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Cited by 670Metabolism, Diabetes, and CancerAdipose Tissue and MetabolismDiabetes, Cardiovascular Risks, and Lipoproteins

Pathogenesis of insulin resistance in skeletal muscle

Open access
Abdul-Ghani, Muhammad A., DeFronzo, Ralph A.·2010·Journal of Biomedicine and Biotechnology
DOI 10.1155/2010/476279PMC PMC2860140
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Abstract

Insulin resistance in skeletal muscle is manifested by decreased insulin-stimulated glucose uptake and results from impaired insulin signaling and multiple post-receptor intracellular defects including impaired glucose transport, glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis. Insulin resistance is a core defect in type 2 diabetes, it is also associated with obesity and the metabolic syndrome. Dysregulation of fatty acid metabolism plays a pivotal role in the pathogenesis of insulin resistance in skeletal muscle. Recent studies have reported a mitochondrial defect in oxidative phosphorylation in skeletal muscle in variety of insulin resistant states. In this review, we summarize the cellular and molecular defects that contribute to the development of insulin resistance in skeletal muscle.

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Crossref · 10.1155/2010/476279

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Claims the paper makes

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  • Findingcitation

    A physiologic increase in FACoA concentration inhibits mitochondrial ATP synthesis in vitro in mitochondria isolated from skeletal muscle of NGT healthy lean subjects.

    “we recently have demonstrated that a physiologic increase in FACoA concentration inhibits mitochondrial ATP synthesis in vitro in mitochondria isolated from skeletal muscle of NGT healthy lean subjects [132]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Abdul-Ghani MA Muller F Liu Y Deleterious effect of elevated fatty acid metabolites concentration on skeletal muscle mitochondrial ATP synthesis Diabetes 2007 56 supplement 1

      Not checked in the free run.

  • Premisecitation

    Using the euglycaemic hyperinsulinaemic clamp, lean and obese type 2 diabetic subjects show a greater than 50% decrease in whole-body glucose disposal during insulin infusion.

    “Using the gold standard euglycemic hyperinsulinemic clamp technique to quantify insulin-stimulated glucose uptake, they demonstrated that both lean and obese T2DM subjects have marked decrease (>50%) in whole body glucose disposal during the insulin clamp.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [1] DeFronzo RA Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes Diabetes Reviews 1997 5 3 177 269

      Not checked in the free run.

    • cites [2] DeFronzo RA The triumvirate: β-cell, muscle, liver. A collusion responsible for NIDDM Diabetes 1988 37 6 667 687 3289989 source

      Not checked in the free run.

    • cites [3] DeFronzo RA Pathogenesis of type 2 diabetes mellitus Medical Clinics of North America 2004 88 4 787 835 15308380 source

      Not checked in the free run.

    • cites [4] Defronzo RA From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus Diabetes 2009 58 4 773 795 19336687 PMC2661582 source

      Not checked in the free run.

    • cites [5] DeFronzo RA Gunnarsson R Bjorkman O Olsson M Wahren J Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus The Journal of Clinical Investigation 1985 76 1 149 155 3894418 PMC423730 source

      Not checked in the free run.

    • cites [21] Groop LC Bonadonna RC DelPrato S Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance The Journal of Clinical Investigation 1989 84 1 205 213 2661589 PMC303971 source

      Not checked in the free run.

    • cites [27] DeFronzo RA Deibert D Hendler R Felig P Soman V Insulin sensitivity and insulin binding to monocytes in maturity-onset diabetes The Journal of Clinical Investigation 1979 63 5 939 946 376552 PMC372035 source

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    • cites [28] DeFronzo RA Soman V Sherwin RS Hendler R Felig P Insulin binding to monocytes and insulin action in human obesity, starvation, and refeeding The Journal of Clinical Investigation 1978 62 1 204 213 350903 PMC371755 source

      Not checked in the free run.

  • Premiseown data

    The onset of insulin action on skeletal muscle glucose uptake is markedly delayed in type 2 diabetic subjects.

    “In addition, the onset of insulin action in skeletal muscle in T2DM subjects is markedly delayed (Figure 2).”
    Quote in the paperSubstantial claim
  • Interpretationcitation

    A mitochondrial oxidative phosphorylation defect in skeletal muscle may contribute to increased intramyocellular fat content.

    “suggest that this mitochondrial defect contributes to the increased intramyocellar fat content.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [16] Roden M Muscle triglycerides and mitochondrial function: possible mechanisms for the development of type 2 diabetes International Journal of Obesity 2005 29 supplement 2 S111 S115 16385762 source

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    • cites [17] Morino K Petersen KF Shulman GI Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction Diabetes 2006 55 supplement 2 S9 S15 17130651 PMC2995546 source

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    • cites [18] Abdul-Ghani MA DeFronzo RA Mitochondrial dysfunction, insulin resistance, and type 2 diabetes mellitus Current Diabetes Reports 2008 8 3 173 178 18625112 source

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    • cites [19] Højlund K Mogensen M Sahlin K Beck-Nielsen H Mitochondrial dysfunction in type 2 diabetes and obesity Endocrinology and Metabolism Clinics of North America 2008 37 3 713 731 18775360 source

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    • cites [20] Lowell BB Shulman GI Mitochondrial dysfunction and type 2 diabetes Science 2005 307 5708 384 387 15662004 source

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  • Premisecitation

    Under postprandial conditions, skeletal muscle energy metabolism switches from predominant fat oxidation during fasting to predominant glucose oxidation.

    “Thus, under postprandial conditions, for example, mixed meal, muscle energy metabolism switches from predominant oxidizion of fat during the fasting state, to predominant oxidizion of glucose [22].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Blaak EE Metabolic fluxes in skeletal muscle in relation to obesity and insulin resistance Best Practice and Research: Clinical Endocrinology and Metabolism 2005 19 3 391 403 16150382 source

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  • May combine two claims. 83
  • Classified as probably not a substantial claim. 6
  • The quote only partly states this claim. 1

  • May combine two claims.

    Interpretationcitation

    Skeletal muscle insulin resistance involves reduced insulin-stimulated glucose uptake and arises from impaired insulin signalling plus several post-receptor defects, including defective glucose transport and phosphorylation and lower glucose oxidation and glycogen synthesis.

    “Insulin resistance in skeletal muscle is manifested by decreased insulin-stimulated glucose uptake and results from impaired insulin signaling and multiple post-receptor intracellular defects including impaired glucose transport, glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis.”
    • Also stated in: § 1. Introduction · plain
      “The decreased insulin-stimulated glucose uptake is due to impaired insulin signaling and multiple postreceptor intracellular defects including impaired glucose transport and glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis [7–10] (Table 1).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [7] Cusi K Maezono K Osman A Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle The Journal of Clinical Investigation 2000 105 3 311 320 10675357 PMC377440 source

      Not checked in the free run.

    • cites [8] Bajaj M DeFronzo RA Metabolic and molecular basis of insulin resistance Journal of Nuclear Cardiology 2003 10 3 311 323 12794631 source

      Not checked in the free run.

    • cites [9] Bouzakri K Koistinen HA Zierath JR Molecular mechanisms of skeletal muscle insulin resistance in type 2 diabetes Current Diabetes Reviews 2005 1 2 167 174 18220592 source

      Not checked in the free run.

    • cites [10] Karlsson HKR Zierath JR Insulin signaling and glucose transport in insulin resistant human skeletal muscle Cell Biochemistry and Biophysics 2007 48 2-3 103 113 17709880 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Skeletal muscle insulin resistance in type 2 diabetes is manifested by both a reduced magnitude and a delayed onset of insulin action.

    “These studies indicate that insulin resistance in skeletal muscle in subjects with T2DM is manefisted, not only by a reduction in the magnitude of insulin action, but also by s delayed onset of insulin action to”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    During fasting, plasma insulin is low, muscle glucose uptake is low, and plasma free fatty acid concentration is elevated because insulin restrains adipocyte lipolysis and stimulates muscle glucose uptake.

    “During the postabsorptive state, the plasma insulin concentration is low. Since the plasma insulin concentration is the principal factor that restrains lipolysis in adipocytes [21] and stimulates glucose uptake in skeletal muscle [21], during the fasting state, muscle glucose uptake is low and the plasma FFA concentration is elevated.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Groop LC Bonadonna RC DelPrato S Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance The Journal of Clinical Investigation 1989 84 1 205 213 2661589 PMC303971 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Under fasting conditions, free fatty acids are the principal fuel for skeletal muscle, whereas the brain uses glucose exclusively.

    “Thus, under fasting conditions, FFA serves as the principal fuel source for energy production in skeletal muscle, while the brain exclusively utilizes glucose.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Groop LC Bonadonna RC DelPrato S Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance The Journal of Clinical Investigation 1989 84 1 205 213 2661589 PMC303971 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    In type 2 diabetes, the dose-response curve for insulin-stimulated glucose uptake is shifted to the right, with an increased EC50 of about 120-140 μU/mL.

    “Thus, the dose response curve relating insulin-stimulated glucose uptake and the plasma insulin concentration shifts to the right with an increase in EC50 (to ~120–140 μU/mL) in subjects with T2DM (Figure 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Postprandial hyperglycaemia stimulates insulin secretion, and the resulting rise in plasma insulin stimulates glucose uptake in skeletal muscle, leading to disposal of ingested glucose.

