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Cited by 137Diabetes, Cardiovascular Risks, and LipoproteinsNitric Oxide and Endothelin EffectsCardiovascular Function and Risk Factors

The Vasculature in Prediabetes

Open access
Wasserman, David H., Wang, Thomas J., Brown, Nancy J.·2018·Circulation Research
DOI 10.1161/circresaha.118.311912PMC PMC5901903
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Abstract

The frequency of prediabetes is increasing as the prevalence of obesity rises worldwide. In prediabetes, hyperglycemia, insulin resistance, and inflammation and metabolic derangements associated with concomitant obesity cause endothelial vasodilator and fibrinolytic dysfunction, leading to increased risk of cardiovascular and renal disease. Importantly, the microvasculature affects insulin sensitivity by affecting the delivery of insulin and glucose to skeletal muscle; thus, endothelial dysfunction and extracellular matrix remodeling promote the progression from prediabetes to diabetes mellitus. Weight loss is the mainstay of treatment in prediabetes, but therapies that improved endothelial function and vasodilation may not only prevent cardiovascular disease but also slow progression to diabetes mellitus.

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Written from the paper’s full text.

TL;DR

This review argues that prediabetes, whose prevalence is rising with obesity, involves endothelial vasodilator and fibrinolytic dysfunction, microvascular impairment, and extracellular matrix remodeling that increase cardiovascular and renal risk and promote progression to diabetes. Weight loss remains the mainstay of treatment, but therapies that improve endothelial function may also slow progression to diabetes.

Key findings

  • Prediabetes affects more than 38% of U.S. adults and reaches 50% among adults in China; it is associated with increased risk of cardiovascular disease, cancer, renal disease, and dementia. Progression rates vary by definition: in a pre-2004 meta-analysis, diabetes incidence was 4–6% with IGT alone, 6–9% with isolated IFG, and 15–19% with both IGT and IFG; in the DPP, annual diabetes incidence in patients with IGT was 11% in the control group.
  • Hyperglycemia, insulin resistance, and obesity-related inflammation cause endothelial vasodilator and fibrinolytic dysfunction. The microvasculature affects insulin and glucose delivery to skeletal muscle; impaired microvascular function and extracellular matrix remodeling promote progression from prediabetes to diabetes. In mice, deletion of skeletal and cardiac muscle VEGF-A reduced capillarity by ~50% and caused glucose intolerance and impaired muscle insulin-stimulated glucose uptake.
  • Weight loss and lifestyle modification reduce incident type 2 diabetes: in the DPP, intensive lifestyle modification led to 5.6 kg weight loss and a 58% reduction in incident diabetes over 2.8 years, with a sustained 34% risk reduction at 10 years; in the Da Qing Study, diet, exercise, and combined diet and exercise reduced incident T2DM by 31%, 46%, and 42%, respectively. Metformin reduced incident diabetes by 31% in the DPP, with an 18% persistent reduction in the DPP Outcomes Study.
  • Other agents also reduce incident diabetes in prediabetes: pioglitazone by 72% in ACT NOW, rosiglitazone by 60% in DREAM, acarbose by 25% in STOP-NIDDM, and liraglutide resulted in 2% versus 6% progression to T2DM over three years in the SCALE Obesity and Prediabetes study. Some therapies that improve endothelial function, such as ACE inhibitors/ARBs and PDE5 inhibitors, may improve insulin sensitivity, but effects on diabetes prevention and cardiovascular outcomes vary.

Methods

  • Narrative review; no primary data collection or systematic search strategy is described.
  • Synthesizes human clinical trials, meta-analyses, physiological studies using glucose clamps and IVGTT, and mechanistic animal studies.
  • Main analysis is qualitative integration of mechanisms linking prediabetes to vascular dysfunction and of treatment effects on diabetes progression and cardiovascular risk.

Limitations

  • The paper does not state limitations.
  • Evident: as a narrative review, it lacks a systematic search or quantitative synthesis, and conclusions depend on cited studies of heterogeneous design, populations, and outcome definitions.
  • Evident: some cited evidence comes from animal models or small proof-of-concept human studies, and one cited reference is listed as “in press.”

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

Integrity signals

Registry

Crossref · 10.1161/circresaha.118.311912

Cites

246 of 246 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 310 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Ford et al estimated a relative risk of cardiovascular disease of 1.20 (95% CI 1.12-1.28) when 6.1 mmol/L was used to define IFG (IFG-WHO).

    “Ford et al estimated a relative risk of cardiovascular disease of 1.20 (95% CI 1.12-1.28) when 6.1 mmol/L (110 mg/dL) was used to define IFG (IFG-WHO)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Ford ES Zhao G Li C Pre-diabetes and the risk for cardiovascular disease: a systematic review of the evidence J Am Coll Cardiol 2010 55 1310 7 20338491 source

      Not checked in the free run.

  • Premisenone given

    HbA1c measurement has less predictive value for progression to diabetes than other prediabetes criteria.

    “In general, HbA1c measurement has less predictive value.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Ford et al estimated a relative risk of cardiovascular disease of 1.18 (95% CI 1.09-1.28) when 5.5 mmol/L (IFG-ADA) was used.

    “a relative risk of 1.18 (95% CI 1.09-1.28) when 5.5 mmol/L (IFG-ADA) was used.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Ford ES Zhao G Li C Pre-diabetes and the risk for cardiovascular disease: a systematic review of the evidence J Am Coll Cardiol 2010 55 1310 7 20338491 source

      Not checked in the free run.

  • Premisecitation

    Subjects with prediabetes require more glucose than a subject with overt type 2 diabetes mellitus during a glucose clamp.

    “subjects with prediabetes require more glucose than a subject with overt type 2 diabetes mellitus (T2DM).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Laakso M Edelman SV Brechtel G Baron AD Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance J Clin Invest 1990 85 1844 52 2189893 PMC296649 source

      Not checked in the free run.

    • cites [7] Laakso M Edelman SV Brechtel G Baron AD Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM Diabetes 1992 41 1076 83 1499861 source

      Not checked in the free run.

  • Premisecitation

    In the Rotterdam Study, 75% of patients with IFG progressed to T2DM over their lifetime.

    “In a population-based Rotterdam Study of adults aged 45 years, 75% of patients with IFG progressed to T2DM over their lifetime.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Ligthart S van Herpt TT Leening MJ Kavousi M Hofman A Stricker BH van Hoek M Sijbrands EJ Franco OH Dehghan A Lifetime risk of developing impaired glucose metabolism and eventual progression from prediabetes to type 2 diabetes: a prospective cohort study Lancet Diabetes Endocrinol 2016 4 44 51 26575606 source

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  • Classified as probably not a substantial claim. 20
  • May combine two claims. 75
  • The quote only partly states this claim. 1

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

    Premisenone given

    Without intervention, prediabetes often progresses to diabetes.

    “Without intervention, prediabetes often progresses to diabetes”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The frequency of prediabetes is increasing as the prevalence of obesity rises worldwide.

    “The frequency of prediabetes is increasing as the prevalence of obesity rises worldwide.”
    • Also stated in: § Introduction · plain
      “As the prevalence of obesity grows worldwide, the prevalence of prediabetes is also increasing.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Menke A Casagrande S Geiss L Cowie CC Prevalence of and Trends in Diabetes Among Adults in the United States, 1988-2012 JAMA 2015 314 1021 9 26348752 source

      Not checked in the free run.

    • cites [2] Guariguata L Whiting DR Hambleton I Beagley J Linnenkamp U Shaw JE Global estimates of diabetes prevalence for 2013 and projections for 2035 Diabetes Res Clin Pract 2014 103 137 49 24630390 source

      Not checked in the free run.

