and retinal capillary cell death. Antioxid Redox Signal. 2005;7:1581–1587. doi: 10.1089/ars.2005.7.1581. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

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

    Interpretationreasoning
    § 8. Diabetes and mitochondrial function in non–insulin-sensitive tissues

    The differences between the two reports on kidney mitochondria could reflect differences in methods, severity, and duration of STZ diabetes.

    “The differences between these two reports could reflect marked differences in methods, with the former study focusing on proximal tubular UCP2 rather than whole-kidney mitochondria. These studies also examined different degrees of severity and duration of STZ diabetes; the former report examined a short (2-week) duration of diabetes with a lower dose of STZ.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § 7. Mitochondrial function in insulin-deficient diabetes

    In insulin deficiency, respiration and perhaps ATP production in muscle and heart mitochondria are impaired, at least when mitochondria are isolated and studied ex vivo.

    “Although these studies have not generated consistent results, taken together, they seem to suggest that respiration and perhaps ATP production in muscle and heart mitochondria are impaired under conditions of insulin deficiency, at least when mitochondria are isolated and studied ex vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 2. ROS and oxidative damage in insulin-sensitive target tissues

    In heart mitochondria of insulin-resistant, obese, leptin receptor-deficient db/db mice, ROS production is increased, ATP production is decreased, and 4-HNE is increased.

    “Boudina et al. (34) reported an increase in ROS production, a decrease in ATP production, and an increase in a marker of oxidative damage (4-HNE) in heart mitochondria of insulin-resistant, obese, and leptin receptor–deficient db/db mice, a model of extreme obesity associated with diabetes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Boudina S. Sena S. Theobald H. Sheng X. Wright JJ. Hu XX. Aziz S. Johnson JI. Bugger H. Zaha VG. Abel ED. Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes. 2007;56:2457–2466. doi: 10.2337/db07-0481. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Premisecitation
    § 8. Diabetes and mitochondrial function in non–insulin-sensitive tissues

    Another report shows increased mitochondrial membrane potential in kidney mitochondria of STZ diabetic rats and reduced UCP2 by immunoblotting.

    “These results appear at odds with another recent report showing increased mitochondrial membrane potential in kidney mitochondria of STZ diabetic rats and reduced UCP2 by immunoblotting of mitochondrial protein (79).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] de Cavanagh EM. Ferder L. Toblli JE. Piotrkowski B. Stella I. Fraga CG. Inserra F. Renal mitochondrial impairment is attenuated by AT1 blockade in experimental Type I diabetes. Am J Physiol Heart Circ Physiol. 2008;294:H456–H465. doi: 10.1152/ajpheart.00926.2007. [DOI] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § 8. Diabetes and mitochondrial function in non–insulin-sensitive tissues

    In kidney mitochondria of STZ diabetic rats, increased membrane potential and reduced UCP2 were prevented by angiotensin-receptor blocker, which also reduced H2O2 production.

    “Interestingly, these changes were prevented with an angiotensin-receptor blocker (which also reduced H2O2 production).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] de Cavanagh EM. Ferder L. Toblli JE. Piotrkowski B. Stella I. Fraga CG. Inserra F. Renal mitochondrial impairment is attenuated by AT1 blockade in experimental Type I diabetes. Am J Physiol Heart Circ Physiol. 2008;294:H456–H465. doi: 10.1152/ajpheart.00926.2007. [DOI] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § 7. Mitochondrial function in insulin-deficient diabetes

    In heart mitochondria from hyperglycemic ketotic streptozotocin diabetic rats, state 3 respiration is reduced, associated with increased state 4 respiration; this is not observed in nonketotic animals.

    “In a recent study of heart mitochondria isolated from hyperglycemic ketotic and hyperglycemic nonketotic streptozotocin diabetic rats, Lashin and Romani (186) reported reduced state 3 respiration but only in the ketotic animals associated with an increase in state 4 respiration.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [186] Lashin O. Romani A. Hyperglycemia does not alter state 3 respiration in cardiac mitochondria from type-I diabetic rats. Mol Cell Biochem. 2004;267:31–37. doi: 10.1023/b:mcbi.0000049360.75392.89. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § 8. Diabetes and mitochondrial function in non–insulin-sensitive tissues

    The increase in proximal tubular UCP2 expression in STZ diabetic rats is reversible by insulin, suggesting hyperglycemia rather than STZ toxicity is the cause.

    “This was reversible by insulin, suggesting that hyperglycemia and not STZ toxicity was the cause.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [108] Friederich M. Fasching A. Hansell P. Nordquist L. Palm F. Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells. Biochim Biophys Acta. 2008;1777:935–940. doi: 10.1016/j.bbabio.2008.03.030. [DOI] [PubMed] [Google Scholar]

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  • May combine two claims.

    Interpretationreasoning
    § 9. Mitochondria and cell-fuel selectivity

    It is plausible that mitochondria might be altered in similar fashion in insulin-deficient states and lose the capacity to switch from fat to glucose metabolism.

    “Therefore, it seems plausible that mitochondria might be altered in similar fashion in insulin-deficient states and lose the capacity to switch from fat to glucose metabolism.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Insulin deficiency is associated with increased circulating fatty acids and accelerated delivery to mitochondria.

  • May combine two claims.

    Premisecitation
    § 8. Diabetes and mitochondrial function in non–insulin-sensitive tissues

    In brain mitochondria from streptozotocin-treated rats, respiration during state 3 and state 4 is decreased, with no change in ADP/O ratio.

    “Recent studies of brain mitochondria isolated from streptozotocin-treated rats revealed decreased respiration during state 3 and state 4, with no change in the ADP/O ratio (223), raising the possibility of impaired electron transport or ATP synthase.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [223] Moreira PI. Rolo AP. Sena C. Seica R. Oliveira CR. Santos MS. Insulin attenuates diabetes-related mitochondrial alterations: a comparative study. Med Chem. 2006;2:299–308. doi: 10.2174/157340606776930754. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 8. Diabetes and mitochondrial function in non–insulin-sensitive tissues

    Kidney mitochondria from STZ diabetic rats with increased proximal tubular UCP2 manifest increased glutamate-stimulated oxygen consumption, blocked by GDP.

    “Isolated mitochondria from kidneys of these diabetic rats manifest increased glutamate-stimulated oxygen consumption, which was blocked by GDP (which inhibits uncoupling protein activity).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Friederich M. Fasching A. Hansell P. Nordquist L. Palm F. Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells. Biochim Biophys Acta. 2008;1777:935–940. doi: 10.1016/j.bbabio.2008.03.030. [DOI] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § 1. Non–insulin-sensitive tissues (retina, renal, neural cells)

    High glucose in the culture medium increased ROS production in bovine retinal capillary endothelial cells and pericytes, associated with apoptosis.

    “Cui et al. (76) used a confocal microscopy approach and reported that high glucose in the culture medium increased ROS production in bovine retinal capillary endothelial cells and pericytes associated with apoptosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Cui Y. Xu X. Bi H. Zhu Q. Wu J. Xia X. Qiushi R. Ho PC. Expression modification of uncoupling proteins and MnSOD in retinal endothelial cells and pericytes induced by high glucose: the role of reactive oxygen species in diabetic retinopathy. Exp Eye Res. 2006;83:807–816. doi: 10.1016/j.exer.2006.03.024. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Mitochondrial ROS measured by lucigenin fluorescence, dichlorodihydrofluorescein fluorescence, or EPR in isolated mitochondria or cells reflects pathologically relevant ROS in vivo.
    • Rests on an assumption: High glucose in cultured retinal, mesangial, or endothelial cells models the diabetic milieu in vivo.

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

    Study design and conductcitation
    § 1. Non–insulin-sensitive tissues (retina, renal, neural cells)

    The study by Busik et al. used specific spin traps to verify intracellular production of superoxide by electron paramagnetic resonance spectroscopy.

    “This study used specific spin traps to verify intracellular production of superoxide by electron paramagnetic resonance spectroscopy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Busik JV. Mohr S. Grant MB. Hyperglycemia-induced reactive oxygen species toxicity to endothelial cells is dependent on paracrine mediators. Diabetes. 2008;57:1952–1965. doi: 10.2337/db07-1520. [DOI] [PMC free article] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § 1. Non–insulin-sensitive tissues (retina, renal, neural cells)

    Astaxanthin blocked the high-glucose-induced ROS fluorescence and potentially harmful cytokine expression in human mesangial cells.