    “The postprandial hyperglycemia stimulates insulin secretion from the pancreas and the rise in plasma insulin concentration stimulates glucose uptake in skeletal muscle leading to the disposal of ingested glucose [1–4].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [1] DeFronzo RA Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes Diabetes Reviews 1997 5 3 177 269

      Not checked in the free run.

    • cites [2] DeFronzo RA The triumvirate: β-cell, muscle, liver. A collusion responsible for NIDDM Diabetes 1988 37 6 667 687 3289989 source

      Not checked in the free run.

    • cites [3] DeFronzo RA Pathogenesis of type 2 diabetes mellitus Medical Clinics of North America 2004 88 4 787 835 15308380 source

      Not checked in the free run.

    • cites [4] Defronzo RA From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus Diabetes 2009 58 4 773 795 19336687 PMC2661582 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After glucose ingestion, hyperinsulinaemia suppresses lipolysis, lowers plasma free fatty acid concentration, and decreases lipid oxidation.

    “Following glucose ingestion, the increase in plasma glucose concentration stimulates insulin secretion from the beta cell and the resultant hyperinsulinemia suppresses lipolysis, leading to decline in plasma FFA concentration and subsequent decrease in the rate of lipid oxidation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] DeFronzo RA Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes Diabetes Reviews 1997 5 3 177 269

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    With increasing plasma insulin, glycogen synthase is activated and glycogen synthesis accounts for about 70% of glucose disposal.

    “However, with increasing plasma insulin concentration, glycogen synthase is activitaed by insulin and glycogen synthesise predominate (~70% of glucose disposal) [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Thiebaud D Jacot E DeFronzo RA Maeder E Jequier E Felber JP The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man Diabetes 1982 31 11 957 963 6757014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Muscle insulin resistance correlates strongly with intramyocellular lipid independently of total body fat mass and diabetes status, whereas the correlation with extramyocellular lipid is not significant.

    “Muscle insulin resistance strongly correlates with IMCL, independent of total body fat mass and diabetes status [56], while the correlation between EMCL and insulin ressitance is not significant.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Krssak M Falk Petersen K Dresner A Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study Diabetologia 1999 42 1 113 116 10027589 source

      Not checked in the free run.

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    Premisecitation

    Intramyocellular lipid contributes only about 1% of total muscle fat content but has a key role in skeletal muscle insulin resistance compared with extramyocellular lipid.

    “More recent studies [55, 56] using magnetic resonance spectroscopy have demonstrated that although IMCL fat content contributes only a small fraction (~1%) to the total muscle fat content, it plays a key role in the development of insulin resistance in skeletal muscle compared to EMCL.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [55] Perseghin G Scifo P De Cobelli F Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents Diabetes 1999 48 8 1600 1606 10426379 source

      Not checked in the free run.

    • cites [56] Krssak M Falk Petersen K Dresner A Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study Diabetologia 1999 42 1 113 116 10027589 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Skeletal muscle insulin resistance has been reported in association with normal ageing, dyslipidaemia, polycystic ovary syndrome, chronic kidney failure, heart failure, myotonic dystrophy, and lipodystrophy.

    “Insulin resistance in skeletal muscle also has been reported in association with the normal ageing process [37], dyslipidemia (increased plasma triglyceride/decreased HDL cholesterol) [4, 26], and in association with many disease states including polycystic ovary syndrome (PCOs) [38], chronic kidney failure [39], heart failure [40], myotonic dystrophy [41], and lipodystrophy [42].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [37] DeFronzo RA Glucose intolerance and aging. Evidence for tissue insensitivity to insulin Diabetes 1979 28 12 1095 1101 510806 source

      Not checked in the free run.

    • cites [4] Defronzo RA From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus Diabetes 2009 58 4 773 795 19336687 PMC2661582 source

      Not checked in the free run.

    • cites [26] Ginsberg H Kimmerling G Olefsky JM Reaven GM Demonstration of insulin resistance in untreated adult onset diabetic subjects with fasting hyperglycemia The Journal of Clinical Investigation 1975 55 3 454 461 1117064 PMC301772 source

      Not checked in the free run.

    • cites [38] Lankarani M Valizadeh N Heshmat R Peimani M Sohrabvand F Evaluation of insulin resistance and metabolic syndrome in patients with polycystic ovary syndrome Gynecological Endocrinology 2009 25 8 504 507 19499403 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Obese normal-glucose-tolerant subjects without a family history of type 2 diabetes, individuals with essential hypertension, and individuals with ischaemic heart disease have a 35-50% decrease in whole-body insulin-mediated glucose disposal.

    “Thus, obese NGT subjects without a family history for T2DM [33, 34] and individuals with essential hypertension [35] and ischemic heart disease [36] also have a 35–50% decrease in whole body insulin-mediated glucose disposal (Figure 3).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [33] Kahn SE Hull RL Utzschneider KM Mechanisms linking obesity to insulin resistance and type 2 diabetes Nature 2006 444 7121 840 846 213 17167471 source

      Not checked in the free run.

    • cites [34] Bogardus C Lillioja S Mott D Reaven GR Kashiwagi A Foley JE Relationship between obesity and maximal insulin-stimulated glucose uptake in vivo and in vitro in Pima Indians The Journal of Clinical Investigation 1984 73 3 800 805 6368588 PMC425083 source

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    • cites [35] Ferrannini E Buzzigoli G Bonadonna R Insulin resistance in essential hypertension The New England Journal of Medicine 1987 317 6 350 357 3299096 source

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    • cites [36] Bressler P Bailey SR Matsuda M DeFronzo RA Insulin resistance and coronary artery disease Diabetologia 1996 39 11 1345 1350 8933003 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both acute (4-hour) and chronic (4-day) physiological elevation of plasma free fatty acid concentration in insulin-sensitive individuals impairs insulin signalling and causes skeletal muscle insulin resistance.

    “Both acute (4 hours) and chronic (4 days) physiologic elevation of plasma FFA concentration in insulin sensitive individuals impairs insulin signaling and causes insulin resistance in skeletal muscle [28, 62–68].”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [28] DeFronzo RA Soman V Sherwin RS Hendler R Felig P Insulin binding to monocytes and insulin action in human obesity, starvation, and refeeding The Journal of Clinical Investigation 1978 62 1 204 213 350903 PMC371755 source

      Not checked in the free run.

    • cites [62] Griffin ME Marcucci MJ Cline GW Free fatty acid-induced insulin resistance is associated with activation of protein kinase C θ and alterations in the insulin signaling cascade Diabetes 2000 48 6 1270 1274 10342815 source

      Not checked in the free run.

    • cites [63] Dresner A Laurent D Marcucci M Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity The Journal of Clinical Investigation 1999 103 2 253 259 9916137 PMC407880 source

      Not checked in the free run.

    • cites [64] Yu C Chen Y Cline GW Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle The Journal of Biological Chemistry 2002 277 52 50230 50236 12006582 source

      Not checked in the free run.

    • cites [65] Belfort R Mandarino L Kashyap S Dose-response effect of elevated plasma free fatty acid on insulin signaling Diabetes 2005 54 6 1640 1648 15919784 source

      Not checked in the free run.

    • cites [66] Itani SI Ruderman NB Schmieder F Boden G Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IκB-α Diabetes 2002 51 7 2005 2011 12086926 source

      Not checked in the free run.

    • cites [67] Richardson DK Kashyap S Bajaj M Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle The Journal of Biological Chemistry 2005 280 11 10290 10297 15598661 source

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    • cites [68] Boden G Chen X Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes The Journal of Clinical Investigation 1995 96 3 1261 1268 7657800 PMC185747 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Although skeletal muscle insulin resistance is a hallmark of type 2 diabetes, it and the accompanying insulin resistance syndrome are more widely prevalent, and their metabolic and clinical consequences affect non-diabetic individuals as well.

    “These studies indicate that although insulin resistance in skeletal muscle is a hallmark of T2DM, muscle insulin resistance and the accompanying insulin resistance syndrome are more widely prevalent and the metabolic and clinical consequences of insulin resistance (e.g., increased cardiovascular risk) affect nondiabetic individuals as well.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Muscle biopsy studies show increased triglyceride content in skeletal muscle of obese normal-glucose-tolerant subjects compared with lean individuals and an inverse relationship between muscle insulin sensitivity and intramuscular triglyceride content.

    “Muscle biopsy studies [53, 54] have demonstrated increased triglyceride content in skeletal muscle of obese NGT subjects compared to lean individuals and an inverse relationship between muscle insulin sensitivity and the intramuscular triglyceride content.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [53] Pan DA Lillioja S Kriketos AD Skeletal muscle triglyceride levels are inversely related to insulin action Diabetes 1997 46 6 983 988 9166669 source

      Not checked in the free run.

    • cites [54] Phillips DIW Caddy S Ilic V Intramuscular triglyceride and muscle insulin sensitivity: evidence for a relationship in nondiabetic subjects Metabolism 1996 45 8 947 950 8769349 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Insulin resistance develops in acute severe illnesses such as injury and sepsis, possibly secondary to the acute inflammatory state.