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

    Premisenone given

    Prediabetes is a heterogeneous disorder based on the classification criteria.

    “Based on the classification criteria, prediabetes is a heterogeneous disorder.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Endothelial dysfunction occurs early in the pathogenesis of atherosclerosis, and predicts future cardiovascular events.

    “Endothelial dysfunction occurs early in the pathogenesis of atherosclerosis, and predicts future cardiovascular events.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [30] Perticone F Ceravolo R Pujia A Ventura G Iacopino S Scozzafava A Ferraro A Chello M Mastroroberto P Verdecchia P Schillaci G Prognostic significance of endothelial dysfunction in hypertensive patients Circulation 2001 104 191 6 11447085 source

      Not checked in the free run.

    • cites [31] Heitzer T Schlinzig T Krohn K Meinertz T Munzel T Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease Circulation 2001 104 2673 8 11723017 source

      Not checked in the free run.

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      Not checked in the free run.

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

    Interpretationnone given

    Increased inflammation associated with obesity promotes endothelial dysfunction, extracellular matrix formation and changes in capillary density and glucose uptake, further promoting insulin resistance.

    “Increased inflammation associated with obesity promotes endothelial dysfunction, extracellular matrix (ECM) formation and changes in capillary density and glucose uptake, further promoting insulin resistance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Endothelial dysfunction and extracellular matrix remodeling promote the progression from prediabetes to diabetes.

    “endothelial dysfunction and extracellular matrix remodeling promote the progression from prediabetes to diabetes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mechanisms of vascular dysfunction observed in rodent models of diet-induced insulin resistance and prediabetes apply to human prediabetes.

  • May combine two claims.

    Interpretationreasoning

    Vascular dysfunction in prediabetes results not only from hyperglycemia but also from vascular insulin resistance and pro-inflammatory and metabolic consequences of attendant obesity.

    “vascular dysfunction results not only from effects of hyperglycemia, but also from vascular insulin resistance and from pro-inflammatory and metabolic consequences of attendant obesity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Prediabetes is associated with increased risk of cardiovascular disease, cancer, renal disease, and dementia.

    “prediabetes is associated with increased risk of cardiovascular disease, cancer, renal disease, and dementia.”
    • Also stated in: § Risk of Cardiovascular and Renal Disease in Prediabetes · plain
      “Even before the development of diabetes, prediabetes is associated with increased risks of macrovascular disease, nephropathy, neuropathy, cancer and dementia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a meta-analysis of prospective studies, the incidence of diabetes was 4-6% in individuals with IGT alone, 6-9% in individuals with isolated IFG, and 15-19% in individuals with both IGT and IFG.

    “the incidence of diabetes was 4-6% in individuals with IGT alone, 6-9% in individuals with isolated IFG, and 15-19% in individuals with both IGT and IFG.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Gerstein HC Santaguida P Raina P Morrison KM Balion C Hunt D Yazdi H Booker L Annual incidence and relative risk of diabetes in people with various categories of dysglycemia: a systematic overview and meta-analysis of prospective studies Diabetes Res Clin Pract 2007 78 305 12 17601626 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The relative risk of all-cause mortality was 1.13, 1.13, and 1.32 in IFG-ADA, IFG-WHO, and IGT, respectively.

    “The relative risk of all-cause mortality was 1.13, 1.13, and 1.32 in the same three groups.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Huang Y Cai X Mai W Li M Hu Y Association between prediabetes and risk of cardiovascular disease and all cause mortality: systematic review and meta-analysis BMJ 2016 355 i5953 27881363 PMC5121106

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IGT is characterized by impaired muscle insulin sensitivity as well as early and late phase insulin responses.

    “IGT is characterized by impaired muscle insulin sensitivity as well as early and late phase insulin responses.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [11] Jani R Molina M Matsuda M Balas B Chavez A DeFronzo RA Abdul-Ghani M Decreased non-insulin-dependent glucose clearance contributes to the rise in fasting plasma glucose in the nondiabetic range Diabetes Care 2008 31 311 5 18000182 source

      Not checked in the free run.

    • cites [12] Kanat M Norton L Winnier D Jenkinson C DeFronzo RA Abdul-Ghani MA Impaired early- but not late-phase insulin secretion in subjects with impaired fasting glucose Acta Diabetol 2011 48 209 17 21553243

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    • cites [13] Kanat M Mari A Norton L Winnier D DeFronzo RA Jenkinson C Abdul-Ghani MA Distinct beta-cell defects in impaired fasting glucose and impaired glucose tolerance Diabetes 2012 61 447 53 22275086 PMC3266412 source

      Not checked in the free run.

    • cites [14] Meyer C Pimenta W Woerle HJ Van Haeften T Szoke E Mitrakou A Gerich J Different mechanisms for impaired fasting glucose and impaired postprandial glucose tolerance in humans Diabetes Care 2006 29 1909 14 16873801 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the Toranomon Hospital Health Management Center Study, 7% of individuals who met HbA1c criteria and 9% of individuals with IFG progressed to diabetes.

    “In the Toranomon Hospital Health Management Center Study 7% of individuals who met HbA1c criteria and 9% of individuals with IFG progressed to diabetes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Kosaka K Noda M Kuzuya T Prevention of type 2 diabetes by lifestyle intervention: a Japanese trial in IGT males Diabetes Res Clin Pract 2005 67 152 62 15649575 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IFG is characterized primarily by impaired hepatic insulin sensitivity and a decrease in the first-phase insulin response.

    “IFG is characterized primarily by impaired hepatic insulin sensitivity and a decrease in the first-phase insulin response”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [11] Jani R Molina M Matsuda M Balas B Chavez A DeFronzo RA Abdul-Ghani M Decreased non-insulin-dependent glucose clearance contributes to the rise in fasting plasma glucose in the nondiabetic range Diabetes Care 2008 31 311 5 18000182 source

      Not checked in the free run.

    • cites [12] Kanat M Norton L Winnier D Jenkinson C DeFronzo RA Abdul-Ghani MA Impaired early- but not late-phase insulin secretion in subjects with impaired fasting glucose Acta Diabetol 2011 48 209 17 21553243

      Not checked in the free run.

    • cites [13] Kanat M Mari A Norton L Winnier D DeFronzo RA Jenkinson C Abdul-Ghani MA Distinct beta-cell defects in impaired fasting glucose and impaired glucose tolerance Diabetes 2012 61 447 53 22275086 PMC3266412 source

      Not checked in the free run.

    • cites [14] Meyer C Pimenta W Woerle HJ Van Haeften T Szoke E Mitrakou A Gerich J Different mechanisms for impaired fasting glucose and impaired postprandial glucose tolerance in humans Diabetes Care 2006 29 1909 14 16873801 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Insulin resistance precedes the development of hyperglycemia and T2DM and results in compensatory hyperinsulinemia.

    “Insulin resistance precedes the development of hyperglycemia and T2DM and results in compensatory hyperinsulinemia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Weyer C Bogardus C Mott DM Pratley RE The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus J Clin Invest 1999 104 787 94 10491414 PMC408438 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Increases in HbA1c that met the ADA definition of prediabetes were associated with increased risk of cardiovascular disease and coronary heart disease, but not with stroke or all-cause mortality.

    “Increases in HbA1C that met the ADA definition of prediabetes were associated with increased risk of cardiovascular disease and coronary heart disease, but not with stroke or all-cause mortality.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In prediabetes, hyperglycemia, insulin resistance, and inflammation and metabolic derangements associated with concomitant obesity cause endothelial vasodilator and fibrinolytic dysfunction, leading to increased risk of cardiovascular and renal disease.