    “Manabe et al. (208) reported that high glucose increased ROS fluorescence in human mesangial cells associated with potentially harmful cytokine expression, an effect that was blocked by astaxanthin, a carotenoid that accumulated in mitochondria.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [208] Manabe E. Handa O. Naito Y. Mizushima K. Akagiri S. Adachi S. Takagi T. Kokura S. Maoka T. Yoshikawa T. Astaxanthin protects mesangial cells from hyperglycemia-induced oxidative signaling. J Cell Biochem. 2008;103:1925–1937. doi: 10.1002/jcb.21583. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: High glucose in cultured retinal, mesangial, or endothelial cells models the diabetic milieu in vivo.

  • May combine two claims.

    Premisecitation
    § 2. ROS and vascular cells

    Both endothelial and smooth muscle cell-mediated vascular reactivity are impaired by diabetes.

    “In part, this could be due to impaired vascular function, because both endothelial and smooth muscle cell–mediated vascular reactivity are impaired by diabetes (20, 292).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] Baron AD. Insulin resistance and vascular function. J Diabetes Complications. 2002;16:92–102. doi: 10.1016/s1056-8727(01)00209-4. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [292] Sivitz WI. Wayson SM. Bayless ML. Sinkey CA. Haynes WG. Obesity impairs vascular relaxation in human subjects: hyperglycemia exaggerates adrenergic vasoconstriction arterial dysfunction in obesity and diabetes. J Diabetes Complications. 2007;21:149–157. doi: 10.1016/j.jdiacomp.2005.12.003. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § 1. Non–insulin-sensitive tissues (retina, renal, neural cells)

    Kidney mitochondria of 12-week streptozotocin diabetic rats show increased H2O2 production accompanied by upregulation of glutathione peroxidase.

    “However, that study did show increased H2O2 production accompanied by upregulation of glutathione peroxidase in kidney mitochondria of the diabetic rats.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [223] Moreira PI. Rolo AP. Sena C. Seica R. Oliveira CR. Santos MS. Insulin attenuates diabetes-related mitochondrial alterations: a comparative study. Med Chem. 2006;2:299–308. doi: 10.2174/157340606776930754. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.
    • Rests on an assumption: Mitochondrial ROS measured by lucigenin fluorescence, dichlorodihydrofluorescein fluorescence, or EPR in isolated mitochondria or cells reflects pathologically relevant ROS in vivo.

  • May combine two claims.

    Premisecitation
    § 1. Non–insulin-sensitive tissues (retina, renal, neural cells)

    MnSOD also suppressed high-glucose-induced H2O2 production in human mesangial cells, despite the expectation that it should increase H2O2 production from superoxide.

    “This was suppressed by reduction in membrane potential by chemical inhibition or by UCP1 overexpression, but, curiously, also suppressed by MnSOD, which should actually increase H2O2 production from superoxide.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] Kiritoshi S. Nishikawa T. Sonoda K. Kukidome D. Senokuchi T. Matsuo T. Matsumura T. Tokunaga H. Brownlee M. Araki E. Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells: potential role in diabetic nephropathy. Diabetes. 2003;52:2570–2577. doi: 10.2337/diabetes.52.10.2570. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • Rests on an assumption: High glucose in cultured retinal, mesangial, or endothelial cells models the diabetic milieu in vivo.

  • May combine two claims.

    Premisecitation
    § 2. ROS and oxidative damage in insulin-sensitive target tissues

    In mitochondria from fatty liver of obese mice, GSH is increased and GPx enzyme activity is reduced.

    “Interestingly, mitochondria isolated from fatty liver of obese mice demonstrated opposite alterations, showing increased GSH and a reduction in GPx enzyme activity (336).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [336] Yang S. Zhu H. Li Y. Lin H. Gabrielson K. Trush MA. Diehl AM. Mitochondrial adaptations to obesity-related oxidant stress. Arch Biochem Biophys. 2000;378:259–268. doi: 10.1006/abbi.2000.1829. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § 1. Non–insulin-sensitive tissues (retina, renal, neural cells)

    Goto-Kakizaki diabetic rats show reduced tissue aconitase activity, a mitochondrial enzyme susceptible to inactivation by reactive oxygen, along with an increase in lipid peroxides.

    “This study showed a reduction in tissue aconitase activity, a mitochondrial enzyme susceptible to inactivation by reactive oxygen, along with an increase in lipid peroxides.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [275] Rosen P. Wiernsperger NF. Metformin delays the manifestation of diabetes and vascular dysfunction in Goto-Kakizaki rats by reduction of mitochondrial oxidative stress. Diabetes Metab Res Rev. 2006;22:323–330. doi: 10.1002/dmrr.623. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § 1. Non–insulin-sensitive tissues (retina, renal, neural cells)

    In human retinal endothelial cells, IL-1β or TNF-α stimulation induces ROS production, suggesting diabetes-related endothelial injury may relate more to cytokines than excess glucose.

    “In contrast to the lack of effect of glucose, these authors (43) found that stimulation by interleukin-1β or TNF-α did induce ROS production in human retinal endothelial cells, suggesting that diabetes-related endothelial injury may be related more to cytokine production than to excess glucose.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Busik JV. Mohr S. Grant MB. Hyperglycemia-induced reactive oxygen species toxicity to endothelial cells is dependent on paracrine mediators. Diabetes. 2008;57:1952–1965. doi: 10.2337/db07-1520. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 2. ROS and vascular cells

    Treating diabetic rats with Tempol abolished the diabetes-induced increase in vascular superoxide, malondialdehyde, and 8-epi-prostaglandin F(2α) and also the impairment in relaxation of aortic rings to acetylcholine.

    “Treating diabetic rats with Tempol, a stable superoxide dismutase mimetic, abolished the diabetes-induced increase in vascular superoxide, malondialdehyde, and 8-epi-prostaglandin F(2α) and also the impairment in relaxation of aortic rings to acetylcholine (232).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [232] Nassar T. Kadery B. Lotan C. Da'as N. Kleinman Y. Haj-Yehia A. Effects of the superoxide dismutase-mimetic compound tempol on endothelial dysfunction in streptozotocin-induced diabetic rats. Eur J Pharmacol. 2002;436:111–118. doi: 10.1016/s0014-2999(01)01566-7. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

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

    Premisecitation
    § VI. Mitochondrial Membrane Potential and Diabetes

    UCP3 is 73% homologous to UCP2 in humans and is predominantly expressed in human and rodent skeletal muscle and in rodent BAT.

    “UCP3 is 73% homologous to UCP2 in humans and is predominantly expressed in human and rodent skeletal muscle and in rodent BAT (32).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Boss O. Samec S. Paoloni-Giacobino A. Rossier C. Dulloo A. Seydoux J. Muzzin P. Giacobino JP. Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett. 1997;408:39–42. doi: 10.1016/s0014-5793(97)00384-0. [DOI] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § 2. ROS and vascular cells

    Treatment of genetically obese mice with CoPP ameliorated obesity, visceral and subcutaneous fat, increased adiponectin, and improved insulin sensitivity.

    “Further, treatment of genetically obese mice with CoPP ameliorated obesity, visceral, and subcutaneous fat, increased adiponectin, and improved insulin sensitivity (192).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] Li M. Kim DH. Tsenovoy PL. Peterson SJ. Rezzani R. Rodella LF. Aronow WS. Ikehara S. Abraham NG. Treatment of obese diabetic mice with a heme oxygenase inducer reduces visceral and subcutaneous adiposity, increases adiponectin levels, and improves insulin sensitivity and glucose tolerance. Diabetes. 2008;57:1526–1535. doi: 10.2337/db07-1764. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

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

    Premisecitation
    § VI. Mitochondrial Membrane Potential and Diabetes

    UCP1 is a 32-kDa protein encoded by a nuclear rather than a mitochondrial gene, is localized to the inner mitochondrial membrane, and is abundantly expressed in rodent brown adipose tissue.

    “UCP1 is a 32-kDa protein encoded by a nuclear rather than a mitochondrial gene, is localized to the inner mitochondrial membrane, and is abundantly expressed in rodent brown adipose tissue (300).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [300] Stuart JA. Cadenas S. Jekabsons MB. Roussel D. Br MD. Mitochondrial proton leak and the uncoupling protein 1 homologues. Biochim Biophys Acta. 2001;1504:144–158. doi: 10.1016/s0005-2728(00)00243-7. [DOI] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § VI. Mitochondrial Membrane Potential and Diabetes

    UCP2 is expressed in a variety of tissues, including adipose tissue, muscle, heart, liver, and pancreatic islets, and is responsive to nutritional regulation.