    “In addition, insulin resistance develops in acute severe illnesses such as injury and sepsis, perhaps secondary to the acute inflammatory state that prevails [43].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Van Cromphaut SJ Vanhorebeek I Van den Berghe G Glucose metabolism and insulin resistance in sepsis Current Pharmaceutical Design 2008 14 19 1887 1899 18691100 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In insulin-resistant individuals, the ability of insulin to inhibit lipolysis and lower plasma free fatty acid concentration is markedly impaired, leading to increased lipolysis and chronic elevation of plasma free fatty acids.

    “In insulin resistant individuals, for example, nondiabetic obese and lean type 2 diabetic subjects, the ability of insulin to inhibit lipolysis and reduce plasma FFA concentration is markedly impaired [21, 59], leading to an increased rate of lipolysis and chronic elevation in the plasma FFA concentration.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Groop LC Bonadonna RC DelPrato S Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance The Journal of Clinical Investigation 1989 84 1 205 213 2661589 PMC303971 source

      Not checked in the free run.

    • cites [59] Groop LC Saloranta C Shank M Bonadonna RC Ferrannini E DeFronzo RA The role of free fatty acid metabolism in the pathogenesis of insulin resistance in obesity and noninsulin-dependent diabetes mellitus Journal of Clinical Endocrinology and Metabolism 1991 72 1 96 107 1986032 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Muscle triglyceride is metabolically inert and does not directly determine insulin sensitivity; it is a marker of imbalance between lipid supply and lipid oxidation in skeletal muscle, whereas intramyocellular fatty acyl-CoA and other lipotoxic metabolites such as DAG and ceramide have a more direct role in skeletal muscle insulin resistance.

    “These observations collectively indicate that muscle triglyceride (which is metabolic inert) is not directly involved in determining insulin sensitivity but rather represents a marker of imbalance between lipid supply and lipid oxidation in skeletal muscle, while increases in intramyocellar FACoA and other lipotoxic metabolites (DAG, ceramide) have a more direct role in the development of skeletal”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    The mitochondrial defect in ATP synthesis rate measured in vivo with magnetic resonance spectroscopy could be due to a reduction in mitochondrial number with normal individual function, an intrinsic defect in a quantitatively normal number of mitochondria, or a combination of both.

    “The mitochondrial defect in ATP synthesis rate documented in vivo with MRS could be due to a reduction in the number of mitochondria in skeletal muscle with normal function of individual mitochondria, an intrinsic defect in a quantitively normal number of mitochondria, or some combination of the two.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Early studies showed that the rate of lipolysis is a key determinant of free fatty acid uptake and oxidation in skeletal muscle and documented a linear relationship between plasma long-chain fatty acid concentration and their rate of uptake and oxidation in muscle.

    “Indeed, early studies demonstrated the rate of lipolysis was a key determinant of FFA uptake and oxidation in skeletal muscle and documented a linear relationship between the plasma LCFA concentration and their rate of uptake and oxidation in the muscle [85–87].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [85] Hagenfeldt L Metabolism of free fatty acids and ketone bodies during exercise in normal and diabetic man Diabetes 1979 28 supplement 1 66 70 104895 source

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    • cites [86] Hagenfeldt L Wahren J Human forearm muscle metabolism during exercise. II. Uptake, release and oxidation of individual FFA and glycerol Scandinavian Journal of Clinical and Laboratory Investigation 1968 21 3 263 276 5708695 source

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    • cites [87] Havel RJ Ekelund LG Holmgren A Kinetic analysis of the oxidation of palmitate-1-14C in man during prolonged heavy muscular exercise Journal of Lipid Research 1967 8 4 366 373 6033603 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Accumulation of fat inside the muscle fibre may originate from excess free fatty acid supply to muscle, decreased muscle fat oxidation, or a combination of the two.

    “The accumulation of fat inside the muscle fiber could originate from excess supply of FFA to the muscle, a decreased rate of muscle fat oxidation, or some combination of the two.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Normal ageing, which is characterized by insulin resistance, is associated with a decrease in mitochondrial ATP synthesis rate and an increase in intramyocellular fat content.

    “Insulin resistance also is a characteristic feature of the normal aging process and is associated with a decrease in mitochondrial ATP synthesis rate and an increase in intramyocellar fat content [109].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Petersen KF Befroy D Dufour S Mitochondrial dysfunction in the elderly: possible role in insulin resistance Science 2003 300 5622 1140 1142 12750520 PMC3004429 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Weight loss induced by bariatric surgery completely normalizes insulin sensitivity despite continued obesity (BMI reduced from 49 to 39 kg/m2), and normalization of muscle insulin sensitivity is associated with reduction of muscle fat content to normal despite persistent increase in total body fat.

    “(vii) weight loss, induced by bariatric surgery, results in a complete normalization of insulin sensitivity despite the presence of continued obesity (BMI reduced from 49 to 39 kg/m2) [79]. The normalization of muscle insulin sensitivity is associated with a reduction of muscle fat content to normal despite a persistent increase in total body fat content [79].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Greco AV Mingrone G Giancaterini A Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion Diabetes 2002 51 1 144 151 11756334 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reducing plasma free fatty acid concentration in insulin-resistant individuals, such as type 2 diabetic subjects, augments insulin-stimulated glucose disposal in skeletal muscle, and the improvement in insulin sensitivity is closely associated with a reduction in intramyocellular fatty acyl-CoA concentration.

    “Conversely, reduction of plasma FFA concentration in insulin resistant individuals, for example, type 2 diabetic subjects, augments insulin-stimulated glucose disposal in skeletal muscle [69–72], and the improvement in insulin sensitivity is closely associated with a reduction in intramyocellular FACoA concentration [69].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [69] Bajaj M Suraamornkul S Romanelli A Effect of a sustained reduction in plasma free fatty acid concentration on intramuscular long-chain fatty acyl-CoAs and insulin action in type 2 diabetic patients Diabetes 2005 54 11 3148 3153 16249438 source

      Not checked in the free run.

    • cites [70] Bajaj M Suraamornkul S Kashyap S Cusi K Mandarino L DeFronzo RA Sustained reduction in plasma free fatty acid concentration improves insulin action without altering plasma adipocytokine levels in subjects with strong family history of type 2 diabetes Journal of Clinical Endocrinology and Metabolism 2004 89 9 4649 4655 15356076 source

      Not checked in the free run.

    • cites [71] Vaag A Skott P Damsbo P Gall M-A Richter EA Beck-Nielsen H Effect of the antilipolytic nicotinic acid analogue acipimox on whole-body and skeletal muscle glucose metabolism in patients with non-insulin-dependent diabetes mellitus The Journal of Clinical Investigation 1991 88 4 1282 1290 1918378 PMC295597 source

      Not checked in the free run.

    • cites [72] Santomauro ATMG Boden G Silva MER Overnight lowering of free fatty acids with acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects Diabetes 1999 48 9 1836 1841 10480616 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    An acquired mitochondrial defect could potentially be reversed or prevented, whereas an inherited defect would be permanent.

    “An acquired defect potentially could be reversed or prevented, while an inherited defect would be permanent.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CD36 has an important role in long-chain fatty acid uptake into skeletal muscle in rodents and humans, and its concentration and activity increase after exercise.

    “There is abundant evidence which indicates that CD36 plays an important role in LCFA uptake into skeletal muscle in rodents and human and its concentration and activity are increased following exercise [89–96].”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [89] Gargiulo CE Stunlsatz-Krouper SM Schaffer JE Localization of adipocyte long-chain fatty acyl-CoA synthetase at the plasma membrane Journal of Lipid Research 1999 40 5 881 892 10224157 source

      Not checked in the free run.

    • cites [90] Ibrahimi A Bonen A Blinn WD Muscle-specific overexpression of FAT/CD36 enhances fatty acid oxidation by contracting muscle, reduces plasma triglycerides and fatty acids, and increases plasma glucose and insulin The Journal of Biological Chemistry 1999 274 38 26761 26766 10480880 source

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    • cites [91] Febbraio M Abumrad NA Hajjar DP A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism The Journal of Biological Chemistry 1999 274 27 19055 19062 10383407 source

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    • cites [92] Luiken JJFP Arumugam Y Dyck DJ Increased rates of fatty acid uptake and plasmalemmal fatty acid transporters in obese Zucker rats The Journal of Biological Chemistry 2001 276 44 40567 40573 11504711 source

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    • cites [93] Steinberg GR Dyck DJ Calles-Escandon J Chronic leptin administration decreases fatty acid uptake and fatty acid transporters in rat skeletal muscle The Journal of Biological Chemistry 2002 277 11 8854 8860 11729182 source

      Not checked in the free run.

    • cites [94] Cameron-Smith D Burke LM Angus DJ A short-term, high-fat diet up-regulates lipid metabolism and gene expression in human skeletal muscle American Journal of Clinical Nutrition 2003 77 2 313 318 12540388 source

      Not checked in the free run.

    • cites [95] Roepstorff C Helge JW Vistisen B Kiens B Studies of plasma membrane fatty acid-binding protein and other lipid-binding proteins in human skeletal muscle Proceedings of the Nutrition Society 2004 63 2 239 244 15294037 source

      Not checked in the free run.