    “In prediabetes, hyperglycemia, insulin resistance, and inflammation and metabolic derangements associated with concomitant obesity cause endothelial vasodilator and fibrinolytic dysfunction, leading to increased risk of cardiovascular and renal disease.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Associations between prediabetes and cardiovascular/renal disease reflect causal effects of prediabetes-related hyperglycemia, insulin resistance, and inflammation.

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

    Premisenone given

    Hyperglycemia and insulin resistance are the common threads of prediabetes.

    “Hyperglycemia and insulin resistance are the common threads of this condition, however.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Hyperglycemia ensues when insulin production cannot overcome insulin resistance.

    “Hyperglycemia ensues when insulin production cannot overcome insulin resistance.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Premisecitation

    The relative risk of cardiovascular disease associated with IGT was similar to that for IFG.

    “The relative risk associated with IGT was similar.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Ford ES Zhao G Li C Pre-diabetes and the risk for cardiovascular disease: a systematic review of the evidence J Am Coll Cardiol 2010 55 1310 7 20338491 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AGEs activate the ERK, JNK, p38, and PI3K pathways and promote activation of NF-κB.

    “AGEs activate the ERK, c-Jun N-terminal kinase (JNK), p38, and PI3K pathways and promote activation of NF-κB.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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    Premisecitation

    Activation of the polyol pathway leads to NADPH depletion and reduced concentration of the anti-oxidant glutathione.

    “activation of the polyol pathway leads to NADPH depletion and reduced concentration of the anti-oxidant glutathione.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Activated PKC contributes to endothelial dysfunction, increased endothelial permeability, and ECM expansion.

    “Activated PKC contributes to endothelial dysfunction,68, 69 increased endothelial permeability,70 and ECM expansion.71”
    Quote in the paperNot a substantial claim0 of 4 sources checked
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  • May combine two claims.

    Premisecitation

    In hyperglycemia, endothelial vasodilator dysfunction precedes the development of T2DM and is seen in both IFG and IGT.

    “In hyperglycemia, endothelial vasodilator dysfunction precedes the development of T2DM and is seen in both IFG and IGT.”
    Quote in the paperSubstantial claim0 of 4 sources checked
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  • May combine two claims.

    Premisecitation

    Insulin vasodilates skeletal muscle and coronary vasculature.

    “Insulin vasodilates skeletal muscle6, 37 and coronary38, 39 vasculature.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [6] Laakso M Edelman SV Brechtel G Baron AD Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance J Clin Invest 1990 85 1844 52 2189893 PMC296649 source

      Not checked in the free run.

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  • May combine two claims.

    Premisecitation

    Vascular insulin resistance leads to downregulation of IRS-1 and 2 and decreased phosphorylation of Akt and eNOS, whereas the ET-1 pathway remains unaffected.

    “Vascular insulin resistance leads to downregulation of IRS-1 and 2 and decreased phosphorylation of Akt and eNOS, whereas the ET-1 pathway remains unaffected.”
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    Premisecitation

    Increased intracellular NADH leads to an increase in glycerol-3-phosphate and activation of protein kinase C.

    “Increased intracellular NADH leads to an increase in glycerol-3-phosphate and activation of protein kinase C (PKC).”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Glycation is less in prediabetes than that defining diabetes.

    “Glycation is less in prediabetes than that defining diabetes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Reduced adiponectin concentrations are associated with increased inflammation and risks of diabetes and cardiovascular disease.

    “reduced adiponectin concentrations are associated with increased inflammation and risks of diabetes and cardiovascular disease.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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  • May combine two claims.

    Premisecitation

    M1-like macrophages secrete inflammatory cytokines such as TNF-α and IL-6, and studies in M1-like macrophage knockout mice suggest they also promote insulin resistance.

    “M1-like macrophages secrete inflammatory cytokines such as TNF-α and IL-6, and studies in M1-like macrophage knockout mice suggest they also promote insulin resistance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Under stimulation by B cells, effector T cells and Th1 cells release cytokines such as interferon-γ to further stimulate activation of macrophages and induce a shift in macrophages from an M2-like phenotype to an M1-like phenotype.

    “Under stimulation by B cells, effector T cells and Th1cells release cytokines such as interferon-γ to further stimulate activation of macrophages and induce a shift in macrophages from an M2-like phenotype to an M1-like phenotype.”
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    Premisenone given

    The total number of T cells, B cells, neutrophils and mast cells is increased in visceral adipose tissue, whereas the number of Th2 and regulatory T cells is unchanged or decreased.

    “The total number of T cells, B cells, neutrophils and mast cells is also increased, whereas the number of T-helper (Th2) and regulatory T cells (Treg) is unchanged or decreased.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Leptin suppresses appetite and enhances energy expenditure, but also stimulates pro-inflammatory immune cells, increases ROS production by endothelial cells, and facilitates formation of foam cells.

    “While leptin suppresses appetite and enhances energy expenditure, it also stimulates pro-inflammatory immune cells, increases ROS production by endothelial cells, and facilitates formation of foam cells.”
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  • May combine two claims.

    Premisecitation

    Lipid-laden macrophages accumulate in crown-like structures around dead adipocytes, and the presence of these crown-like structures is associated with inflammation and insulin resistance.

    “lipid-laden macrophages accumulate in crown-like structures around dead adipocytes.”
    • Also stated in: § Endothelial Vasodilator Dysfunction in Prediabetes · plain
      “The presence of these crown-like structures is associated with inflammation and insulin resistance.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [85] Cinti S Mitchell G Barbatelli G Murano I Ceresi E Faloia E Wang S Fortier M Greenberg AS Obin MS Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans J Lipid Res 2005 46 2347 55 16150820 source

      Not checked in the free run.

    • cites [86] Murano I Barbatelli G Parisani V Latini C Muzzonigro G Castellucci M Cinti S Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice J Lipid Res 2008 49 1562 8 18390487

      Not checked in the free run.

    • cites [87] Apovian CM Bigornia S Mott M Meyers MR Ulloor J Gagua M McDonnell M Hess D Joseph L Gokce N Adipose macrophage infiltration is associated with insulin resistance and vascular endothelial dysfunction in obese subjects Arterioscler Thromb Vasc Biol 2008 28 1654 9 18566296 PMC2728436

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FFAs reduce tyrosine phosphorylation of IRS-1/2 and inhibit the PI3K/Akt pathway, leading to decreased glucose transport and decreased phosphorylation of eNOS.

    “FFAs reduce tyrosine phosphorylation of IRS-1/2 and inhibit the PI3K/Akt pathway, leading to decreased glucose transport and decreased phosphorylation of eNOS.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [75] Dresner A Laurent D Marcucci M Griffin ME Dufour S Cline GW Slezak LA Andersen DK Hundal RS Rothman DL Petersen KF Shulman GI Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity J Clin Invest 1999 103 253 9 9916137 PMC407880 source

      Not checked in the free run.

    • cites [76] Wang XL Zhang L Youker K Zhang MX Wang J LeMaire SA Coselli JS Shen YH Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase Diabetes 2006 55 2301 10 16873694

      Not checked in the free run.

    • cites [77] Griffin ME Marcucci MJ Cline GW Bell K Barucci N Lee D Goodyear LJ Kraegen EW White MF Shulman GI Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade Diabetes 1999 48 1270 4 10342815 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, resistin concentrations are increased in prediabetes and elevated resistin concentrations are associated with cardiovascular events.