    “UCP2 is expressed in a variety of tissues, including adipose tissue, muscle, heart, liver, and pancreatic islets, and is responsive to nutritional regulation (31, 106) and, as discussed (Section IV.C.6), may be important in regulating insulin release.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Boss O. Hagen T. Lowell BB. Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. Diabetes. 2000;49:143–156. doi: 10.2337/diabetes.49.2.143. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [106] Fleury C. Neverova M. Collins S. Raimbault S. Champigny O. Levi-Meyrueis C. Bouillaud F. Seldin MF. Surwit RS. Ricquier D. Warden CH. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet. 1997;15:269–272. doi: 10.1038/ng0397-269. [DOI] [PubMed] [Google Scholar]

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

    Premisecitation
    § VI. Mitochondrial Membrane Potential and Diabetes

    "Mild uncoupling" has been proposed as a means of defense against mitochondrial oxidative stress.

    “Superoxide production by mitochondria may be sensitive to membrane potential, and “mild uncoupling” has been proposed as a means of defense against mitochondrial oxidative stress (295).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [295] Skulachev VP. Uncoupling: new approaches to an old problem of bioenergetics. Biochim Biophys Acta. 1998;1363:100–124. doi: 10.1016/s0005-2728(97)00091-1. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § C. Summary

    ROS contribute to defects in both insulin secretion and insulin action and to the long-term complications of diabetes.

    “ROS contribute to defects in both insulin secretion and insulin action and to the long-term complications of diabetes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisenone given
    § VI. Mitochondrial Membrane Potential and Diabetes

    UCP2 and UCP3 knockout mice are not obese or diabetic.

    “UCP2 and UCP3 KO mice are not obese or diabetic.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § 1. Lifestyle modification

    Calorie restriction prolongs the lifetime of rodents, nematodes, and maybe humans.

    “Calorie restriction is known to prolong the lifetime of rodents, nematodes, and maybe humans (265).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [265] Redman LM. Ravussin E. Endocrine alterations in response to calorie restriction in humans. Mol Cell Endocrinol. 2008;299:129–136. doi: 10.1016/j.mce.2008.10.014. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

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

    Premisecitation
    § VII. Coenzyme Q and Diabetes

    About one half of total body CoQ is synthesized endogenously, whereas the remainder derives from the diet.

    “About one half of total body CoQ is synthesized endogenously, whereas the remainder derives from the diet (113).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Ghirlanda G. Oradei A. Manto A. Lippa S. Uccioli L. Caputo S. Greco AV. Littarru GP. Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J Clin Pharmacol. 1993;33:226–229. doi: 10.1002/j.1552-4604.1993.tb03948.x. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § C. Summary

    UCP2 in pancreatic tissue and UCP3 in muscle and heart are important in the pathogenesis of diabetes.

    “UCP2 in pancreatic tissue and UCP3 in muscle and heart are important in the pathogenesis of diabetes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § VI. Mitochondrial Membrane Potential and Diabetes

    GDP-sensitive proton conductance triggered by superoxide or 4-HNE is not present in mitochondria from the muscle of UCP3 knockout mice or from the kidney of UCP2-deficient mice.

    “Importantly, GDP-sensitive proton conductance triggered by superoxide or 4-HNE is not present in mitochondria from the muscle of UCP3 knockout mice (91) or from the kidney of UCP2-deficient mice (176).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [91] Echtay KS. Esteves TC. Pakay JL. Jekabsons MB. Lambert AJ. Portero-Otin M. Pamplona R. Vidal-Puig AJ. Wang S. Roebuck SJ. Br MD. A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. EMBO J. 2003;22:4103–4110. doi: 10.1093/emboj/cdg412. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [176] Krauss S. Zhang CY. Scorrano L. Dalgaard LT. St-Pierre J. Grey ST. Lowell BB. Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction [see comment] J Clin Invest. 2003;112:1831–1842. doi: 10.1172/JCI19774. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

    Premisecitation
    § VI. Mitochondrial Membrane Potential and Diabetes

    UCP1 overexpression in BAE cells protected against ROS.

    “Work reported several years ago suggested that UCP1 overexpression in BAE cells protected against ROS (240).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [240] Novials A. Vidal J. Franco C. Ribera F. Sener A. Malaisse WJ. Gomis R. Mutation in the calcium-binding domain of the mitochondrial glycerophosphate dehydrogenase gene in a family of diabetic subjects. Biochem Biophys Res Commun. 1997;231:570–572. doi: 10.1006/bbrc.1997.6147. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Mitochondrial ROS measured by lucigenin fluorescence, dichlorodihydrofluorescein fluorescence, or EPR in isolated mitochondria or cells reflects pathologically relevant ROS in vivo.

  • May combine two claims.

    Interpretationreasoning
    § C. Summary

    UCP2 and UCP3 upregulation occurs at a cost of reduced ATP, which could result in loss of insulin secretory capacity by islet β cells or loss of function in heart and muscle.

    “Conversely, this occurs at a cost of reduced ATP, which could result in loss of insulin secretory capacity by islet β cells or loss of function in heart and in muscle.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 1. Lifestyle modification

    Exercise increases electron-transport activity in muscle, stimulates mitochondrial biogenesis through effects on PGC-1α, and improves sensitivity to insulin.

    “In this regard, exercise offers several benefits, including increased electron-transport activity in muscle, stimulation of mitochondrial biogenesis through effects on PGC-1α, and improved sensitivity to insulin (266, 269).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [266] Reznick RM. Shulman GI. The role of AMP-activated protein kinase in mitochondrial biogenesis. J Physiol. 2006;574:33–39. doi: 10.1113/jphysiol.2006.109512. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [269] Rockl KS. Witczak CA. Goodyear LJ. Signaling mechanisms in skeletal muscle: acute responses and chronic adaptations to exercise. IUBMB Life. 2008;60:145–153. doi: 10.1002/iub.21. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Interpretationreasoning
    § C. Summary

    UCP2 and UCP3 are induced by and appear protective against superoxide-induced damage.

    “These proteins are induced by and appear protective against superoxide-induced damage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 1. Lifestyle modification

    Exercise activates AMPK, which improves both glucose and fat oxidation.

    “Exercise also activates AMPK, which improves both glucose and fat oxidation (266).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [266] Reznick RM. Shulman GI. The role of AMP-activated protein kinase in mitochondrial biogenesis. J Physiol. 2006;574:33–39. doi: 10.1113/jphysiol.2006.109512. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

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

    Premisecitation
    § VII. Coenzyme Q and Diabetes

    In rats and mice, the predominant form of CoQ contains nine 5-carbon units and is designated CoQ9.

    “In rats and mice, unlike humans, the predominant form contains nine 5-carbon units and is designated CoQ9 (2, 297).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Aberg F. Appelkvist EL. Dallner G. Ernster L. Distribution and redox state of ubiquinones in rat and human tissues. Arch Biochem Biophys. 1992;295:230–234. doi: 10.1016/0003-9861(92)90511-t. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [297] Sohal RS. Forster MJ. Coenzyme Q, oxidative stress and aging. Mitochondrion. 2007;7(suppl):S103–S111. doi: 10.1016/j.mito.2007.03.006. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 1. Lifestyle modification

    Calorie restriction favors mitochondrial biogenesis, oxygen use and ATP formation, and expression of SIRT1, which activates PGC1-α.

    “How this is related to mitochondrial function is not clear, but evidence suggests that calorie restriction favors mitochondrial biogenesis, oxygen use and ATP formation, and expression of SIRT1, which activates PGC1-α (121, 203).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [121] Guarente L. Mitochondria: a nexus for aging, calorie restriction, and sirtuins? Cell. 2008;132:171–176. doi: 10.1016/j.cell.2008.01.007. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [203] Lopez-Lluch G. Hunt N. Jones B. Zhu M. Jamieson H. Hilmer S. Cascajo MV. Allard J. Ingram DK. Navas P. de Cabo R. Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci U S A. 2006;103:1768–1773. doi: 10.1073/pnas.0510452103. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § VII. Coenzyme Q and Diabetes

    Later studies with HPLC reported a reduction in liver and kidney mitochondrial CoQ content and an ∼75% reduction in heart mitochondria of 8-week STZ-diabetic rats.

    “However, later studies with HPLC reported a reduction in liver (180) and kidney (180, 223) mitochondrial CoQ content and an ∼75% reduction in heart mitochondria of 8-week STZ-diabetic rats (180).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [180] Kucharska J. Braunova Z. Ulicna O. Zlatos L. Gvozdjakova A. Deficit of coenzyme Q in heart and liver mitochondria of rats with streptozotocin-induced diabetes. Physiol Res. 2000;49:411–418. [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [223] Moreira PI. Rolo AP. Sena C. Seica R. Oliveira CR. Santos MS. Insulin attenuates diabetes-related mitochondrial alterations: a comparative study. Med Chem. 2006;2:299–308. doi: 10.2174/157340606776930754. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.
    • Rests on an assumption: Mitochondrial CoQ content measured by HPLC or cytochrome c oxidation reflects functional mitochondrial CoQ status.