    • cites [96] Bonen A Parolin ML Steinberg GR Triacylglycerol accumulation in human obesity and type 2 diabetes is associated with increased rates of skeletal muscle fatty acid transport increased sarcolemmal FAT/CD36 FASEB Journal 2004 18 10 1144 1146 15132977 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Impaired fat oxidation in insulin-resistant individuals suggests a mitochondrial defect that contributes to impaired muscle fat oxidation and increased intramyocellular lipid content.

    “Since the majority of fat oxidation take place in the mitochondria, impaired fat oxidation in insulin resistant individuals suggests the presence of a mitochondrial defect that contributes to the impaired muscle fat oxidation and increased IMCL fat content.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    When fat oxidation is decreased and CD36 levels are increased, muscle uptake of long-chain fatty acids increases, resulting in increased muscle triglyceride synthesis and increased intramyocellular lipid content.

    “During conditions of decreased fat oxidation and increased CD36 levels, muscle uptake of LCFA increased, resulting in increased muscle triglyceride synthesis and increased IMCL content [97, 98].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [97] Kiens B Roemen THM Van der Vusse GJ Muscular long-chain fatty acid content during graded exercise in humans American Journal of Physiology 1999 276 2 E352 E357 9950796

      Not checked in the free run.

    • cites [98] Roepstorff C Vistisen B Roepstorff K Kiens B Regulation of plasma long-chain fatty acid oxidation in relation to uptake in human skeletal muscle during exercise American Journal of Physiology 2004 287 4 E696 E705 15186996 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reducing plasma free fatty acid concentration with acipimox in insulin-resistant individuals is associated with a reduction in intracellular fatty acyl-CoA content, and the magnitude of the decrease in insulin resistance correlates with the decrease in fatty acyl-CoA content.

    “(ii) the decrease in insulin resistance brought about by reducing the plasma FFA concentration with acipimox in insulin resistant individuals is associated with a reduction in intracellular FACoA content, and the magnitude of decrease in insulin resistance strongly correlates with the decrease in FACoA content [69];”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Bajaj M Suraamornkul S Romanelli A Effect of a sustained reduction in plasma free fatty acid concentration on intramuscular long-chain fatty acyl-CoAs and insulin action in type 2 diabetic patients Diabetes 2005 54 11 3148 3153 16249438 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rodents, injection of recombinant adiponectin increases fat oxidation, reduces intramyocellular lipid, and improves insulin sensitivity.

    “(v) in rodents, injection of recombinant adiponectin increases fat oxidation, reduces intamyocellular lipid, and improves insulin sensitivity [77];”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Yamauchi T Kamon J Waki H The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity Nature Medicine 2001 7 8 941 946 11479627 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subjects with type 2 diabetes have decreased exercise tolerance and impaired recovery of intracellular phosphocreatinine concentration after exercise.

    “Subjects with T2DM also have decreased exercise tolerance and impaired recovery of intracellular phosphocreatinine concentration following exercise [107, 108]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [107] Scheuermann-Freestone M Madsen PL Manners D Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes Circulation 2003 107 24 3040 3046 12810608 source

      Not checked in the free run.

    • cites [108] Schrauwen-Hinderling VB Kooi ME Hesselink MKC Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects Diabetologia 2007 50 1 113 120 17093944 source

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  • May combine two claims.

    Interpretationcitation

    Under marked increases in muscle energy demand, such as exercise, long-chain fatty acid uptake initially increases linearly and then plateaus, suggesting a facilitated transport mechanism for long-chain fatty acids into skeletal muscle.

    “More recent studies have reported that under conditions of marked increase in energy demand in the muscle, for example, during exercise, LCFAs uptake initially increases linearly then plateaus [88], suggesting the existence of a facilitated transport mechanism for LCFA into skeletal muscle.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] Kiens B Essen-Gustavsson B Christensen NJ Saltin B Skeletal muscle substrate utilization during submaximal exercise in man: effect of endurance training Journal of Physiology 1993 469 459 478 8271208 PMC1143880 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CD36 content and long-chain fatty acid transport capacity are increased in obese and type 2 diabetic individuals and correlate with increased muscle triglyceride content, while fat oxidation is decreased.

    “The CD36 content and LCFA transport capacity have been reported to be increased in obese and T2DM individuals and correlate with increased muscle triglyceride content, while fat oxidation is decreased.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Obesity and type 2 diabetes involve an intrinsic defect in mitochondrial capacity to oxidize fat.

    “Collectively, these studies indicate the existence of an intrensic defect in mitochondrial capacity to oxidize fat in obesity and T2DM.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Muscle-specific overexpression of lipoprotein lipase leads to accumulation of fat and fatty acyl-CoA in muscle and severe muscle insulin resistance, while fat content and insulin sensitivity in other tissues such as liver remain unchanged.

    “(vi) muscle-specific over expression of lipoprotein lipase leads to the accumulation of fat/FACoA in muscle and severe muscle insulin resistance, while the fat content and insulin sensitivity in other tissues, that is, liver, remain unchanged [78];”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Kim JK Fillmore JJ Chen Y Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance Proceedings of the National Academy of Sciences of the United States of America 2001 98 13 7522 7527 11390966 PMC34701 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The mitochondrial defect in oxidative phosphorylation could contribute to increased intramyocellular FFA metabolite levels and to insulin resistance in obesity and T2DM.

    “The mitochondrial defect in oxidative phosphorylation described in vivo with MRS and ex vivo in muscle fibers and isolated mitochondria could contribute to the increase in intramyocellar FFA metabolite levels observed in obesity and T2DM and contribute to the insulin resistance.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    It cannot be completely excluded that the mitochondrial defect results secondary to insulin resistance.

    “one cannot completely exclude the possibility that the mitochondrial defect results secondary to insulin resistance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Brehm A Krssak M Schmid AI Nowotny P Waldhäusl W Roden M Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle Diabetes 2006 55 1 136 140 16380486 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The mitochondrial defect and insulin resistance are acquired as part of normal ageing.

    “Thus, normal mitochondrial function in young, insulin-sensitive subjects suggests that the mitochondrial defect and insulin-resistance are acquired as part of the normal ageing process.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    An inherited defect in mitochondrial oxidative capacity should be present at or shortly after birth and should not be reversible.

    “An inherited defect in mitochondrial oxidative capacity should be present at or shortly after birth and, most importantly, not be reversable.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Downregulation of electron transport chain activity in mice by knocking down AIF enhanced insulin sensitivity and protected against fat-induced insulin resistance.

    “Down regulation of electron transport chain activity in mice by knocking down apoptosis inintiating factor (AIF) resulted in enhanced insulin sensitivity and protection the animal from fat-induced insulin resistance [137].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Pospisilik JA Knauf C Joza N Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes Cell 2007 131 3 476 491 17981116 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Modest weight reduction of about 10% of body weight produced by dieting and increased physical activity reduces insulin resistance and intramyocellular lipid content, and these changes are associated with increased fat oxidation in skeletal muscle; the magnitude of increase in fat oxidation after weight loss correlates strongly with the decrease in insulin resistance.

    “(i) modest weight reduction (~10% of body weight), produced by dieting and increased physical activity, reduces insulin resistance and intramyocellular lipid content and these changes are associated with increased fat oxidation in skeletal muscle [123]. Furthermore, the magnitude of increase in fat oxidation following weight loss correlated strongly with the decrease in insulin resistance [123];”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] Goodpaster BH Katsiaras A Kelley DE Enhanced fat oxidation through physical activity is associated with improvements in insulin sensitivity in obesity Diabetes 2003 52 9 2191 2197 12941756 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Downregulation of mitochondrial function in myotubes with oligomycin or ethidium bromide increased intracellular fat content, impaired insulin signaling, and decreased insulin-stimulated glucose uptake.

    “Down regulation of mitochondrial function in myotubes with oligomycin, which inhibits mitochondrial ATP synthesis, and with ethidium bromide, which impairs mitochondrial DNA replication, caused an increase in intracellular fat content, impaired insulin signaling, and decreased insulin-stimulated glucose uptake [135].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Lim JH Lee JI Suh YH Kim W Song JH Jung MH Mitochondrial dysfunction induces aberrant insulin signalling and glucose utilisation in murine C2C12 myotube cells Diabetologia 2006 49 8 1924 1936 16736133 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PGC-1α overexpression in mouse skeletal muscle enhanced mitochondrial activity, increased expression of proteins involved in fat oxidation and glucose transport, and increased insulin-stimulated glucose uptake by about 35%.

    “Over expression of the PGC-1 alpha gene in skeletal muscle in mice in vivo enhanced mitochondrial activity, augmented the expression of multiple proteins involved in fat oxidation and glucose transport, and increased by ~35% insulin-stimulated glucose uptake [133].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Benton CR Nickerson JG Lally J Modest PGC-1α overexpression in muscle in vivo is sufficient to increase insulin sensitivity and palmitate oxidation in subsarcolemmal, not intermyofibrillar, mitochondria The Journal of Biological Chemistry 2008 283 7 4228 4240 18079123 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Biochemical studies have reported decreased activity of a variety of mitochondrial enzymes in type 2 diabetic subjects, supporting an intrinsic functional mitochondrial defect.

    “Biochemical studies have reported a decrease in the activity of a variety of mitochondrial enzymes [122], also supporting an intrinsic functional mitochondrial defect in type 2 diabetic subjects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Mogensen M Sahlin K Fernström M Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes Diabetes 2007 56 6 1592 1599 17351150 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Marked weight reduction after bariatric surgery in morbidly obese, severely insulin-resistant subjects completely normalized insulin sensitivity, and correction of the insulin resistance was accompanied by depletion of intramyocellular fat content.