    “In humans, resistin concentrations are increased in prediabetes and elevated resistin concentrations are associated with cardiovascular events.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [92] Reilly MP Lehrke M Wolfe ML Rohatgi A Lazar MA Rader DJ Resistin is an inflammatory marker of atherosclerosis in humans Circulation 2005 111 932 9 15710760

      Not checked in the free run.

    • cites [93] Muse ED Feldman DI Blaha MJ Dardari ZA Blumenthal RS Budoff MJ Nasir K Criqui MH Cushman M McClelland RL Allison MA The association of resistin with cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis Atherosclerosis 2015 239 101 8 25585029 PMC4331252

      Not checked in the free run.

    • cites [94] Ohmori R Momiyama Y Kato R Taniguchi H Ogura M Ayaori M Nakamura H Ohsuzu F Associations between serum resistin levels and insulin resistance, inflammation, and coronary artery disease J Am Coll Cardiol 2005 46 379 80 16022972

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Insulin-induced capillary recruitment and microvascular dilation, measured by laser Doppler flowmetry during iontophoresis of acetylcholine, correlate with insulin sensitivity and are reduced in obese compared to lean women.

    “Insulin-induced capillary recruitment and microvascular dilation, measured by laser Doppler flowmetry during iontophoresis of acetylcholine, correlate with insulin sensitivity and are reduced in obese compared to lean women.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] de Jongh RT Serne EH IJ RG de Vries G Stehouwer CD Impaired microvascular function in obesity: implications for obesity-associated microangiopathy, hypertension, and insulin resistance Circulation 2004 109 2529 35 15136505 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endothelial t-PA release is diminished in obesity and in conditions associated with prediabetes, such as hypertension, but the effect of hyperglycemia is not well-defined.

    “Endothelial t-PA release is diminished in obesity and in conditions associated with prediabetes, such as hypertension, but the effect of hyperglycemia is not well-defined.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [130] Ridderstrale W Saluveer O Carlstrom M Jern S Hrafnkelsdottir TJ The impaired fibrinolytic capacity in hypertension is unaffected by acute blood pressure lowering J Thromb Thrombolysis 2011 32 399 404 21614456 source

      Not checked in the free run.

    • cites [131] Van Guilder GP Hoetzer GL Greiner JJ Stauffer BL DeSouza CA Metabolic syndrome and endothelial fibrinolytic capacity in obese adults Am J Physiol Regul Integr Comp Physiol 2008 294 R39 44 17959703 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    T-PA antigen levels are associated with increased risk of thrombotic events, but this is largely because 80% of t-PA antigen circulates complexed to PAI-1.

    “T-PA antigen levels are also associated with increased risk of thrombotic events, but this is largely because 80% of t-PA antigen circulates complexed to PAI-1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Chandler WL Alessi MC Aillaud MF Henderson P Vague P Juhan-Vague I Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex: relationship to elevated TPA antigen in patients with high PAI-1 activity levels Circulation 1997 96 761 8 9264480 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Impaired endothelium-dependent vasodilation results not only in impaired macrovascular function, but also in microvascular dysfunction, as measured by retinal artery vasodilation and heat-induced skin hyperemia.

    “Impaired endothelium-dependent vasodilation results not only in impaired macrovascular function, but also in microvascular dysfunction, as measured by retinal artery vasodilation and heat-induced skin hyperemia.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [105] Dorner GT Garhofer G Kiss B Polska E Polak K Riva CE Schmetterer L Nitric oxide regulates retinal vascular tone in humans Am J Physiol Heart Circ Physiol 2003 285 H631 6 12750062 source

      Not checked in the free run.

    • cites [106] Choi PJ Brunt VE Fujii N Minson CT New approach to measure cutaneous microvascular function: an improved test of NO-mediated vasodilation by thermal hyperemia J Appl Physiol (1985) 2014 117 277 83 24903917 PMC4122693 source

      Not checked in the free run.

    • cites [107] Kellogg DL Jr Liu Y Kosiba IF O’Donnell D Role of nitric oxide in the vascular effects of local warming of the skin in humans J Appl Physiol (1985) 1999 86 1185 90 10194201 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The prevalence of microalbuminuria, a marker of microvascular dysfunction, is increased in prediabetes and predicts cardiovascular morbidity.

    “the prevalence of microalbuminuria, a marker of microvascular dysfunction, is increased in prediabetes and predicts cardiovascular morbidity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Tissue-type plasminogen activator (t-PA) is stored in the endothelium and protects against local thrombosis.

    “Tissue-type plasminogen activator (t-PA) is stored in the endothelium and protects against local thrombosis.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [110] Emeis JJ van den Eijnden-Schrauwen Y van den Hoogen CM de Priester W Westmuckett A Lupu F An endothelial storage granule for tissue-type plasminogen activator J Cell Biol 1997 139 245 56 9314543 PMC2139817

      Not checked in the free run.

    • cites [111] Manneville JB Etienne-Manneville S Skehel P Carter T Ogden D Ferenczi M Interaction of the actin cytoskeleton with microtubules regulates secretory organelle movement near the plasma membrane in human endothelial cells J Cell Sci 2003 116 3927 38 12928328

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the Maastricht Study, microvascular function was impaired in prediabetes and there was a linear relationship between microvascular dysfunction and HbA1c and fasting glucose.

    “In the Maastricht Study, microvascular function was impaired in prediabetes and there was a linear relationship between microvascular dysfunction and HbA1c and fasting glucose.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Sorensen BM Houben AJ Berendschot TT Schouten JS Kroon AA van der Kallen CJ Henry RM Koster A Sep SJ Dagnelie PC Schaper NC Schram MT Stehouwer CD Prediabetes and Type 2 Diabetes Are Associated With Generalized Microvascular Dysfunction: The Maastricht Study Circulation 2016 134 1339 1352 27678264

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with IGT in the DPP, intensive lifestyle modification increased adiponectin and decreased CRP, IL-6, fibrinogen, and adhesion molecules e-selectin and ICAM-1, as well as insulin resistance.

    “In patients with IGT in the DPP, intensive lifestyle modification increased adiponectin and decreased CRP, IL-6, fibrinogen, and adhesion molecules e-selectin and intercellular adhesion molecule-1 (ICAM-1), as well as insulin resistance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Goldberg RB Temprosa M Mele L Orchard T Mather K Bray G Horton E Kitabchi A Krakoff J Marcovina S Perreault L White N Diabetes Prevention Program Research G Change in adiponectin explains most of the change in HDL particles induced by lifestyle intervention but not metformin treatment in the Diabetes Prevention Program Metabolism 2016 65 764 75 27085783 PMC5122461

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Insulin and insulin-like growth factor increase PAI-1 expression; several forkhead proteins are involved in the regulation of PAI-1 expression by insulin.

    “Insulin and insulin-like growth factor also increase PAI-1 expression; several forkhead proteins are involved in the regulation of PAI-1 expression by insulin.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [116] Schneider DJ Sobel BE Augmentation of synthesis of plasminogen activator inhibitor type 1 by insulin and insulin-like growth factor type I: implications for vascular disease in hyperinsulinemic states Proc Natl Acad Sci U S A 1991 88 9959 63 1719559 PMC52846

      Not checked in the free run.

    • cites [117] Vulin AI Stanley FM A Forkhead/winged helix-related transcription factor mediates insulin-increased plasminogen activator inhibitor-1 gene transcription J Biol Chem 2002 277 20169 76 11919188

      Not checked in the free run.

    • cites [118] Jag UR Zavadil J Stanley FM Insulin acts through FOXO3a to activate transcription of plasminogen activator inhibitor type 1 Mol Endocrinol 2009 23 1587 602 19608644 PMC2754891

      Not checked in the free run.