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

    Premisecitation
    § VII. Coenzyme Q and Diabetes

    CoQ is present in Golgi vesicles and lysosomes and in other membrane structures in addition to mitochondrial membranes.

    “In addition to mitochondrial membranes, CoQ also is present in Golgi vesicles and lysosomes and is present in other membrane structures as well (315).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [315] Turunen M. Olsson J. Dallner G. Metabolism and function of coenzyme Q. Biochim Biophys Acta. 2004;1660:171–199. doi: 10.1016/j.bbamem.2003.11.012. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    Use of thiazolidinediones is limited by a tendency for weight gain due to increased subcutaneous but not intraabdominal fat and by fluid retention by an uncertain mechanism.

    “Interestingly, however, the use of thiazolidinediones is limited by a tendency for weight gain in part because of increased subcutaneous, but not intraabdominal, fat (337) and, in part, because of fluid retention by an uncertain mechanism (29).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [337] Yang X. Smith U. Adipose tissue distribution and risk of metabolic disease: does thiazolidinedione-induced adipose tissue redistribution provide a clue to the answer? Diabetologia. 2007;50:1127–1139. doi: 10.1007/s00125-007-0640-1. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [29] Berlie HD. Kalus JS. Jaber LA. Thiazolidinediones and the risk of edema: a meta-analysis. Diabetes Res Clin Pract. 2007;76:279–289. doi: 10.1016/j.diabres.2006.09.010. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

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

    Interpretationreasoning
    § C. Summary

    Mild uncoupling reduces ROS production through reduced potential, but the issue is still controversial.

    “Reasons exist to believe that mild uncoupling reduces ROS production through reduced potential; however, the issue is still controversial.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § VI. Mitochondrial Membrane Potential and Diabetes

    A small, chemically induced 10-mV decrease in mitochondrial membrane potential in intact rat cerebellar cells did not affect mitochondrial superoxide production and actually increased cytoplasmic superoxide.

    “Recent work by this group (151) showed that a small, chemically induced 10-mV decrease in mitochondrial membrane potential in intact cells (rat cerebellar cells) did not affect mitochondrial superoxide production and actually increased cytoplasmic superoxide.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [151] Johnson-Cadwell LI. Jekabsons MB. Wang A. Polster BM. Nicholls DG. “Mild uncoupling” does not decrease mitochondrial superoxide levels in cultured cerebellar granule neurons but decreases spare respiratory capacity and increases toxicity to glutamate and oxidative stress. J Neurochem. 2007;101:1619–1631. doi: 10.1111/j.1471-4159.2007.04516.x. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Mitochondrial ROS measured by lucigenin fluorescence, dichlorodihydrofluorescein fluorescence, or EPR in isolated mitochondria or cells reflects pathologically relevant ROS in vivo.

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

    Premisenone given
    § VII. Coenzyme Q and Diabetes

    CoQ is fat soluble and localizes to hydrophobic regions within mitochondrial membranes wherein it is mobile and functions as an electron carrier.

    “CoQ is fat soluble and localizes to hydrophobic regions within mitochondrial membranes wherein it is mobile and functions as an electron carrier.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    Pioglitazone induces mitochondrial biogenesis in adipose tissue as well as expression of PGC-1α and genes in the fatty acid-oxidation pathway.

    “The thiazolidinedione, pioglitazone, was found to induce mitochondrial biogenesis in adipose tissue as well as expression of PGC-1α and genes in the fatty acid–oxidation pathway (30).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Bogacka I. Xie H. Bray GA. Smith SR. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes. 2005;54:1392–1399. doi: 10.2337/diabetes.54.5.1392. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § VI. Mitochondrial Membrane Potential and Diabetes

    Type 2 diabetes is characterized by decreased oxidative phosphorylation activity, altered mitochondrial morphology, and damage to mitochondrial DNA.

    “Consistent with this finding, type 2 diabetes also is characterized by decreased oxidative phosphorylation activity (161), altered mitochondrial morphology (161), and damage to mitochondrial DNA (197).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [161] Kelley DE. He J. Menshikova EV. Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes. 2002;51:2944–2950. doi: 10.2337/diabetes.51.10.2944. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [197] Liang P. Hughes V. Fukagawa NK. Increased prevalence of mitochondrial DNA deletions in skeletal muscle of older individuals with impaired glucose tolerance: possible marker of glycemic stress. Diabetes. 1997;46:920–923. doi: 10.2337/diab.46.5.920. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Interpretationreasoning
    § C. Summary

    UCP2 and UCP3 are upregulated under conditions of excess fatty acid flux and counter lipotoxicity.

    “UCP2 and UCP3 are upregulated under conditions of excess fatty acid flux and counter lipotoxicity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § VI. Mitochondrial Membrane Potential and Diabetes

    Humans with a splice-donor mutation in the UCP3 gene have decreased UCP3 levels and diminished fat oxidation.

    “In addition, humans with a splice-donor mutation in the UCP3 gene have decreased UCP3 levels and diminished fat oxidation (17).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Argyropoulos G. Brown AM. Willi SM. Zhu J. He Y. Reitman M. Gevao SM. Spruill I. Garvey WT. Effects of mutations in the human uncoupling protein 3 gene on the respiratory quotient and fat oxidation in severe obesity and type 2 diabetes. J Clin Invest. 1998;102:1345–1351. doi: 10.1172/JCI4115. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    In vivo, α-lipoic acid is enzymatically reduced to dihydrolipoic acid and is an effective scavenger of superoxide.

    “In vivo, α-lipoic acid is enzymatically reduced to dihydrolipoic acid and, as such, is an effective scavenger of superoxide (343).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [343] Yorek MA. Coppey LJ. Gellett JS. Davidson EP. Lund DD. Effect of fidarestat and alpha-lipoic acid on diabetes-induced epineurial arteriole vascular dysfunction. Exp Diabesity Res. 2004;5:123–135. doi: 10.1080/15438600490277824. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    Oral α-lipoic acid improved peripheral neuropathy but caused nausea, vomiting, and vertigo.

    “Oral α-lipoic acid also improved peripheral neuropathy but caused nausea, vomiting, and vertigo (351).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [351] Ziegler D. Ametov A. Barinov A. Dyck PJ. Gurieva I. Low PA. Munzel U. Yakhno N. Raz I. Novosadova M. Maus J. Samigullin R. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006;29:2365–2370. doi: 10.2337/dc06-1216. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    Glucose oxidation, as well as fat oxidation, was increased in cardiac muscle of ACC2 knockout mice.

    “Consistent with this concept, glucose oxidation, as well as fat oxidation, was increased in cardiac muscle of ACC2 KO mice (99).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Essop MF. Camp HS. Choi CS. Sharma S. Fryer RM. Reinhart GA. Guthrie PH. Bentebibel A. Gu Z. Shulman GI. Taegtmeyer H. Wakil SJ. Abu-Elheiga L. Reduced heart size and increased myocardial fuel substrate oxidation in ACC2 mutant mice. Am J Physiol Heart Circ Physiol. 2008;295:H256–H265. doi: 10.1152/ajpheart.91489.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    H2O2 appears to activate AMPK through an increase in the AMP/ATP ratio and by threonine phosphorylation.

    “H2O2 appears to activate AMPK through an increase in the AMP/ATP ratio and by threonine phosphorylation (60).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Choi SL. Kim SJ. Lee KT. Kim J. Mu J. Birnbaum MJ. Soo Kim S. Ha J. The regulation of AMP-activated protein kinase by H(2)O(2) Biochem Biophys Res Commun. 2001;287:92–97. doi: 10.1006/bbrc.2001.5544. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    Attempts to treat diabetes with CoQ in rodents or humans have met with variable results, showing either a beneficial effect on markers of oxidative damage or glycemia, no effect, or mixed results depending on tissue and markers of oxidative damage.

    “Attempts to treat diabetes, either in rodents (220, 264) or in humans (13, 133, 220, 302), have met with variable results, showing either a beneficial effect on markers of oxidative damage (182, 302) or glycemia (220), no effect (13, 133), or mixed results depending on tissue and markers of oxidative damage (264).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [220] Modi K. Santani DD. Goyal RK. Bhatt PA. Effect of coenzyme Q10 on catalase activity and other antioxidant parameters in streptozotocin-induced diabetic rats. Biol Trace Elem Res. 2006;109:25–34. doi: 10.1385/BTER:109:1:025. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [264] Rauscher FM. Sanders RA. Watkins JB., 3rd Effects of coenzyme Q10 treatment on antioxidant pathways in normal and streptozotocin-induced diabetic rats. J Biochem Mol Toxicol. 2001;15:41–46. doi: 10.1002/1099-0461(2001)15:1<41::aid-jbt5>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [13] Andersen CB. Henriksen JE. Hother-Nielsen O. Vaag A. Mortensen SA. Beck-Nielsen H. The effect of coenzyme Q10 on blood glucose and insulin requirement in patients with insulin dependent diabetes mellitus. Mol Aspects Med. 1997;18(suppl):S307–S309. doi: 10.1016/s0098-2997(97)00010-1. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    Intraperitoneal CoQ treatment for 7 weeks improved the respiratory-control ratio and the ADP/O ratio in brain mitochondria and slightly reduced glucose in diabetic Goto-Kakizaki rats treated with a neurotoxin.