    “(ii) marked weight reduction following bariatric surgery in morbidly obese, severely insulin-resistant subjects completely normalized insulin sensitivity, and correction of the insulin resistance was accompanied by depletion of intramyocellar fat content [124].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [124] Greco AV Mingrone G Giancaterini A Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion Diabetes 2002 51 1 144 151 11756334 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    An intrinsic mitochondrial defect, with or without decreased mitochondrial density, would be expected to cause impaired lipid oxidation, increased intramyocellular lipid content, and development or exacerbation of insulin resistance.

    “An intrinsic mitochondrial defect, with or without a decrease in mitochondrial density, would be expected to result in impaired lipid oxidation, an increase in intramyocellular lipid content, and the development/exacerbation of insulin resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Both decreased mitochondrial fat oxidation and increased FFA influx into skeletal muscle occur during insulin resistance.

    “In summary it can be concluded that both decreased mitochondrial fat oxidation and increased FFA influx into skeletal muscle take place during insulin resistance state.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mutagenesis of any of the three major phosphorylation sites (residues 1158, 1163, and 1162) impairs insulin receptor tyrosine kinase activity, decreasing metabolic and growth-promoting effects of insulin.

    “Mutagenesis of any of the three major phosphorylation sites (at residues 1158, 1163, and 1162) impairs insulin receptor tyrosine kinase activity, leading to a decrease in the metabolic and growth-promoting effects of insulin [141, 142].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [141] Ellis L Clauser E Morgan DO Edery M Roth RA Rutter WJ Replacement of insulin receptor tyrosine residues 1162 and 1163 compromises insulin-stimulated kinase activity and uptake of 2-deoxyglucose Cell 1986 45 5 721 732 3518947 source

      Not checked in the free run.

    • cites [142] Chou CK Dull TJ Russell DS Human insulin receptors mutated at the ATP-binding site lack protein tyrosine kinase activity and fail to mediate postreceptor effects of insulin The Journal of Biological Chemistry 1987 262 4 1842 1847 3100537 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ex vivo measurement of electron transport chain activity and mitochondrial ATP synthesis in isolated mitochondria shows decreased electron transport chain activity and ATP synthesis in obese insulin-resistant individuals compared with lean insulin-sensitive subjects.

    “Ex vivo measurement of electron transport chain activity (ETC) [112] and mitochondrial ATP synthesis in isolated mitochondria [120, 121] have demonstrated a decrease in ETC activity and ATP synthesis in obese insulin-resistant individuals compared to lean insulin-sensitive subjects.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [112] 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 1 8 14 15616005 source

      Not checked in the free run.

    • cites [120] Abdul-Ghani MA Jani R Molina M Chavez A Tripathy D DeFronzo RA Decreased mitochondrial ATP synthesis in obese non-diabetic subjects Diabetes 2008 56 supplement 1

      Not checked in the free run.

    • cites [121] Phielix E Schrauwen-Hinderling VB Mensink M Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients Diabetes 2008 57 11 2943 2949 18678616 PMC2570390 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise-induced improvement in insulin sensitivity is associated with improved muscle oxidative capacity and increased mitochondrial density and activity.

    “the improvement in insulin sensitivity following exercise is associated with improved muscle oxidative capacity [125, 126] and increases in both mitochondrial density [127] and activity [128–130]”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [125] Jubrias SA Esselman PC Price LB Cress ME Conley KE Large energetic adaptations of elderly muscle to resistance and endurance training Journal of Applied Physiology 2001 90 5 1663 1670 11299253 source

      Not checked in the free run.

    • cites [126] Holloszy JO Coyle EF Adaptations of skeletal muscle to endurance exercise and their metabolic consequences Journal of Applied Physiology Respiratory Environmental and Exercise Physiology 1984 56 4 831 838 6373687

      Not checked in the free run.

    • cites [127] Chilibeck PD Syrotuik DG Bell GJ The effect of concurrent endurance and strength training on quantitative estimates of subsarcolemmal and intermyofibrillar mitochondria International Journal of Sports Medicine 2002 23 1 33 39 11774064 source

      Not checked in the free run.

    • cites [128] Østergård T Andersen JL Nyholm B Impact of exercise training on insulin sensitivity, physical fitness, and muscle oxidative capacity in first-degree relatives of type 2 diabetic patients American Journal of Physiology 2006 290 5 E998 E1005 16352678 source

      Not checked in the free run.

    • cites [129] Menshikova EV Ritov VB Toledo FGS Ferrell RE Goodpaster BH Kelley DE Effects of weight loss and physical activity on skeletal muscle mitochondrial function in obesity American Journal of Physiology 2005 288 4 E818 E825 15585590 source

      Not checked in the free run.

    • cites [130] Short KR Vittone JL Bigelow ML Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity Diabetes 2003 52 8 1888 1896 12882902 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    When oxygen consumption is related to mitochondrial copy number, diabetic and non-diabetic subjects have similar rates of muscle oxygen consumption, implying decreased mitochondrial density without an intrinsic mitochondrial defect in type 2 diabetes.

    “However, when oxygen consumption was related to mitochondrial copy number, both diabetic and nondiabetic subjects had similar rates of muscle oxygen consumption, implying a decrease in mitochondrial density without an intrinsic mitochondrial defect in T2DM subjects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Because electron transport chain activity and mitochondrial ATP synthesis rate were related to mitochondrial protein and/or citrate synthase activity, these observations indicate a basic functional defect in mitochondrial activity in skeletal muscle of obese insulin-resistant individuals.

    “Since, in these studies [112, 120], ETC activity and mitochondrial ATP synthesis rate were related to the amount of mitochondrial protein and/or citrate synthase activity, these observations indicate the existence of a basic functional defect in mitochondrial activity in skeletal muscle of obese insulin-resistant individuals [115].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [112] 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 1 8 14 15616005 source

      Not checked in the free run.

    • cites [120] Abdul-Ghani MA Jani R Molina M Chavez A Tripathy D DeFronzo RA Decreased mitochondrial ATP synthesis in obese non-diabetic subjects Diabetes 2008 56 supplement 1

      Not checked in the free run.

    • cites [115] Boushel R Gnaiger E Schjerling P Skovbro M Kraunsøe R Dela F Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle Diabetologia 2007 50 4 790 796 17334651 PMC1820754 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SIRT1 activation with resveratrol in mice increased mitochondrial activity and protected against diet-induced obesity and insulin resistance.

    “activation of SIRT1 with resveratrol in mice resulted in increased mitochondrial activity and protected the animals from diet-induced obesity and insulin resistance [134].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Lagouge M Argmann C Gerhart-Hines Z Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α Cell 2006 127 6 1109 1122 17112576 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Electron microscopy studies have demonstrated a variety of morphological abnormalities in mitochondria in insulin-resistant individuals, and these changes were reversible with weight loss and increased physical activity.

    “EM studies have demonstrated a variety of morphological abnormalities in mitochondria in insulin-resistant individuals [118] and these changes were reversable with weight loss and increased physical activity [119].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [118] Kelley DE He J Menshikova EV Ritov VB Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes Diabetes 2002 51 10 2944 2950 12351431 source

      Not checked in the free run.

    • cites [119] Toledo FGS Watkins S Kelley DE Changes induced by physical activity and weight loss in the morphology of intermyofibrillar mitochondria in obese men and women Journal of Clinical Endocrinology and Metabolism 2006 91 8 3224 3227 16684829 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment of muscle cells with azide increased basal glucose uptake without affecting insulin-stimulated glucose uptake in myotubes.

    “treatment of the muscle cells with azide, an inhibitor of mitochondrial complex IV, increased basal glucose uptake without affecting insulin-stimulated glucose uptake in myotubes [136].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [136] Brown AE Elstner M Yeaman SJ Turnbull DM Walker M Does impaired mitochondrial function affect insulin signaling and action in cultured human skeletal muscle cells? American Journal of Physiology 2008 294 1 E97 E102 17957036 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibitors of PI3K inhibit glycogen synthase activity and abolish glycogen synthesis.

    “Studies [138, 150] have demonstrated convincingly that inhibitors of PI3K inhibit glycogen synthase activity and abolish glycogen synthesis.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [138] Saltiel AR Kahn CR Insulin signalling and the regulation of glucose and lipid metabolism Nature 2001 414 6865 799 806 11742412 source

      Not checked in the free run.

    • cites [150] Shepherd PR Nave BT Siddle K Insulin stimulation of glycogen synthesis and glycogen synthase activity is blocked by wortmannin and rapamycin in 3T3-L1 adipocytes: evidence for the involvement of phosphoinositide 3-kinase and p70 ribosomal protein-56 kinase Biochemical Journal 1995 305 1 25 28 7826337 PMC1136424 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Conditions that increase serine phosphorylation of IRS-1 impair its tyrosine phosphorylation by the insulin receptor and interrupt the insulin signaling cascade.

    “Thus, conditions that increase serine phosphorylation of IRS-1 impair tyrosine phosphorylation by the insulin receptor and its activation, thus, leading to an impartment in the insulin signaling cascade.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Association of p85 subunit of PI3K with IRS-1 and PI3K activation are greatly attenuated in obese nondiabetic and type 2 diabetic subjects compared with lean healthy controls.