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

    Premisecitation

    T-PA is released both constitutively and in response to receptor stimulation by bradykinin, acetylcholine or methacholine, substance P, and norepinephrine.

    “T-PA is released both constitutively and in response to receptor stimulation by bradykinin, acetylcholine or methacholine, substance P, and norepinephrine.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [125] Jern S Selin L Bergbrant A Jern C Release of tissue-type plasminogen activator in response to muscarinic receptor stimulation in human forearm Thromb Haemost 1994 72 588 94 7878638

      Not checked in the free run.

    • cites [126] Brown NJ Gainer JV Murphey LJ Vaughan DE Bradykinin stimulates tissue plasminogen activator release from human forearm vasculature through B(2) receptor-dependent, NO synthase-independent, and cyclooxygenase-independent pathway Circulation 2000 102 2190 6 11056091

      Not checked in the free run.

    • cites [127] Newby DE McLeod AL Uren NG Flint L Ludlam CA Webb DJ Fox KA Boon NA Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis Circulation 2001 103 1936 41 11306520

      Not checked in the free run.

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

    Premisenone given

    Increased shear force stimulates t-PA release.

    “Increased shear force also stimulates t-PA release.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Ang II, aldosterone, and inflammatory cytokines such as IL-6 and TNF-α, all of which are increased in visceral obesity, also stimulate PAI-1 expression.

    “Ang II, aldosterone, and inflammatory cytokines such as IL-6 and TNF-α, all of which are increased in visceral obesity, also stimulate PAI-1 expression.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [120] Vaughan DE Lazos SA Tong K Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis J Clin Invest 1995 95 995 1001 7884001 PMC441432

      Not checked in the free run.

    • cites [121] Brown NJ Kim KS Chen YQ Blevins LS Nadeau JH Meranze SG Vaughan DE Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production J Clin Endocrinol Metab 2000 85 336 44 10634408

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    cGMP decreases PAI-1 expression and impaired endothelial NO production may contribute to impaired fibrinolytic balance in prediabetes.

    “Conversely, cGMP decreases PAI-1 expression and impaired endothelial NO production may contribute to impaired fibrinolytic balance in prediabetes.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [122] Bouchie JL Hansen H Feener EP Natriuretic factors and nitric oxide suppress plasminogen activator inhibitor-1 expression in vascular smooth muscle cells. Role of cGMP in the regulation of the plasminogen system Arterioscler Thromb Vasc Biol 1998 18 1771 9 9812917

      Not checked in the free run.

    • cites [123] Ayers K Byrne LM DeMatteo A Brown NJ Differential effects of nebivolol and metoprolol on insulin sensitivity and plasminogen activator inhibitor in the metabolic syndrome Hypertension 2012 59 893 8 22353614 PMC3402551

      Not checked in the free run.

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

    Premisenone given

    Glucose can easily traverse narrow paracellular gaps.

    “Glucose can easily traverse narrow paracellular gaps.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Liraglutide treatment increases NO, decreases ET-1, normalizes endothelial function, and increases microvasculature blood flow and glucose disposal in obese rats.

    “Liraglutide treatment increases NO, decreases ET-1, normalizes endothelial function, and increases microvasculature blood flow and glucose disposal in obese rats.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [160] Chai W Fu Z Aylor KW Barrett EJ Liu Z Liraglutide prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats Am J Physiol Endocrinol Metab 2016 311 E640 8 27436611 PMC5142002 source

      Not checked in the free run.

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

    Premisenone given

    Fluid-phase transport can occur through paracellular junctions or by transcytosis through vesicles formed in endothelial cells.

    “Fluid-phase transport can occur through paracellular junctions or by transcytosis through vesicles formed in endothelial cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The gradient in insulin concentration from plasma to interstitial fluid is increased in humans with prediabetes and in mouse models of prediabetes during an insulin clamp, suggesting impaired microvascular insulin delivery.

    “the gradient in insulin concentration from plasma to interstitial fluid is increased in humans with prediabetes and in mouse models of prediabetes during an insulin clamp,152-154 suggesting impaired microvascular insulin delivery.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [152] Sjostrand M Gudbjornsdottir S Holmang A Lonn L Strindberg L Lonnroth P Delayed transcapillary transport of insulin to muscle interstitial fluid in obese subjects Diabetes 2002 51 2742 8 12196467 source

      Not checked in the free run.

    • cites [153] Kubota T Kubota N Kumagai H Yamaguchi S Kozono H Takahashi T Inoue M Itoh S Takamoto I Sasako T Kumagai K Kawai T Hashimoto S Kobayashi T Sato M Tokuyama K Nishimura S Tsunoda M Ide T Murakami K Yamazaki T Ezaki O Kawamura K Masuda H Moroi M Sugi K Oike Y Shimokawa H Yanagihara N Tsutsui M Terauchi Y Tobe K Nagai R Kamata K Inoue K Kodama T Ueki K Kadowaki T Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle Cell Metab 2011 13 294 307 21356519 source

      Not checked in the free run.

    • cites [154] Sandqvist M Strindberg L Schmelz M Lonnroth P Jansson PA Impaired delivery of insulin to adipose tissue and skeletal muscle in obese women with postprandial hyperglycemia J Clin Endocrinol Metab 2011 96 E1320 4 21677042 source

      Not checked in the free run.

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

    Premisecitation

    miR-33a and miR-33b are co-transcribed and act in conjunction with their host genes, Srebp1 and Srebp2, to regulate cholesterol synthesis.

    “They are co-transcribed and act in conjunction with their host genes, Srebp1 and Srebp2, to regulate cholesterol synthesis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [143] Najafi-Shoushtari SH Kristo F Li Y Shioda T Cohen DE Gerszten RE Naar AM MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis Science 2010 328 1566 9 20466882 PMC3840500 source

      Not checked in the free run.

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

    Premisecitation

    A variety of microRNAs influence pancreatic beta cell development and function.

    “a variety of microRNAs have been shown to influence pancreatic beta cell development and function.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [136] Lynn FC Skewes-Cox P Kosaka Y McManus MT Harfe BD German MS MicroRNA expression is required for pancreatic islet cell genesis in the mouse Diabetes 2007 56 2938 45 17804764 source

      Not checked in the free run.

    • cites [137] Melkman-Zehavi T Oren R Kredo-Russo S Shapira T Mandelbaum AD Rivkin N Nir T Lennox KA Behlke MA Dor Y Hornstein E miRNAs control insulin content in pancreatic beta-cells via downregulation of transcriptional repressors EMBO J 2011 30 835 45 21285947 PMC3049206 source

      Not checked in the free run.

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

    Premisecitation

    The most abundant microRNA in the liver is miR-122.

    “The most abundant microRNA in the liver is miR-122.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [134] Fernandez-Hernando C Ramirez CM Goedeke L Suarez Y MicroRNAs in metabolic disease Arterioscler Thromb Vasc Biol 2013 33 178 85 23325474 PMC3740757 source

      Not checked in the free run.

    • cites [140] Esau C Davis S Murray SF Yu XX Pandey SK Pear M Watts L Booten SL Graham M McKay R Subramaniam A Propp S Lollo BA Freier S Bennett CF Bhanot S Monia BP miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting Cell Metab 2006 3 87 98 16459310 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of the PDE5 inhibitor sildenafil to obese mice prevents inflammation and insulin resistance.