    “Further, intraperitoneal CoQ treatment for 7 weeks reportedly improved the respiratory-control ratio and the ADP/O ratio in brain mitochondria and slightly reduced glucose in diabetic Goto-Kakizaki rats treated with a neurotoxin (224).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [224] Moreira PI. Santos MS. Sena C. Nunes E. Seica R. Oliveira CR. CoQ10 therapy attenuates amyloid beta-peptide toxicity in brain mitochondria isolated from aged diabetic rats. Exp Neurol. 2005;196:112–119. doi: 10.1016/j.expneurol.2005.07.012. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    Metformin has mitigating effects on ROS production, activates AMPK, and favors mitochondrial proliferation.

    “Metformin has mitigating effects on ROS production, activates AMPK, and favors mitochondrial proliferation (181, 353).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [181] Kukidome D. Nishikawa T. Sonoda K. Imoto K. Fujisawa K. Yano M. Motoshima H. Taguchi T. Matsumura T. Araki E. Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes. 2006;55:120–127. [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [353] Zou MH. Kirkpatrick SS. Davis BJ. Nelson JS. Wiles WGt. Schlattner U. Neumann D. Brownlee M. Freeman MB. Goldman MH. Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo: role of mitochondrial reactive nitrogen species. J Biol Chem. 2004;279:43940–43951. doi: 10.1074/jbc.M404421200. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    In mice, resveratrol improves insulin resistance, protects against diet-induced obesity, induces genes for oxidative phosphorylation, and activates PGC-1α.

    “In mice, resveratrol improves insulin resistance, protects against diet-induced obesity, induces genes for oxidative phosphorylation, and activates PGC-1α (22, 184).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Baur JA. Pearson KJ. Price NL. Jamieson HA. Lerin C. Kalra A. Prabhu VV. Allard JS. Lopez-Lluch G. Lewis K. Pistell PJ. Poosala S. Becker KG. Boss O. Gwinn D. Wang M. Ramaswamy S. Fishbein KW. Spencer RG. Lakatta EG. Le Couteur D. Shaw RJ. Navas P. Puigserver P. Ingram DK. de Cabo R. Sinclair DA. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444:337–342. doi: 10.1038/nature05354. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [184] Lagouge M. Argmann C. Gerhart-Hines Z. Meziane H. Lerin C. Daussin F. Messadeq N. Milne J. Lambert P. Elliott P. Geny B. Laakso M. Puigserver P. Auwerx J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006;127:1109–1122. doi: 10.1016/j.cell.2006.11.013. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

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

    Premisecitation
    § 2. Pharmacologic intervention

    Water-soluble ascorbic acid (vitamin C) is widely marketed for its antioxidant properties and appears to regenerate reduced vitamin E.

    “Water-soluble ascorbic acid (vitamin C) is widely marketed for its antioxidant properties (212, 296) and, as stated earlier, appears to regenerate reduced vitamin E.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [212] May JM. Qu ZC. Li X. Ascorbic acid blunts oxidant stress due to menadione in endothelial cells. Arch Biochem Biophys. 2003;411:136–144. doi: 10.1016/s0003-9861(02)00715-4. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [296] Smith AR. Visioli F. Hagen TM. Vitamin C matters: increased oxidative stress in cultured human aortic endothelial cells without supplemental ascorbic acid. FASEB J. 2002;16:NIL_125–NIL_144. doi: 10.1096/fj.01-0825fje. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    Vitamin E did not improve cardiovascular outcomes in a large multicenter trial and actually increased congestive heart failure.

    “However, despite this, vitamin E did not improve cardiovascular outcomes in a large multicenter trial and actually increased congestive heart failure (201).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] Lonn E. Bosch J. Yusuf S. Sheridan P. Pogue J. Arnold JM. Ross C. Arnold A. Sleight P. Probstfield J. Dagenais GR. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293:1338–1347. doi: 10.1001/jama.293.11.1338. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    Resveratrol has anti-aging effects in lower organisms, reduces signs of aging in mice, and extends survival.

    “Resveratrol, an ingredient in red wines, is a polyphenolic SIRT1 activator that, like calorie restriction, has anti-aging effects in lower organisms (22, 143, 331), reduces signs of aging in mice (248), and extends survival (22).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22] Baur JA. Pearson KJ. Price NL. Jamieson HA. Lerin C. Kalra A. Prabhu VV. Allard JS. Lopez-Lluch G. Lewis K. Pistell PJ. Poosala S. Becker KG. Boss O. Gwinn D. Wang M. Ramaswamy S. Fishbein KW. Spencer RG. Lakatta EG. Le Couteur D. Shaw RJ. Navas P. Puigserver P. Ingram DK. de Cabo R. Sinclair DA. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444:337–342. doi: 10.1038/nature05354. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [143] Howitz KT. Bitterman KJ. Cohen HY. Lamming DW. Lavu S. Wood JG. Zipkin RE. Chung P. Kisielewski A. Zhang LL. Scherer B. Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003;425:191–196. doi: 10.1038/nature01960. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [331] Wood JG. Rogina B. Lavu S. Howitz K. Helfand SL. Tatar M. Sinclair D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004;430:686–689. doi: 10.1038/nature02789. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    Oral decylQ, a CoQ analogue, reduced plasma malondialdehyde, blood pressure, and cholesterol in an SHR rat model prone to stroke.

    “In another report, oral decylQ (a CoQ analogue) reduced plasma malondialdehyde, blood pressure, and cholesterol in an SHR rat model prone to stroke (229).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [229] Murad LB. Guimaraes MR. Vianna LM. Effects of decylubiquinone (coenzyme Q10 analog) supplementation on SHRSP. Biofactors. 2007;30:13–18. doi: 10.1002/biof.5520300102. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    Angiotensin-receptor blockers or inhibitors of angiotensin-converting enzyme improve insulin sensitivity and enhance mitochondrial biogenesis and reduce oxidative stress.

    “Another group of drugs that improve insulin sensitivity and enhance mitochondrial biogenesis are the angiotensin-receptor blockers or inhibitors of angiotensin-converting enzyme. These agents also reduce oxidative stress, although the mechanisms still require clarification (164).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] Kim JA. Wei Y. Sowers JR. Role of mitochondrial dysfunction in insulin resistance. Circ Res. 2008;102:401–414. doi: 10.1161/CIRCRESAHA.107.165472. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    Prolonged vitamin E supplementation offered no benefit or even had vasoconstrictive effects on endothelial function in diabetes.

    “Moreover, despite reports that short-term vitamin E may have beneficial effects on endothelial function in diabetes, prolonged vitamin E supplementation offered no benefit or even had vasoconstrictive effects on endothelial function (23, 95).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Beckman JA. Goldfine AB. Gordon MB. Garrett LA. Keaney JF., Jr Creager MA. Oral antioxidant therapy improves endothelial function in Type 1 but not Type 2 diabetes mellitus. Am J Physiol Heart Circ Physiol. 2003;285:H2392–H2398. doi: 10.1152/ajpheart.00403.2003. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [95] Economides PA. Khaodhiar L. Caselli A. Caballero AE. Keenan H. Bursell SE. King GL. Johnstone MT. Horton ES. Veves A. The effect of vitamin E on endothelial function of micro- and macrocirculation and left ventricular function in type 1 and type 2 diabetic patients. Diabetes. 2005;54:204–211. doi: 10.2337/diabetes.54.1.204. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    CoQ effectively reduced elevated insulin concentrations, improved endothelial function, and reduced markers of oxidative damage when administered through the drinking water to variants of the spontaneously hypertensive rat that have features of the metabolic syndrome.

    “CoQ effectively reduced elevated insulin concentrations, improved endothelial function, and reduced markers of oxidative damage when administered through the drinking water to variants of the spontaneously hypertensive rat (SHR), that have features of the metabolic syndrome (182).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [182] Kunitomo M. Yamaguchi Y. Kagota S. Otsubo K. Beneficial effect of coenzyme Q10 on increased oxidative and nitrative stress and inflammation and individual metabolic components developing in a rat model of metabolic syndrome. J Pharmacol Sci. 2008;107:128–137. doi: 10.1254/jphs.fp0072365. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

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

    Premisenone given
    § 2. Pharmacologic intervention

    Metformin, unlike insulin or insulin secretagogues, is not associated with weight gain.