    “Association of the p85 subunit of PI3K with IRS-1 and activation of PI3K also are greatly attenuated in obese nondiabetic and type 2 diabetic subjects compared with lean healthy controls [7, 165, 166].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Cusi K Maezono K Osman A Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle The Journal of Clinical Investigation 2000 105 3 311 320 10675357 PMC377440 source

      Not checked in the free run.

    • cites [165] Krook A Björnholm M Galuska D Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients Diabetes 2000 49 2 284 292 10868945 source

      Not checked in the free run.

    • cites [166] Kim Y-B Nikoulina SE Ciaraldi TP Henry RR Kahn BB Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes The Journal of Clinical Investigation 1999 104 6 733 741 10491408 PMC408433 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased PKC-β and δ activity has been reported in insulin-resistant states and can be induced during lipid infusion.

    “Increased activity of protein kinase C (PKC-β and δ has been reported in insulin resistant states and can be induced during lipid infusion [174, 175].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [174] Schmitz-Peiffer C Browne CL Oakes ND Alterations in the expression and cellular localization of protein kinase C isozymes ε and θ are associated with insulin resistance in skeletal muscle of the high-fat-fed rat Diabetes 1997 46 2 169 178 9000691 source

      Not checked in the free run.

    • cites [175] Schmitz-Peiffer C Oakes ND Browne CL Kraegen EW Biden TJ Reversal of chronic alterations of skeletal muscle protein kinase C from fat-fed rats by BRL-49653 American Journal of Physiology 1997 273 5 E915 E921 9374677

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Impaired association of PI3K with IRS-1 and its subsequent activation are characteristic abnormalities in type 2 diabetics and correlate closely with in vivo muscle insulin resistance.

    “In summary, impaired association of PI3K with IRS-1 and its subsequent activation are characteristic abnormalities in type 2 diabetics, and these defects are correlated closely with in vivo muscle insulin resistance.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    A common IRS-1 gene mutation (Gly-972-Arg) has been associated with type 2 diabetes, insulin resistance, and obesity, but its physiologic significance remains to be established.

    “A common mutation in the IRS-1 gene (Gly-972-Arg) has been associated with type 2 diabetes, insulin resistance, and obesity, but the physiologic significance of this mutation remains to be established [170].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [170] Hitman GA Hawrami K McCarthy MI Insulin receptor substrate-1 gene mutations in NIDDM; implications for the study of polygenic disease Diabetologia 1995 38 4 481 486 7796990 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In obese nondiabetic subjects, insulin activation of insulin receptor and IRS-1 tyrosine phosphorylation in muscle is modestly reduced; in type 2 diabetics it is severely impaired.

    “The ability of insulin to activate insulin receptor and IRS-1 tyrosine phosphorylation in muscle in obese nondiabetic subjects is modestly reduced; whereas in type 2 diabetics insulin-stimulated insulin receptor and IRS-1 tyrosine phosphorylation are severely impaired [7].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Cusi K Maezono K Osman A Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle The Journal of Clinical Investigation 2000 105 3 311 320 10675357 PMC377440 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because nitric oxide synthase is activated by the IRS-1/PI3K pathway, impaired insulin signaling reduces nitric oxide generation and causes endothelial dysfunction, which has been implicated in accelerated atherosclerosis in T2DM.

    “Because nitric oxide synthase also is activated by the IRS-1/PIS-K pathway, impaired insulin signaling leads to reduced nitric oxide generation and endothelial dysfunction, which have implicated in the development of accelerated atherosclerosis in T2DM individuals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A decrease in insulin receptor number cannot be demonstrated in over half of type 2 diabetic subjects, and reduced insulin binding correlates poorly with severity of insulin resistance.

    “a decrease in insulin receptor number cannot be demonstrated in over half of type 2 diabetic subjects, and it has been difficult to demonstrate a correlation between reduced insulin binding and the severity of insulin resistance [156–158].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [156] Kashiwagi A Verso MA Andrews J In vitro insulin resistance of human adipocytes isolated from subjects with noninsulin-dependent diabetes mellitus The Journal of Clinical Investigation 1983 72 4 1246 1254 6355180 PMC370408 source

      Not checked in the free run.

    • cites [157] Lonnroth P Digirolamo M Krotkiewski M Smith U Insulin binding and responsiveness in fat cells from patients with reduced glucose tolerance and type II diabetes Diabetes 1983 32 8 748 754 6347772 source

      Not checked in the free run.

    • cites [158] Olefsky JM Reaven GM Insulin binding in diabetes. Relationships with plasma insulin levels and insulin sensitivity Diabetes 1977 26 7 680 688 873075 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of the MAPK kinase pathway prevents insulin-stimulated cell growth but has no effect on insulin's metabolic actions.

    “Inhibition of the MAPK kinase pathway prevents the stimulation of cell growth by insulin but has no effect on the metabolic actions of the hormone [147].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Lazar DF Wiese RJ Brady MJ Mitogen-activated protein kinase kinase inhibition does not block the stimulation of glucose utilization by insulin The Journal of Biological Chemistry 1995 270 35 20801 20807 7657664 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PI3K inhibitors impair glucose transport and block activation of glycogen synthase and HK-II expression.

    “Inhibitors of PI3K impair glucose transport and block the activation of glycogen synthase and hexokinase- (HK-) II expression [138–146]”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [138] Saltiel AR Kahn CR Insulin signalling and the regulation of glucose and lipid metabolism Nature 2001 414 6865 799 806 11742412 source

      Not checked in the free run.

    • cites [139] Pessin JE Saltiel AR Signaling pathways in insulin action: molecular targets of insulin resistance The Journal of Clinical Investigation 2000 106 2 165 169 10903329 PMC314316 source

      Not checked in the free run.

    • cites [140] Whitehead JP Clark SF Ursø B James DE Signalling through the insulin receptor Current Opinion in Cell Biology 2000 12 2 222 228 10712920 source

      Not checked in the free run.

    • cites [141] Ellis L Clauser E Morgan DO Edery M Roth RA Rutter WJ Replacement of insulin receptor tyrosine residues 1162 and 1163 compromises insulin-stimulated kinase activity and uptake of 2-deoxyglucose Cell 1986 45 5 721 732 3518947 source

      Not checked in the free run.

    • cites [142] Chou CK Dull TJ Russell DS Human insulin receptors mutated at the ATP-binding site lack protein tyrosine kinase activity and fail to mediate postreceptor effects of insulin The Journal of Biological Chemistry 1987 262 4 1842 1847 3100537 source

      Not checked in the free run.

    • cites [143] Virkamäki A Ueki K Kahn CR Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance The Journal of Clinical Investigation 1999 103 7 931 943 10194465 PMC408269 source

      Not checked in the free run.

    • cites [144] Sun XJ Miralpeix M Myers MG Jr. Expression and function of IRS-1 in insulin signal transmission Journal of Biological Chemistry 1992 267 31 22662 22672 1385403 source

      Not checked in the free run.

    • cites [145] Cross D Alessi D Vandenheed J McDowell H Hundal H Cohen P The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin but not rapamycin Biochemical Journal 1994 267 303 321 PMC1137550 7945242

      Not checked in the free run.

    • cites [146] Osawa H Sutherland C Robey RB Printz RL Granner DK Analysis of the signaling pathway involved in the regulation of hexokinase II gene transcription by insulin The Journal of Biological Chemistry 1996 271 28 16690 16694 8663315 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early studies found a modest 20-30% reduction in insulin binding to monocytes and adipocytes from type 2 diabetic patients, but this was not a consistent finding.

    “Early studies have demonstrated a modest 20–30% reduction in insulin binding to monocytes and adipocytes from type 2 diabetic patients, but this has not been a consistent finding [1, 151–154].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [1] DeFronzo RA Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes Diabetes Reviews 1997 5 3 177 269

      Not checked in the free run.

    • cites [151] Freidenberg GR Henry RR Klein HH Reichart DR Olefsky JM Decreased kinase activity of insulin receptors from adipocytes of non-insulin-dependent diabetic subjects Journal of Clinical Investigation 1987 79 1 240 250 3540010 PMC424032 source

      Not checked in the free run.

    • cites [152] Caro JF Sinha MK Raju SM Insulin receptor kinase in human skeletal muscle from obese subjects with and without noninsulin dependent diabetes The Journal of Clinical Investigation 1987 79 5 1330 1337 3033021 PMC424378 source

      Not checked in the free run.

    • cites [153] Caro JF Ittoop O Pories WJ Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity The Journal of Clinical Investigation 1986 78 1 249 258 3522628 PMC329556 source

      Not checked in the free run.

    • cites [154] Trischitta V Brunetti A Chiavetta A Benzi L Papa V Vigneri R Defects in insulin-receptor internalization and processing in monocytes of obese subjects and obese NIDDM patients Diabetes 1989 38 12 1579 1584 2684714 source

      Not checked in the free run.

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

    Premisecitation

    Hexokinase isoenzymes HK-I-IV catalyze the first committed step of glucose metabolism, converting free glucose to glucose-6-phosphate.