    “Administration of the phosphodiesterase (PDE5) inhibitor sildenafil to obese mice prevents inflammation162 and insulin resistance.159”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [162] Kang L Ayala JE Lee-Young RS Zhang Z James FD Neufer PD Pozzi A Zutter MM Wasserman DH Diet-induced muscle insulin resistance is associated with extracellular matrix remodeling and interaction with integrin alpha2beta1 in mice Diabetes 2011 60 416 26 21270253 PMC3028340 source

      Not checked in the free run.

    • cites [159] Ayala JE Bracy DP Julien BM Rottman JN Fueger PT Wasserman DH Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice Diabetes 2007 56 1025 33 17229936 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    miR-33 participates in the regulation of cholesterol synthesis, fatty acid metabolism, and insulin signaling.

    “These microRNAs participate in the regulation of cholesterol synthesis, fatty acid metabolism, and insulin signaling.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [141] Davalos A Goedeke L Smibert P Ramirez CM Warrier NP Andreo U Cirera-Salinas D Rayner K Suresh U Pastor-Pareja JC Esplugues E Fisher EA Penalva LO Moore KJ Suarez Y Lai EC Fernandez-Hernando C miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling Proc Natl Acad Sci U S A 2011 108 9232 7 21576456 PMC3107310

      Not checked in the free run.

    • cites [142] Rayner KJ Suarez Y Davalos A Parathath S Fitzgerald ML Tamehiro N Fisher EA Moore KJ Fernandez-Hernando C MiR-33 contributes to the regulation of cholesterol homeostasis Science 2010 328 1570 3 20466885 PMC3114628

      Not checked in the free run.

    • cites [143] Najafi-Shoushtari SH Kristo F Li Y Shioda T Cohen DE Gerszten RE Naar AM MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis Science 2010 328 1566 9 20466882 PMC3840500 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Skeletal muscle represents the bulk of insulin-sensitive tissue and is a major determinant of glucose tolerance.

    “Skeletal muscle represents the bulk of insulin-sensitive tissue and is a major determinant of glucose tolerance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Direct visualization of fluorescent insulin across the endothelium of capillaries perfusing mouse muscle using confocal microscopy shows that insulin moves across the capillary endothelium by a mechanism that is unsaturable, insulin receptor-independent, and conforms to the properties of fluid phase transport.

    “Direct visualization of fluorescent insulin across the endothelium of capillaries perfusing mouse muscle using confocal microscopy shows that insulin moves across the capillary endothelium by a mechanism that is unsaturable, insulin receptor-independent, and conforms to the properties of fluid phase transport”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158] Williams IM Valenzuela FA Kahl SD Ramkrishna D Mezo AR Young JD Wells KS Wasserman DH Insulin exits skeletal muscle capillaries by fluid-phase transport J Clin Invest 2018 in press PMC5785264 29309051

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of miR-122 reduces plasma cholesterol and hepatic steatosis, though the specific gene regulatory pathways involved are unclear.

    “Inhibition of miR-122 reduces plasma cholesterol and hepatic steatosis, though the specific gene regulatory pathways involved are unclear.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Esau C Davis S Murray SF Yu XX Pandey SK Pear M Watts L Booten SL Graham M McKay R Subramaniam A Propp S Lollo BA Freier S Bennett CF Bhanot S Monia BP miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting Cell Metab 2006 3 87 98 16459310 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Impaired adipose tissue blood flow does not contribute substantially to glucose disposal in prediabetes but may contribute to impaired lipid storage in adipocytes and increased ectopic lipid stores.

    “Impaired adipose tissue blood flow does not contribute substantially to glucose disposal in prediabetes but may contribute to impaired lipid storage in adipocytes and increased ectopic lipid stores.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [151] Emanuel AL Meijer RI Muskiet MH van Raalte DH Eringa EC Serne EH Role of Insulin-Stimulated Adipose Tissue Perfusion in the Development of Whole-Body Insulin Resistance Arterioscler Thromb Vasc Biol 2017 37 411 418 28126826

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of miR-375 is associated with reduced insulin secretion, thought to be mediated by inhibition of myotrophin.

    “Overexpression of miR-375 is associated with reduced insulin secretion, thought to be mediated by inhibition of myotrophin, a protein involved in insulin exocystosis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Poy MN Eliasson L Krutzfeldt J Kuwajima S Ma X Macdonald PE Pfeffer S Tuschl T Rajewsky N Rorsman P Stoffel M A pancreatic islet-specific microRNA regulates insulin secretion Nature 2004 432 226 30 15538371

      Not checked in the free run.

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

    Premisecitation

    The transition from normoglycemia to prediabetes and diabetes involves changes in the expression of many genes involved in fat and glucose metabolism.

    “The transition from normoglycemia to prediabetes and diabetes involves changes in the expression of many genes involved in fat and glucose metabolism.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Rome S Are extracellular microRNAs involved in type 2 diabetes and related pathologies? Clin Biochem 2013 46 937 45 23499584

      Not checked in the free run.

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

    Premisenone given

    Fluid-phase transport is determined by the balance between hydrostatic and oncotic pressures.

    “Fluid-phase transport is determined by the balance between hydrostatic and oncotic pressures.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Insulin-induced blood flow increases its own tissue delivery, as well as the delivery of nutrient substrates.

    “Insulin-induced blood flow increases its own tissue delivery, as well as the delivery of nutrient substrates.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155] Barrett EJ Wang H Upchurch CT Liu Z Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature Am J Physiol Endocrinol Metab 2011 301 E252 63 21610226 PMC3154531

      Not checked in the free run.

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

    Premisecitation

    miR-375 is an islet-specific microRNA that regulates both insulin secretion and beta cell mass.

    “miR-375, an islet-specific microRNA that regulates both insulin secretion and beta cell mass.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [138] Poy MN Eliasson L Krutzfeldt J Kuwajima S Ma X Macdonald PE Pfeffer S Tuschl T Rajewsky N Rorsman P Stoffel M A pancreatic islet-specific microRNA regulates insulin secretion Nature 2004 432 226 30 15538371

      Not checked in the free run.

    • cites [139] Poy MN Hausser J Trajkovski M Braun M Collins S Rorsman P Zavolan M Stoffel M miR-375 maintains normal pancreatic alpha- and beta-cell mass Proc Natl Acad Sci U S A 2009 106 5813 8 19289822 PMC2656556 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    miR-375 regulates many genes involved in cellular proliferation, which likely underlies its effect on the maintenance of beta cell mass.

    “miR-375 also regulates many genes involved in cellular proliferation, which likely underlies its effect on the maintenance of beta cell mass.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Poy MN Hausser J Trajkovski M Braun M Collins S Rorsman P Zavolan M Stoffel M miR-375 maintains normal pancreatic alpha- and beta-cell mass Proc Natl Acad Sci U S A 2009 106 5813 8 19289822 PMC2656556 source

      Not checked in the free run.

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

    Premisenone given

    In addition to reducing hyperglycemia, weight loss leads to significant improvements in other cardiovascular risk factors including blood pressure, lipids and biomarkers of inflammation.

    “In addition to reducing hyperglycemia, weight loss leads to significant improvements in other cardiovascular risk factors including blood pressure, lipids and biomarkers of inflammation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the DPP study of 3234 patients with IGT and BMI ≥24 kg/m2, intensive lifestyle modification led to a loss of 5.6 kg over an average follow-up of 2.8 years, and this was associated with a 58% reduction in incident diabetes.