    “In clinical use, metformin, unlike insulin or insulin secretagogues, is not associated with weight gain.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    Other related small molecules are more potent than resveratrol to enhance the action of SIRT1 on substrates for deacetylation and improve insulin sensitivity in obese rodents.

    “Other related small molecules are more potent than resveratrol to enhance the action of SIRT1 on substrates for deacetylation (218). These compounds also improve insulin sensitivity in obese rodents (218).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [218] Milne JC. Lambert PD. Schenk S. Carney DP. Smith JJ. Gagne DJ. Jin L. Boss O. Perni RB. Vu CB. Bemis JE. Xie R. Disch JS. Ng PY. Nunes JJ. Lynch AV. Yang H. Galonek H. Israelian K. Choy W. Iffland A. Lavu S. Medvedik O. Sinclair DA. Olefsky JM. Jirousek MR. Elliott PJ. Westphal CH. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007;450:712–716. doi: 10.1038/nature06261. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • Rests on an assumption: Findings from rodent models of diabetes can be extrapolated to human diabetes.

  • May combine two claims.

    Premisecitation
    § C. Mitochondria-targeted antioxidants

    Tempol both prevented β-cell dysfunction and increased superoxide induced by hyperglycemia.

    “Tempol both prevented β-cell dysfunction and increased superoxide induced by hyperglycemia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [307] Tang C. Han P. Oprescu AI. Lee SC. Gyulkhandanyan AV. Chan GN. Wheeler MB. Giacca A. Evidence for a role of superoxide generation in glucose-induced beta-cell dysfunction in vivo. Diabetes. 2007;56:2722–2731. doi: 10.2337/db07-0279. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Mitochondria-targeted antioxidants

    MitoQ reduced ROS and reduced activation of the mitogen-activated protein kinase, p42ERK2, in endothelial cells after hypoxic stress.

    “Moreover, mitoQ also reduced ROS and reduced activation of the mitogen-activated protein kinase, p42ERK2, in endothelial cells after hypoxic stress (283).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [283] Schafer M. Schafer C. Ewald N. Piper HM. Noll T. Role of redox signaling in the autonomous proliferative response of endothelial cells to hypoxia. Circ Res. 2003;92:1010–1015. doi: 10.1161/01.RES.0000070882.81508.FC. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

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

    Premisecitation
    § C. Mitochondria-targeted antioxidants

    Two such compounds incorporating ubiquinone or vitamin E, termed mitoQ and mitoVit E, have been synthesized.

    “Two such compounds (alkyltriphenylphosphonium cations) incorporating ubiquinone or vitamin E, termed mitoQ and mitoVit E, respectively, have been synthesized (162).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Kelso GF. Porteous CM. Coulter CV. Hughes G. Porteous WK. Ledgerwood EC. Smith RA. Murphy MP. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chem. 2001;276:4588–4596. doi: 10.1074/jbc.M009093200. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 2. Pharmacologic intervention

    Inducers of heme oxygenase mitigated islet damage, improved glucose in diabetic mice, and improved obesity and insulin sensitivity in genetically obese mice.

    “As indicated in Section V, inducers of heme oxygenase mitigated islet damage, improved glucose in diabetic mice (193), and improved obesity and insulin sensitivity in genetically obese mice (192).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [193] Li M. Peterson S. Husney D. Inaba M. Guo K. Terada E. Morita T. Patil K. Kappas A. Ikehara S. Abraham NG. Interdiction of the diabetic state in NOD mice by sustained induction of heme oxygenase: possible role of carbon monoxide and bilirubin. Antioxid Redox Signal. 2007;9:855–863. doi: 10.1089/ars.2007.1568. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [192] Li M. Kim DH. Tsenovoy PL. Peterson SJ. Rezzani R. Rodella LF. Aronow WS. Ikehara S. Abraham NG. Treatment of obese diabetic mice with a heme oxygenase inducer reduces visceral and subcutaneous adiposity, increases adiponectin levels, and improves insulin sensitivity and glucose tolerance. Diabetes. 2008;57:1526–1535. doi: 10.2337/db07-1764. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Mitochondria-targeted antioxidants

    Tempol was observed to prevent excess total as well as mitochondrial superoxide.

    “Tempol was observed to prevent excess total as well as mitochondrial superoxide, as evidenced by the effect of this agent on DHE and mitochondria-targeted DHE fluorescence (see Section III.E).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [307] Tang C. Han P. Oprescu AI. Lee SC. Gyulkhandanyan AV. Chan GN. Wheeler MB. Giacca A. Evidence for a role of superoxide generation in glucose-induced beta-cell dysfunction in vivo. Diabetes. 2007;56:2722–2731. doi: 10.2337/db07-0279. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning
    § C. Mitochondria-targeted antioxidants

    DHPA fluorescence measures matrix superoxide largely from complex I, whereas EPR detects superoxide released external to mitochondria, largely from complex III.

    “Based on the considerations depicted in Fig. 6 (Section III.D), DHPA fluorescence measures matrix superoxide largely from complex I, whereas EPR detects superoxide released external to mitochondria, largely from complex III.”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § 2. Pharmacologic intervention

    NAC is used to mitigate contrast-induced nephropathy in diabetes patients undergoing coronary angiography.

    “NAC also is used to mitigate contrast-induced nephropathy in diabetes patients undergoing coronary angiography (150).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Jo SH. Koo BK. Park JS. Kang HJ. Kim YJ. Kim HL. Chae IH. Choi DJ. Sohn DW. Oh BH. Park YB. Choi YS. Kim HS. N-acetylcysteine versus ascorbic acid for preventing contrast-induced nephropathy in patients with renal insufficiency undergoing coronary angiography NASPI study: a prospective randomized controlled trial. Am Heart J. 2009;157:576–583. doi: 10.1016/j.ahj.2008.11.010. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Mitochondria-targeted antioxidants

    Oral administration of mitoQ to normal male rats protected heart muscle function, prevented myocardial cell death, and improved the respiratory-control ratio in rats subject to ischemia/reperfusion injury.

    “Oral administration of mitoQ (500 μM in drinking water administered ad libitum) to normal male rats protected heart muscle function, prevented myocardial cell death, and improved the respiratory-control ratio (state 3 to state 4 respiration) in rats subject to ischemia/reperfusion injury (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Adlam VJ. Harrison JC. Porteous CM. James AM. Smith RA. Murphy MP. Sammut IA. Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. FASEB J. 2005;19:1088–1095. doi: 10.1096/fj.05-3718com. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

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

    Premisecitation
    § 2. Pharmacologic intervention

    NAC interacts with multiple radical species, forming NAC disulfide as the end product.

    “NAC interacts with multiple radical species, forming NAC disulfide as the end product (71).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Cotgreave IA. N-acetylcysteine: pharmacological considerations and experimental and clinical applications. Adv Pharmacol. 1997;38:205–227. [PubMed] [Google Scholar]

      Not checked in the free run.

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

    Interpretationnone given
    § C. Mitochondria-targeted antioxidants

    Although mitoQ appears to have protective effects in certain cell types, the mechanism of action is not well defined and appears complex.

    “Although mitoQ appears to have protective effects in certain cell types, the mechanism of action is not well defined and appears complex.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § C. Mitochondria-targeted antioxidants

    Such peptides reduce intracellular ROS and cell death in neuronal and pancreatic islet cells and reduce skeletal myocyte H2O2 production and preserve insulin sensitivity in rats fed a high-fat diet.

    “Such peptides reduce intracellular ROS and cell death in neuronal (256) and pancreatic islet cells (309) and recently were reported to reduce skeletal myocyte H2O2 production and to preserve insulin sensitivity in rats fed a high-fat diet (14).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [256] Petri S. Kiaei M. Damiano M. Hiller A. Wille E. Manfredi G. Calingasan NY. Szeto HH. Beal MF. Cell-permeable peptide antioxidants as a novel therapeutic approach in a mouse model of amyotrophic lateral sclerosis. J Neurochem. 2006;98:1141–1148. doi: 10.1111/j.1471-4159.2006.04018.x. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [309] Thomas DA. Stauffer C. Zhao K. Yang H. Sharma VK. Szeto HH. Suthanthiran M. Mitochondrial targeting with antioxidant peptide SS-31 prevents mitochondrial depolarization, reduces islet cell apoptosis, increases islet cell yield, and improves posttransplantation function. J Am Soc Nephrol. 2007;18:213–222. doi: 10.1681/ASN.2006080825. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [14] Anderson EJ. Lustig ME. Boyle KE. Woodlief TL. Kane DA. Lin CT. Price JW., 3rd Kang L. Rabinovitch PS. Szeto HH. Houmard JA. Cortright RN. Wasserman DH. Neufer PD. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest. 2009 doi: 10.1172/JCI37048. [Epub ahead of print]. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Mitochondria-targeted antioxidants

    Tempol is an SOD mimetic that has been administered to rodents, apparently without toxicity.