    “Hexokinase isoenzymes (HK-I–IV) catalyze the first committed step of glucose metabolism, the intracellular conversion of free glucose to glucose-6-phosphate (Glu-6-P) [183, 184, 186, 198].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [183] Bell GI Kayano T Buse JB Molecular biology of mammalian glucose transporters Diabetes Care 1990 13 3 198 208 2407475 source

      Not checked in the free run.

    • cites [184] Joost H-G Bell GI Best JD Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators American Journal of Physiology 2002 282 4 E974 E976 11882521

      Not checked in the free run.

    • cites [186] Rogers PA Fisher RA Harris H An electrophoretic study of the distribution and properties of human hexokinases Biochemical Genetics 1975 13 11-12 857 866 1239274 source

      Not checked in the free run.

    • cites [198] Printz RL Ardehali H Koch S Granner DK Human hexokinase II mRNA and gene structure Diabetes 1995 44 3 290 294 7883116 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Muscle tissue from lean and obese type 2 diabetic subjects has normal or increased GLUT4 mRNA expression and normal GLUT4 protein levels, showing that GLUT4 transcriptional and translational regulation is not impaired.

    “Muscle tissue from lean and obese type 2 diabetic subjects exhibits normal or increased levels of GLUT4 mRNA expression and normal levels of GLUT4 protein, thus demonstrating that transcriptional and translational regulation of GLUT4 is not impaired [190, 191].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [190] Pedersen O Bak JF Andersen PH Evidence against altered expression of GLUT1 or GLUT4 in skeletal muscle of patients with obesity for NIDDM Diabetes 1990 39 7 865 870 2354749 source

      Not checked in the free run.

    • cites [191] Eriksson J Koranyi L Bourey R Insulin resistance in type 2 (non-insulin-dependent) diabetic patients and their relatives is not associated with a defect in the expression of the insulin-responsive glucose transporter (GLUT-4) gene in human skeletal muscle Diabetologia 1992 35 2 143 147 1547918 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Point mutations in the HK-II gene found in type 2 diabetes are not close to glucose and ATP binding sites and are not associated with insulin resistance.

    “Several groups have looked for point mutations in the HK-II gene in individuals with type 2 diabetes, and, although several nucleotide substitutions have been found, none are close to the glucose and ATP binding sites and none have been associated with insulin resistance [203–205].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [203] Lehto M Huang X Davis EM Human hexokinase II gene: exon-intron organization, mutation screening in NIDDM, and its relationship to muscle hexokinase activity Diabetologia 1995 38 12 1466 1474 8786021 source

      Not checked in the free run.

    • cites [204] Laakso M Malkki M Kekalainen P Kuusisto J Deeb SS Polymorphisms of the human hexokinase II gene: lack of association with NIDDM and insulin resistance Diabetologia 1995 38 5 617 622 7489847 source

      Not checked in the free run.

    • cites [205] Echwald SM Bjorbaek C Hansen T Identification of four amino acid substitutions in hexokinase II and studies of relationships to NIDDM, glucose effectiveness, and insulin sensitivity Diabetes 1995 44 3 347 353 7883123 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations in the GLUT4 gene are very uncommon in type 2 diabetics and, when detected, have questionable physiologic significance.

    “Large populations of type 2 diabetics have been screened for mutations in the GLUT4 gene [196]. Such mutations are very uncommon and, when detected, have been of questionable physiologic significance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [196] Choi W-H O’Rahilly S Buse JB Molecular scanning of insulin-responsive glucose transporter (GLUT4) gene in NIDDM subjects Diabetes 1991 40 12 1712 1718 1756912 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Impaired glycogen synthesis has been documented in normal-glucose-tolerant offspring of two diabetic parents, first-degree relatives of type 2 diabetic individuals, and the normoglycemic twin of a monozygotic twin pair in which the other twin has type 2 diabetes.

    “Impaired glycogen synthesis also has been documented in the normal-glucose tolerant offspring of two diabetic parents, in the first-degree relatives of type 2 diabetic individuals, and in the normoglycemic twin of a monozygotic twin pair in which the other twin has type 2 diabetes [206, 210, 211].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [206] 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 12 1575 1586 1446799 source

      Not checked in the free run.

    • cites [210] Rothman DL Magnusson I Cline G Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus Proceedings of the National Academy of Sciences of the United States of America 1995 92 4 983 987 7862678 PMC42621 source

      Not checked in the free run.

    • cites [211] Vaag A Henriksen JE Madsbad S Holm N Beck-Nielsen H Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus The Journal of Clinical Investigation 1995 95 2 690 698 7860750 PMC295536 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In type 2 diabetic individuals, although both glucose transport and glucose phosphorylation are severely resistant to insulin, impaired glucose phosphorylation (HK-II) appears to be the rate-limiting step for insulin action.

    “These observations indicate that in type 2 diabetic individuals, although both glucose transport and glucose phosphorylation are severely resistant to the action of insulin, impaired glucose phosphorylation (HK-II) appears to be the rate-limiting step for insulin action.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Physiologic euglycemic hyperinsulinemia for 2 to 4 hours increases HK-II cytosolic activity, protein content, and mRNA by 50% to 200% in healthy nondiabetic subjects, with translocation of HK-II from cytosol to mitochondria.

    “In response to physiologic euglycemic hyperinsulinemia of 2 to 4 hours' duration, HK-II cytosolic activity, protein content, and mRNA levels increase by 50% to 200% in healthy nondiabetic subjects, and this is associated with the translocation of hexokinase II from the cytosol to the mitochondria.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Because GLUT4 transporter number in muscle of diabetic subjects is normal, impaired GLUT4 translocation and decreased intrinsic activity of the glucose transporter must be responsible for the defect in muscle glucose transport.

    “Because the number of GLUT4 transporters in the muscle of diabetic subjects is normal, impaired GLUT4 translocation and decreased intrinsic activity of the glucose transporter must be responsible for the defect in muscle glucose transport.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    These studies consistently show that abnormalities in both muscle glucose phosphorylation and glucose transport are well established early in the natural history of type 2 diabetes and cannot be explained by glucose toxicity.

    “Nonetheless, these studies are consistent in demonstrating that abnormalities in both muscle glucose phosphorylation and glucose transport are well established early in the natural history of type 2 diabetes and cannot be explained by glucose toxicity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In human skeletal muscle, HK-II transcription is regulated by insulin, whereas HK-I mRNA and protein levels are not affected by insulin.

    “In human skeletal muscle, HK-II transcription is regulated by insulin, whereas HK-I mRNA and protein levels are not affected by insulin [199, 200].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [199] Vogt C Ardehali H Iozzo P Regulation of hexokinase II expression in human skeletal muscle in vivo Metabolism 2000 49 6 814 818 10877213 source

      Not checked in the free run.

    • cites [200] Pendergrass M Koval J Vogt C Insulin-induced hexokinase II expression is reduced in obesity and NIDDM Diabetes 1998 47 3 387 394 9519744 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Studies using 31P NMR with [1-14C] glucose demonstrated that both insulin-stimulated muscle glucose transport and glucose phosphorylation are impaired in type 2 diabetic subjects, but the transport defect exceeds the phosphorylation defect.

    “Studies using 31P nuclear magnetic resonance in combination with [1-14C] glucose also have demonstrated that both insulin-stimulated muscle glucose transport and glucose phosphorylation are impaired in type 2 diabetic subjects, but the defect in transport exceeds the defect in phosphorylation [194].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [194] Cline GW Petersen KF Krssak M Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes The New England Journal of Medicine 1999 341 4 240 246 10413736 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The PP1 regulatory subunit has two serine phosphorylation sites, site 1 and site 2; phosphorylation of site 2 by cAMP-dependent protein kinase inactivates PP1, while phosphorylation of site 1 by insulin activates PP1 and stimulates glycogen synthase.

    “The regulatory subunit of PP1 has two serine phosphorylation sites, called site 1 and site 2. Phosphorylation of site 2 by cAMP-dependent protein kinase inactivates PP1; whereas phosphorylation of site 1 by insulin activates PP1, leading to the stimulation of glycogen synthase.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In forearm muscle of lean type 2 diabetics, insulin-stimulated glucose transport is markedly impaired, but intracellular glucose phosphorylation is impaired even more, increasing free intracellular glucose.

    “In forearm muscle, insulin-stimulated glucose transport (measured with the triple-tracer technique) is markedly impaired in lean type 2 diabetics [192, 193], but the rate of intracellular glucose phosphorylation is impaired to an even greater extent, resulting in an increase in the free glucose concentration within the intracellular space that is accessible to glucose.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [192] Bonadonna RC Del Prato S Saccomani MP Transmembrane glucose transport in skeletal muscle of patients with non-insulin-dependent diabetes The Journal of Clinical Investigation 1993 92 1 486 494 8326013 PMC293636 source

      Not checked in the free run.

    • cites [193] Bonadonna RC Del Prato S Bonora E Roles of glucose transport and glucose phosphorylation in muscle insulin resistance of NIDDM Diabetes 1996 45 supplement 3 915 925 8666143 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GLUT4 is the insulin-regulatable glucose transporter in skeletal muscle, has a Km of about 5 mmol/L close to plasma glucose, and is associated with HK-II.