    “In the DPP study of 3234 patients with IGT and BMI ≥24 kg/m2 (≥22 kg/m2 for Asian-Americans), intensive lifestyle modification led to a loss of 5.6 kg over an average follow-up of 2.8 years, and this was associated with a 58% reduction in incident diabetes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [189] Knowler WC Barrett-Connor E Fowler SE Hamman RF Lachin JM Walker EA Nathan DM Diabetes Prevention Program Research G Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin N Engl J Med 2002 346 393 403 11832527 PMC1370926 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Genetic deletion of the α2 subunit has no effect on insulin action in lean mice but increases capillaries and insulin action in obese mice.

    “Genetic deletion of the α2 subunit has no effect on insulin action in lean mice but increases capillaries and insulin action in obese mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Treatments that improve insulin action in rodent models of prediabetes normalize collagen levels and increase muscle capillaries.

    “Treatments that improve insulin action in rodent models of prediabetes normalize collagen levels and increase muscle capillaries.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [161] Bonner JS Lantier L Hocking KM Kang L Owolabi M James FD Bracy DP Brophy CM Wasserman DH Relaxin treatment reverses insulin resistance in mice fed a high-fat diet Diabetes 2013 62 3251 60 23801576 PMC3749347 source

      Not checked in the free run.

    • cites [162] Kang L Ayala JE Lee-Young RS Zhang Z James FD Neufer PD Pozzi A Zutter MM Wasserman DH Diet-induced muscle insulin resistance is associated with extracellular matrix remodeling and interaction with integrin alpha2beta1 in mice Diabetes 2011 60 416 26 21270253 PMC3028340 source

      Not checked in the free run.

    • cites [173] Kang L Lantier L Kennedy A Bonner JS Mayes WH Bracy DP Bookbinder LH Hasty AH Thompson CB Wasserman DH Hyaluronan accumulates with high-fat feeding and contributes to insulin resistance Diabetes 2013 62 1888 96 23349492 PMC3661617 source

      Not checked in the free run.

    • cites [179] Kang L Mokshagundam S Reuter B Lark DS Sneddon CC Hennayake C Williams AS Bracy DP James FD Pozzi A Zent R Wasserman DH Integrin-Linked Kinase in Muscle Is Necessary for the Development of Insulin Resistance in Diet-Induced Obese Mice Diabetes 2016 65 1590 600 27207548 PMC4878430 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Relaxin did not improve insulin action in isolated muscle, demonstrating the reliance on the microvascular for its insulin-sensitizing effect.

    “Relaxin did not improve insulin action in isolated muscle, demonstrating the reliance on the microvascular for its insulin-sensitizing effect.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [161] Bonner JS Lantier L Hocking KM Kang L Owolabi M James FD Bracy DP Brophy CM Wasserman DH Relaxin treatment reverses insulin resistance in mice fed a high-fat diet Diabetes 2013 62 3251 60 23801576 PMC3749347 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anti-CD44 antibody treatment reduces inflammation, and improves insulin sensitivity in obese mice.

    “Anti-CD44 antibody treatment reduces inflammation, and improves insulin sensitivity in obese mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [177] Kodama K Toda K Morinaga S Yamada S Butte AJ Anti-CD44 antibody treatment lowers hyperglycemia and improves insulin resistance, adipose inflammation, and hepatic steatosis in diet-induced obese mice Diabetes 2015 64 867 75 25294945 PMC4392898 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There was no impairment in insulin action in muscle isolated from lean VEGF-A knockout mice, demonstrating the requirement for intact microvasculature for this effect.

    “There was no impairment in insulin action in muscle isolated from lean VEGF-A knockout mice, demonstrating the requirement for intact microvasculature for this effect.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [165] Bonner JS Lantier L Hasenour CM James FD Bracy DP Wasserman DH Muscle-specific vascular endothelial growth factor deletion induces muscle capillary rarefaction creating muscle insulin resistance Diabetes 2013 62 572 80 23002035 PMC3554359

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    siRNA knockdown of FAK impairs glucose tolerance and insulin action in lean mice.

    “siRNA knockdown of FAK impairs glucose tolerance and insulin action in lean mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [184] Bisht B Srinivasan K Dey CS In vivo inhibition of focal adhesion kinase causes insulin resistance J Physiol 2008 586 3825 37 18587052 PMC2538921

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Hyaluronan is a major component of the glycocalyx of capillary lumens, where it may affect the access of insulin to tissues.

    “Hyaluronan is a major component of the glycocalyx of capillary lumens, where it may affect the access of insulin to tissues.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The pro-inflammatory prediabetic state results in an increase in skeletal muscle collagens and other ECM proteins and ECM remodeling.

    “The pro-inflammatory prediabetic state results in an increase in skeletal muscle collagens and other ECM proteins162, 171 and ECM remodeling.172”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [162] Kang L Ayala JE Lee-Young RS Zhang Z James FD Neufer PD Pozzi A Zutter MM Wasserman DH Diet-induced muscle insulin resistance is associated with extracellular matrix remodeling and interaction with integrin alpha2beta1 in mice Diabetes 2011 60 416 26 21270253 PMC3028340 source

      Not checked in the free run.

    • cites [171] Coletta DK Mandarino LJ Mitochondrial dysfunction and insulin resistance from the outside in: extracellular matrix, the cytoskeleton, and mitochondria Am J Physiol Endocrinol Metab 2011 301 E749 55 21862724 PMC3214002

      Not checked in the free run.

    • cites [172] Berria R Wang L Richardson DK Finlayson J Belfort R Pratipanawatr T De Filippis EA Kashyap S Mandarino LJ Increased collagen content in insulin-resistant skeletal muscle Am J Physiol Endocrinol Metab 2006 290 E560 5 16249255

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ECM expansion occurs in adipose tissue of obese subjects and limits adipocyte fat storage, leading to ectopic fat stores in liver and skeletal muscle, lipotoxicity, oxidative stress, and inflammation.

    “ECM expansion occurs in adipose tissue of obese subjects and limits adipocyte fat storage,185 leading to ectopic fat stores in liver and skeletal muscle, lipotoxicity, oxidative stress, and inflammation.186”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [185] Crewe C An YA Scherer PE The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis J Clin Invest 2017 127 74 82 28045400 PMC5199684 source

      Not checked in the free run.

    • cites [186] Williams AS Kang L Wasserman DH The extracellular matrix and insulin resistance Trends Endocrinol Metab 2015 26 357 66 26059707 PMC4490038 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased PAI-1 in prediabetes contributes to fibrosis, as does elevated concentrations of the adipokine thrombospondin-1.

    “Increased PAI-1 in prediabetes contributes to fibrosis, as does elevated concentrations of the adipokine thrombospondin-1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Varma V Yao-Borengasser A Bodles AM Rasouli N Phanavanh B Nolen GT Kern EM Nagarajan R Spencer HJ 3rd Lee MJ Fried SK McGehee RE Jr Peterson CA Kern PA Thrombospondin-1 is an adipokine associated with obesity, adipose inflammation, and insulin resistance Diabetes 2008 57 432 9 18057090 PMC2877915 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Relaxin administration caused endothelial relaxation and reversed insulin resistance in obese mice.

    “Relaxin administration caused endothelial relaxation and reversed insulin resistance in obese mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [161] Bonner JS Lantier L Hocking KM Kang L Owolabi M James FD Bracy DP Brophy CM Wasserman DH Relaxin treatment reverses insulin resistance in mice fed a high-fat diet Diabetes 2013 62 3251 60 23801576 PMC3749347 source

      Not checked in the free run.

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

    Premisecitation

    The ECM is a dynamic structure comprised of proteins and proteoglycans that remodels in responses to injury and inflammation.