    “Tempol is an SOD mimetic that has been administered to rodents, apparently without toxicity (308).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [308] Thiemermann C. Membrane-permeable radical scavengers (tempol) for shock, ischemia-reperfusion injury, and inflammation. Crit Care Med. 2003;31:S76–S84. doi: 10.1097/00003246-200301001-00011. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Mitochondria-targeted antioxidants

    In another study of rats infused with oleate for 48 h, co-infusion of Tempol improved insulin secretion and mitigated oxidative stress in islets subsequently studied ex vivo.

    “In another study of rats infused with oleate for 48 h, co-infusion of Tempol improved insulin secretion and mitigated oxidative stress in islets subsequently studied ex vivo (245).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [245] Oprescu AI. Bikopoulos G. Naassan A. Allister EM. Tang C. Park E. Uchino H. Lewis GF. Fantus IG. Rozakis-Adcock M. Wheeler MB. Giacca A. Free fatty acid-induced reduction in glucose-stimulated insulin secretion: evidence for a role of oxidative stress in vitro and in vivo. Diabetes. 2007;56:2927–2937. doi: 10.2337/db07-0075. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Mitochondria-targeted antioxidants

    These peptides also possess potent opioid-receptor affinity and activity.

    “Unfortunately, these peptides also possess potent opioid-receptor affinity and activity (285, 347, 348).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [285] Schiller PW. Nguyen TM. Berezowska I. Dupuis S. Weltrowska G. Chung NN. Lemieux C. Synthesis and in vitro opioid activity profiles of DALDA analogues. Eur J Med Chem. 2000;35:895–901. doi: 10.1016/s0223-5234(00)01171-5. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [347] Zhao GM. Qian X. Schiller PW. Szeto HH. Comparison of [Dmt1]DALDA and DAMGO in binding and G protein activation at μ, d, and κ opioid receptors. J Pharmacol Exp Ther. 2003;307:947–954. doi: 10.1124/jpet.103.054775. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [348] Zhao K. Luo G. Zhao GM. Schiller PW. Szeto HH. Transcellular transport of a highly polar 3+ net charge opioid tetrapeptide. J Pharmacol Exp Ther. 2003;304:425–432. doi: 10.1124/jpet.102.040147. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Mitochondria-targeted antioxidants

    Peptides containing tyrosine residues have been found effectively to scavenge oxygen radicals and peroxynitrite and to inhibit lipid peroxidation.

    “Peptides containing tyrosine residues have been found effectively to scavenge oxygen radicals and peroxynitrite and to inhibit lipid peroxidation (304, 349).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [304] Szeto HH. Development of mitochondria-targeted aromatic-cationic peptides for neurodegenerative diseases. Ann N Y Acad Sci. 2008;1147:112–121. doi: 10.1196/annals.1427.013. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [349] Zhao K. Zhao GM. Wu D. Soong Y. Birk AV. Schiller PW. Szeto HH. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem. 2004;279:34682–34690. doi: 10.1074/jbc.M402999200. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Mitochondria-targeted antioxidants

    Tempol reportedly reduced renal mesangial expansion and decreased transforming growth factor β in diabetic rats.

    “The agent reportedly reduced renal mesangial expansion and decreased transforming growth factor β in diabetic rats (18).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Asaba K. Tojo A. Onozato ML. Goto A. Fujita T. Double-edged action of SOD mimetic in diabetic nephropathy. J Cardiovasc Pharmacol. 2007;49:13–19. doi: 10.1097/FJC.0b013e31802b6530. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given
    § IX. Summary

    Mitochondria play a primary role in the etiology of genetic forms of 'mitochondrial' diabetes.

    “Mitochondria also play a primary role in the etiology of genetic forms of “mitochondrial” diabetes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § C. Mitochondria-targeted antioxidants

    Eight weeks of subcutaneous Tempol treatment mitigated endothelial dysfunction as well as oxidative damage to vascular cells in rats with STZ-diabetes.

    “In another report, 8 weeks of subcutaneous Tempol treatment was found to mitigate endothelial dysfunction as well as oxidative damage to vascular cells in rats with STZ-diabetes (232).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [232] Nassar T. Kadery B. Lotan C. Da'as N. Kleinman Y. Haj-Yehia A. Effects of the superoxide dismutase-mimetic compound tempol on endothelial dysfunction in streptozotocin-induced diabetic rats. Eur J Pharmacol. 2002;436:111–118. doi: 10.1016/s0014-2999(01)01566-7. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given
    § IX. Summary

    At the islet β-cell level, acute insulin release is regulated by mitochondrial ATP production and mitochondrial ROS may contribute to the long-term deterioration of insulin secretory capacity seen in type 2 diabetes.

    “At the islet β-cell level, acute insulin release is regulated by mitochondrial ATP production and mitochondrial ROS may contribute to the long-term deterioration of insulin secretory capacity seen in type 2 diabetes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given
    § IX. Summary

    ROS appear important in the autoimmune destruction that characterizes type 1 diabetes, as well as in the pathophysiology of the long-term complications that characterize both classes of diabetes.

    “Moreover, ROS appear important in the autoimmune destruction that characterizes type 1 diabetes, as well as in the pathophysiology of the long-term complications that characterize both classes of diabetes.”
    Quote in the paperNot a substantial claim
152 of 152

  • The paper relies on this without support.

    Type 2 diabetes is associated with both impaired insulin action at target tissues and impaired insulin release.

    “Type 2 diabetes is associated with both impaired insulin action at target tissues and impaired insulin release.”

  • The paper relies on this without support.

    Defects in insulin action and insulin release are evident early in the course of type 2 diabetes.

    “Defects at both levels are evident early in the course of the disorder”

  • The paper relies on this without support.

    Mitochondria play a role in both impaired insulin action and impaired insulin release in type 2 diabetes.

    “evidence suggests that mitochondria play a role in both processes.”

  • The paper relies on this without support.

    Type 1 diabetes results primarily from autoimmune β-cell destruction.

    “In contrast, type 1 diabetes results primarily from autoimmune β-cell destruction.”

  • The paper relies on this without support.

    Mitochondria are important in type 1 diabetes in treatment of the disorder and in prevention of long-term consequences.

    “Nonetheless, mitochondria also are important in type 1 diabetes, if not in pathogenesis, then in treatment of the disorder and in prevention of long-term consequences.”

  • The paper relies on this without support.

    Both type 1 and type 2 diabetes, and less common forms, are associated with similar long-term complications that at least in part result from pathogenic processes at the mitochondrial level.

    “Both type 1 and type 2 diabetes, and less common forms as well, are associated with similar long-term complications that, at least in part, appear to result from pathogenic processes at the mitochondrial level.”

  • The paper relies on this without support.

    Qualitative, quantitative, and functional perturbations in mitochondria affect the cause and complications of diabetes.

    “Qualitative, quantitative, and functional perturbations in mitochondria have been identified and affect the cause and complications of diabetes.”

  • The paper relies on this without support.

    Reactive oxygen species per se are important in the pathophysiology of diabetes and its complications.

    “Evidence is accumulating that these radicals per se are important in the pathophysiology of diabetes and its complications.”

  • The paper relies on this without support.

    Cyclosporin A inhibits the mitochondrial permeability transition pore by interacting with cyclophilin D, and the pore requires calcium for opening.

    “Cyclosporin A, which interacts with the matrix protein cyclophilin D, inhibits the MPTP. The pore requires calcium for opening.”

  • The paper relies on this without support.

    Most intact-cell studies do not separate mitochondrial from cytoplasmic reactive oxygen species.

    “However, most intact-cell studies do not separate mitochondrial from cytoplasmic ROS.”

  • The paper relies on this without support.

    MitoSOX is a dihydroethidine derivative conjugated to triphenylphosphonium, resulting in potential-dependent accumulation of the probe in the mitochondrial matrix.

    “MitoSOX is a DHE derivative conjugated to the cation triphenylphosphonium, resulting in potential-dependent accumulation of the probe in the mitochondrial matrix.”

  • The paper relies on this without support.

    Oxidative damage to DNA can cause structural modifications of nucleotide bases or cross-linking, leading to gene mutation and cell damage.