    “GLUT4, the insulin regulatable transporter, is found in skeletal muscle, has a Km of approximately 5 mmol/L, which is close to that of the plasma glucose concentration, and is associated with HK-II [173, 174].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [173] Yu C Chen Y Cline GW Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle The Journal of Biological Chemistry 2002 277 52 50230 50236 12006582 source

      Not checked in the free run.

    • cites [174] Schmitz-Peiffer C Browne CL Oakes ND Alterations in the expression and cellular localization of protein kinase C isozymes ε and θ are associated with insulin resistance in skeletal muscle of the high-fat-fed rat Diabetes 1997 46 2 169 178 9000691 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The impairment in glycogen synthase activation is likely due to a defect in the ability of insulin to phosphorylate IRS-1, causing a reduced association of the p85 subunit of PI 3-kinase with IRS-1 and decreased activation of PI3K.

    “The impairment in glycogen synthase activation is likely due to a defect in the ability of insulin to phosphorylate IRS-1, causing a reduced association of the p85 subunit of PI 3-kinase with IRS-1 and decreased activation of the enzyme PI3K.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Glycogen synthase mRNA and protein levels are decreased in muscle of type 2 diabetic patients, partly explaining decreased glycogen synthase activity.

    “Glycogen synthase mRNA and protein levels, however, are decreased in muscle of type 2 diabetic patients, partly explaining the decreased glycogen synthase activity [221, 222].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [221] Vestergaard H Lund S Larsen FS Bjerrum OJ Pedersen O Glycogen synthase and phosphofructokinase protein and mRNA levels in skeletal muscle from insulin-resistant patients with non-insulin-dependent diabetes mellitus The Journal of Clinical Investigation 1993 91 6 2342 2350 8514849 PMC443291 source

      Not checked in the free run.

    • cites [222] Vestergaard H Bjorbaek C Andersen PH Bak JF Pedersen O Impaired expression of glycogen synthase mRNA in skeletal muscle of NIDDM patients Diabetes 1991 40 12 1740 1745 1756915 source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    In Danish type 2 diabetic subjects, several silent nucleotide substitutions were found in the PP1 and ISPK-1 genes.

    “Several silent nucleotide substitutions were found in the PP1 and ISPK-1 genes in the Danish population”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [226] Bjørbæk C Vik TA Echwald SM Cloning of a human insulin-stimulated protein kinase (ISPK-1) gene and analysis of coding regions and mRNA levels of the ISPK-1 and the protein phosphatase-1 genes in muscle from NIDDM patients Diabetes 1995 44 1 90 97 7813820 source

      Not checked in the free run.

    • cites [227] Prochazka M Mochizuki H Baier LJ Cohen PTW Bogardus C Molecular and linkage analysis of type-1 protein phosphatase catalytic beta-subunit gene: lack of evidence for its major role in insulin a resistance in Pima Indians Diabetologia 1995 38 4 461 466 7796987 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Insulin has no effect on muscle PFK activity, mRNA levels, or protein content in either nondiabetic or diabetic individuals.

    “Insulin has no effect on muscle PFK activity, mRNA levels, or protein content in either nondiabetic or diabetic individuals [221].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [221] Vestergaard H Lund S Larsen FS Bjerrum OJ Pedersen O Glycogen synthase and phosphofructokinase protein and mRNA levels in skeletal muscle from insulin-resistant patients with non-insulin-dependent diabetes mellitus The Journal of Clinical Investigation 1993 91 6 2342 2350 8514849 PMC443291 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under basal conditions, total glycogen synthase activity in type 2 diabetic subjects is reduced, and insulin's ability to activate glycogen synthase is severely impaired.

    “Under basal conditions, total glycogen synthase activity in type 2 diabetic subjects is reduced, and the ability of insulin to activate glycogen synthase is severely impaired [7, 215–217].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [7] Cusi K Maezono K Osman A Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle The Journal of Clinical Investigation 2000 105 3 311 320 10675357 PMC377440 source

      Not checked in the free run.

    • cites [215] Damsbo P Vaag A Hother-Nielsen O Beck-Nielsen H Reduced glycogen synthase activity in skeletal muscle from obese patients with and without type 2 (non-insulin-dependent) diabetes mellitus Diabetologia 1991 34 4 239 245 1906024 source

      Not checked in the free run.

    • cites [216] Mandarino LJ Wright KS Verity LS Effects of insulin infusion on human skeletal muscle pyruvate dehydrogenase, phosphofructokinase, and glycogen synthase: evidence for their role in oxidative and nonoxidative glucose metabolism The Journal of Clinical Investigation 1987 80 3 655 663 2957389 PMC442287 source

      Not checked in the free run.

    • cites [217] Thorburn AW Gumbiner B Bulacan F Wallace P Henry RR Intracellular glucose oxidation and glycogen synthase activity are reduced in non-insulin-dependent (type II) diabetes independent of impaired glucose uptake The Journal of Clinical Investigation 1990 85 2 522 529 2105341 PMC296454 source

      Not checked in the free run.

86 of 86

  • The paper relies on this without support.

    Basal and insulin-stimulated glucose oxidation rates are not reduced in normal glucose-tolerant offspring of two diabetic parents and in first-degree relatives of type 2 diabetic subjects, but are decreased in overtly diabetic subjects.

    “Consistent with this scenario, the rates of basal and insulin-stimulated glucose oxidation are not reduced in the normal glucose-tolerant offspring of two diabetic parents and in the first-degree relatives of type 2 diabetic subjects; whereas they are decreased in overtly diabetic subjects.”
1 of 1

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?

  • Any impairments occur on main phosphorylation sites will reduce insulin receptor tyrosine kinase activity, eventually affecting the insulin function.

    “Therefore, any impairments occur on main phosphorylation sites will reduce insulin receptor tyrosine kinase activity, eventually affecting the insulin function (88–90).”

    From Diabetes and Sarcopenic Obesity: Pathogenesis, Diagnosis, and Treatments (2020) · cites this paper as [88]

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.

  • Conflicting receptor-phosphorylation results for diabetic offspring

    Minor

    The paper says insulin-resistant offspring of diabetic parents have substantially decreased insulin receptor tyrosine phosphorylation, then says the same group has a normal increase in that measurement. These opposing results concern the signaling defect discussed in the section.

1 of 1

Cites

2 retracted

Flagged first, then by citations

Research works printed but not linked: 25

  1. 1997, Diabetes Reviews, 5, 177
  2. 1939, Clinical Science, 4, 120
  3. 1994, Diabetes Reviews, 2, 29
  4. 1996, Journal of Hypertension, 14, 489
  5. 1982, International Journal of Obesity, 6, 73
  6. 1990, Current Opinion in Cardiology, 5, 586
  7. 1999, American Journal of Physiology, 276, E352
  8. 2003, American Journal of Physiology, 284, E741
  9. 2007, Diabetes, 56
  10. 2008, Diabetes, 56
  11. 2002, Diabetes, 51, 144, 10.2337/diabetes.51.1.144 · DOI · Paper page
  12. 1984, Journal of Applied Physiology Respiratory Environmental and Exercise Physiology, 56, 831
  13. 2007, Diabetes, 56
  14. 1994, Biochemical Journal, 267, 303
  15. 2001, Diabetes, 50, 2572
  16. 1999, The Journal of Clinical Investigation, 103, 253, 10.1172/JCI5001 · DOI · Paper page
  17. 10.1074/jbc.M200958200 · DOI · Paper page
  18. 1997, American Journal of Physiology, 273, E915
  19. 1999, American Journal of Cardiology, 84, 21J
  20. 2002, American Journal of Physiology, 282, E974
  21. 2000, Diabetes, 49, 284, 10.2337/diabetes.49.2.284 · DOI · Paper page
  22. 2001, American Journal of Physiology, 281, E72
  23. 1995, American Journal of Physiology, 269, E701
  24. 1986, American Journal of Physiology, 251, E489
  25. 1992, American Journal of Physiology, 263, E79

Cited by

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Related

Authors
Abdul-Ghani, M. A., & DeFronzo, R. A.
Affiliations
  • Division of Diabetes, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229, USA
  • The University of Texas at San Antonio Health Science Center (US)
ORCID
DeFronzo, Ralph A.
Venue
Journal of Biomedicine and Biotechnology
Publisher
Hindawi Limited
Published
2010
Volume
2010
Pages
1-19
ISSN
  • 1110-7243 (ISSN-L)
  • 1110-7251
DOI
10.1155/2010/476279
PMC
PMC2860140
OpenAlex
W2033524876
Semantic Scholar
ae0836fd0213314956d83d1c268fc71c268be37f
Cited by
670
References
236
Citations by year
2026: 28 · 2025: 40 · 2024: 46 · 2023: 57 · 2022: 55 · 2021: 56 · 2020: 47 · 2019: 38 · 2018: 44 · 2017: 42 · 2016: 43 · 2015: 38 · 2014: 36 · 2013: 32 · 2012: 38
FWCI
2.78
Type
journal article
Language
en
Open access
Licence
Locations
  • BioMed Research International (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
insulin resistance, skeletal muscle, insulin signaling, glucose uptake, glucose transport, glucose phosphorylation, glycogen synthesis, glucose oxidation, type 2 diabetes, obesity, metabolic syndrome, fatty acid metabolism, mitochondrial dysfunction, oxidative phosphorylation
MeSH terms
Animals, Humans, Insulin Resistance, Muscle, Skeletal

About these checks

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

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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