    “The ECM is a dynamic structure comprised of proteins and proteoglycans that remodels in responses to injury and inflammation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Hynes RO The extracellular matrix: not just pretty fibrils Science 2009 326 1216 9 19965464 PMC3536535 source

      Not checked in the free run.

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

    Premisenone given

    The integrin α2 subunit is highly expressed in endothelial cells, fibroblasts and other cell types.

    “The integrin α2 subunit is highly expressed in endothelial cells, fibroblasts and other cell types.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Skeletal muscle ILK knockout has no effect on insulin action in lean mice but increases capillaries and insulin action in obese mice.

    “Skeletal muscle ILK knockout has no effect on insulin action in lean mice but increases capillaries and insulin action in obese mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [179] Kang L Mokshagundam S Reuter B Lark DS Sneddon CC Hennayake C Williams AS Bracy DP James FD Pozzi A Zent R Wasserman DH Integrin-Linked Kinase in Muscle Is Necessary for the Development of Insulin Resistance in Diet-Induced Obese Mice Diabetes 2016 65 1590 600 27207548 PMC4878430 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Capillary skeletal and cardiac muscle rarefaction resulted in glucose intolerance and impairments in skeletal and cardiac muscle insulin-stimulated glucose uptake in vivo.

    “Capillary skeletal and cardiac muscle rarefaction resulted in glucose intolerance and impairments in skeletal and cardiac muscle insulin-stimulated glucose uptake in vivo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [165] Bonner JS Lantier L Hasenour CM James FD Bracy DP Wasserman DH Muscle-specific vascular endothelial growth factor deletion induces muscle capillary rarefaction creating muscle insulin resistance Diabetes 2013 62 572 80 23002035 PMC3554359

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the XENDOS study, orlistat therapy resulted in a 5.8 kg weight loss and reduced the progression of IGT to T2DM by 37%.

    “In the XENDOS study, orlistat therapy resulted in a 5.8 kg weight loss and reduced the progression of IGT to T2DM by 37%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] Torgerson JS Hauptman J Boldrin MN Sjostrom L XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients Diabetes Care 2004 27 155 61 14693982 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At ten years, the sustained risk reduction was 34% in the lifestyle arm compared to placebo even though weights were no longer different between groups.

    “At ten years, the sustain risk reduction was 34% in the lifestyle arm compared to placebo even though weights were no longer different between groups.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Diabetes Prevention Program Research G Knowler WC Fowler SE Hamman RF Christophi CA Hoffman HJ Brenneman AT Brown-Friday JO Goldberg R Venditti E Nathan DM 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study Lancet 2009 374 1677 86 19878986 PMC3135022 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effect of metformin in the DPP was greater in more obese patients and those with a higher fasting glucose.

    “The effect was greater in more obese patients and those with a higher fasting glucose.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [189] Knowler WC Barrett-Connor E Fowler SE Hamman RF Lachin JM Walker EA Nathan DM Diabetes Prevention Program Research G Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin N Engl J Med 2002 346 393 403 11832527 PMC1370926 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The reduction of incident diabetes appears to be proportionate to the amount of weight loss, but plateaus at a loss of 10% of body mass.

    “The reduction of incident diabetes appears to be proportionate to the amount of weight loss, but plateaus at a loss of 10% of body mass.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The GLP-1 receptor-independent vasodilation requires degradation of GLP-1 to GLP-1 (9-36) by DPP-4 and involves NO.

    “The latter requires degradation of GLP-1 to GLP-1 (9-36) by DPP-4 and involves NO.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [211] Green JB Bethel MA Armstrong PW Buse JB Engel SS Garg J Josse R Kaufman KD Koglin J Korn S Lachin JM McGuire DK Pencina MJ Standl E Stein PP Suryawanshi S Van de Werf F Peterson ED Holman RR Group TS Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes New England Journal of Medicine 2015 373 232 42 26052984

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sildenafil treatment improved fibrinolytic balance, decreasing PAI-1 concentrations without altering t-PA concentrations.

    “Sildenafil treatment also improved fibrinolytic balance, decreasing PAI-1 concentrations without altering t-PA concentrations.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [234] Ramirez CE Nian H Yu C Gamboa JL Luther JM Brown NJ Shibao CA Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial J Clin Endocrinol Metab 2015 100 4533 40 26580240 PMC4667163 source

      Not checked in the free run.

90 of 90

  • The paper relies on this without support.

    Mechanisms of vascular dysfunction observed in rodent models of diet-induced insulin resistance and prediabetes apply to human prediabetes.

    “Administration of the phosphodiesterase (PDE5) inhibitor sildenafil to obese mice prevents inflammation162 and insulin resistance.159”
    “Relaxin administration caused endothelial relaxation and reversed insulin resistance in obese mice.161”

  • The paper relies on this without support.

    Associations between prediabetes and cardiovascular/renal disease reflect causal effects of prediabetes-related hyperglycemia, insulin resistance, and inflammation.

    “prediabetes is associated with increased risk of cardiovascular disease, cancer, renal disease, and dementia.”
    “Among patients with prediabetes, factors associated with insulin resistance including increased oxidative stress, inflammation, and dyslipidemia contribute to microvascular and macrovascular disease.”
2 of 2

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?

  • Obesity and prediabetes cause endothelial dysfunction, which is reversible with weight loss if severe vascular injury has not occurred.

    “Obesity and prediabetes also cause endothelial dysfunction, which is reversible with weight loss if severe vascular injury has not occurred38,39.”

    From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [39]

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.

  • GLP-1 receptor antagonism is substituted for agonism

    Minor

    The treatment discussed is a GLP-1 receptor agonist, but the passage then calls its potential effect an effect of receptor antagonism. The same substitution recurs in the discussion of cardiovascular risk.

1 of 1

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Related

Authors
Wasserman, D. H., Wang, T. J., & Brown, N. J.
Affiliations
Vanderbilt University Medical Center (US)
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-04-13
Volume
122
Issue
8
Pages
1135-1150
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.118.311912
PMC
PMC5901903
OpenAlex
W2797223469
Semantic Scholar
35d7868ad62914a681d2e2484938facca3edd0a9
Cited by
137
References
246
Citations by year
2026: 12 · 2025: 13 · 2024: 10 · 2023: 22 · 2022: 28 · 2021: 16 · 2020: 18 · 2019: 10 · 2018: 7 · 2017: 1
FWCI
1.96
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL128983, R01HL132320, R01HL102780, T32HL007411, R01HL125426)
  • National Institute of Diabetes and Digestive and Kidney Diseases (U2CDK059637, R01DK108159, U24DK059637, R37DK050277, R01DK054902, R01DK050277, R56DK054902, R24DK096527, R01DK081572)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Keywords
prediabetes, endothelial dysfunction, microcirculation, insulin resistance, obesity, hyperglycemia, inflammation, vasodilation, fibrinolysis, extracellular matrix remodeling, weight loss, cardiovascular risk, diabetic nephropathy
MeSH terms
Angiotensin-Converting Enzyme Inhibitors, Animals, Blood Vessels, Cardiovascular Diseases, Combined Modality Therapy, Diabetes Mellitus, Type 2, Diet, Reducing, Endothelium, Vascular, Extracellular Matrix, Fatty Acids, Nonesterified, Fibrinolysis, Glucose, Humans, Hyperglycemia, Hypoglycemic Agents, Inflammation, Insulin Resistance, Life Style, Microcirculation, Obesity, Prediabetic State, Risk, Weight Loss, Disease Progression, Muscle, Skeletal, Metabolic Syndrome, MicroRNAs, Mice

About these checks

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

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

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

Statistics and arithmetic are recomputed, not judged.

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

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