    “Oxidative damage to DNA can cause structural modifications of the nucleotide bases or by cross-linking. This can lead to gene mutation and cell damage.”

  • The paper relies on this without support.

    Findings from rodent models of diabetes are applicable to human diabetes.

    “To the extent that these findings might be applicable to human type 2 diabetes, it is possible that reduced adipose mitochondrial function may result in a lack of suppression of lipolysis.”

  • The paper relies on this without support.

    Markers of lipid peroxidation (e.g., 8-isoprostane, 4-HNE) reflect mitochondrial oxidative damage in diabetes.

    “Certain methods can be used to measure oxidative damage specifically within mitochondria. One method is to determine the activity of the aconitase enzyme, a protein that is highly sensitive to oxidative damage (110).”

  • The authors state this as an assumption.

    Metabolism of glucose or fatty acids generates high levels of substrate flux to mitochondria and, consequently, greater overall electron-transport activity and more electron leak.

    “The supposition is that metabolism of these nutrients generates high levels of substrate flux to mitochondria and, consequently, greater overall electron-transport activity and more electron leak.”

  • The paper relies on this without support.

    Insulin deficiency is associated with increased circulating fatty acids and accelerated delivery to mitochondria.

    “Insulin deficiency, like high-fat feeding, is also a state associated with increased circulating fatty acids and accelerated delivery to mitochondria.”

  • The paper relies on this without support.

    Circulating free fatty acid concentrations are increased because of insulin resistance or decreased circulating insulin or both.

    “Moreover, circulating FFA concentrations are increased because of insulin resistance or decreased circulating insulin or both.”

  • The paper relies on this without support.

    Glucose oxidation provides less ATP per molecule oxidized and requires less oxygen per ATP generated than fatty acid oxidation.

    “By comparison, glucose oxidation provides less ATP per molecule oxidized. However, glucose oxidation requires less oxygen per ATP generated.”

  • The paper relies on this without support.

    Superoxide reacts with nitric oxide to form peroxynitrite.

    “As indicated in Section II.C, superoxide reacts with nitric oxide to form peroxynitrite.”

  • The paper relies on this without support.

    Hydrogen peroxide produced from superoxide by MnSOD can react with iron to form the very reactive hydroxyl molecule.

    “Moreover, hydrogen peroxide, produced from superoxide by MnSOD, can react with iron to form the very reactive hydroxyl molecule.”

  • The paper relies on this without support.

    The ability of cells to switch between substrate utilization is essential to survival.

    “The ability of cells to switch between substrate utilization is essential to survival, as is obvious when fat stores are used by muscle during starvation.”

  • The paper relies on this without support.

    Findings from rodent models of diabetes can be extrapolated to human diabetes.

    “UCP2 in pancreatic tissue and UCP3 in muscle and heart are important in the pathogenesis of diabetes.”
    “Evidence suggests that mitochondrial ROS contribute to diabetic nephropathy.”

  • The paper relies on this without support.

    Mitochondrial ROS measured by lucigenin fluorescence, dichlorodihydrofluorescein fluorescence, or EPR in isolated mitochondria or cells reflects pathologically relevant ROS in vivo.

    “Kanwar et al. (156) reported that superoxide production, measured as lucigenin fluorescence, was increased in retinal tissue isolated from streptozotocin-diabetic mice with blood glucose concentrations ∼400 mg/dl.”
    “High glucose also reportedly increased H2O2 production by dichlorodihydrofluorescein fluorescence in human mesangial cells (165).”

  • The paper relies on this without support.

    High glucose in cultured retinal, mesangial, or endothelial cells models the diabetic milieu in vivo.

    “Cui et al. (76) used a confocal microscopy approach and reported that high glucose in the culture medium increased ROS production in bovine retinal capillary endothelial cells and pericytes associated with apoptosis.”
    “Manabe et al. (208) reported that high glucose increased ROS fluorescence in human mesangial cells associated with potentially harmful cytokine expression, an effect that was blocked by astaxanthin, a carotenoid that accumulated in mitochondria.”

  • The paper relies on this without support.

    Mitochondrial CoQ content measured by HPLC or cytochrome c oxidation reflects functional mitochondrial CoQ status.

    “However, later studies with HPLC reported a reduction in liver (180) and kidney (180, 223) mitochondrial CoQ content and an ∼75% reduction in heart mitochondria of 8-week STZ-diabetic rats (180).”

  • The paper relies on this without support.

    Mitochondrial ROS play a role in human disease.

    “The likely role of mitochondrial ROS in human disease has led to efforts to develop effective antioxidant compounds targeted to mitochondria.”

  • The paper relies on this without support.

    Dihydrolipoic acid regenerates other antioxidants including glutathione, vitamin C, and vitamin E.

    “In this form, the compound regenerates other antioxidants including glutathione, vitamin C, and vitamin E.”

  • The paper relies on this without support.

    NAC penetrates cells and its thiol group confers antioxidant activity, effectively removing H2O2 by transfer of electrons from the SH group.

    “This agent penetrates cells where the thiol group confers antioxidant activity, effectively removing H2O2 by transfer of electrons from the SH group.”

  • The paper relies on this without support.

    NAC rapidly reduces ·OH and HOCl, interacts slowly with H2O2, and minimally with O·−.

    “With respect to oxygen radicals, NAC rapidly reduces ·OH and HOCl. Interaction with H2O2 is slow, and interaction with O·− is minor at most.”

  • The paper relies on this without support.

    NAC may exert antioxidant effects through increasing GSH, facilitating the action of GPx.

    “In vitro evidence indicates that NAC may exert antioxidant effects through increasing GSH, facilitating the action of GPx.”

  • The paper relies on this without support.

    Tempol is not specific for mitochondrial superoxide but its effects include mitochondria.

    “The agent is not specific for mitochondrial as opposed to total cellular superoxide, but effects do appear to include mitochondria.”
31 of 31

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?

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.

  • Citation 240 does not describe the claimed UCP1 experiment

    Minor

    The text cites reference 240 for UCP1 overexpression in bovine aortic endothelial cells. Reference 240 is titled as a study of a mitochondrial glycerophosphate dehydrogenase gene mutation in diabetic subjects.

  • The mitochondrial mutation is named two different ways

    Minor

    The text identifies A3243G as the mutation associated with mitochondrial diabetes, but later calls the mutation associated with MELAS A3243AG. The two labels differ by an additional A.

  • Rat tissue findings are described as findings in mouse islets

    Minor

    The preceding description concerns mitochondria from the heart, gastrocnemius muscle, and liver of streptozotocin-diabetic rats. Its concluding sentence instead attributes the inferred exposure to islets from insulin-deficient mice.

3 of 3

The citation lists haven’t been fetched yet

References 359 · Cited by 742

Research works printed but not linked: 1

  1. Gnaiger E. Mitochondrial pathways and respiratory control. Innsbruck: OROBOROS MiPNet Publications, 2008; 7–15.

Authors
Sivitz, W. I., & Yorek, M. A.
Affiliations
University of Iowa (US)
ORCID
Venue
Antioxidants & Redox Signaling
Publisher
SAGE Publications
Published
2010-02
Volume
12
Issue
4
Pages
537-577
ISSN
  • 1523-0864 (ISSN-L)
  • 1557-7716
DOI
10.1089/ars.2009.2531
PMC
PMC2824521
OpenAlex
W1974939683
Semantic Scholar
7315363f436019d5f5b3c7bc3473b992c0836cfe
Cited by
742
References
359
Citations by year
2026: 29 · 2025: 35 · 2024: 45 · 2023: 65 · 2022: 68 · 2021: 66 · 2020: 68 · 2019: 52 · 2018: 48 · 2017: 61 · 2016: 46 · 2015: 49 · 2014: 28 · 2013: 24 · 2012: 27
FWCI
1.45
Type
journal article
Language
en
Open access
Licence
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations
  • Antioxidants and Redox Signaling (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs (DK073990)
  • National Institutes of Health (DK073990, DK25295)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 073990, DK-25295, R01DK073990, P30DK025295)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
mitochondrial dysfunction, diabetes mellitus, reactive oxygen species, mitochondrial uncoupling, coenzyme Q10, insulin secretion, insulin sensitivity, diabetes complications, mitochondrial therapy, aerobic metabolism
MeSH terms
Insulin Secretion, Animals, Blood Glucose, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Electron Transport, Humans, Insulin, Insulin Resistance, Mitochondria, Superoxides, Ubiquinone, Reactive Oxygen Species, Oxidative Stress, Cell Respiration, Mitochondrial Diseases, Insulin-Secreting Cells, Mice, Rats, Membrane Potential, Mitochondrial

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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 2026-10-10.

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