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Cited by 177Nitric Oxide and Endothelin EffectsDiabetes, Cardiovascular Risks, and LipoproteinsCardiovascular Health and Disease Prevention

Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone

Open access
Tack, C. J. J., Ong, M. K. E., Lutterman, J. A., Smits, P.·1998·Diabetologia
DOI 10.1007/s001250050948
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Abstract

Insulin resistance is associated with a decreased vasodilator response to insulin. Because insulin's vasodilator effect is nitric oxide dependent, this impairment may reflect endothelial dysfunction. Troglitazone, an insulin-sensitiser, might thus improve insulin-dependent and/or endothelium-dependent vascular function in insulin resistant obese subjects. For 8 weeks, fifteen obese subjects were treated with either 400 mg troglitazone once daily or placebo, in a randomised, double-blind, cross-over design. At the end of each treatment period, we measured forearm vasodilator responses (plethysmography) to intra-arterial administered acetylcholine and sodium nitroprusside; insulin sensitivity and insulin-induced vascular and neurohumoral responses (clamp); vasoconstrictor responses to NC-monomethyl-L-arginine (L-NMMA) during hyperinsulinaemia; and ambulatory 24-h blood pressure (ABPM). Baseline data (placebo) of obese subjects were compared with those obtained in lean control subjects. Obese subjects were insulin resistant compared with leans (whole-body glucose uptake: 26.8+/-3.0 vs. 53.9+/-4.3 [tmol kgl min-, p < 0.001). Troglitazone improved whole-body glucose uptake (to 31.9+/-3.3 micromol x kg(-1) x min(-1) , p=0.028), and forearm glucose uptake (from 1.09+/-0.54 to 2.31+/-0.69 micromol dL(-1) x min(-1), p=0.006). Insulin-induced vasodilatation was blunted in obese subjects (percent increase in forearm blood flow (FBF) in lean 66.5+/-23.0%, vs. 10.1+/-11.3% in obese, p=0.04), but did not improve during troglitazone. Vascular responses to acetylcholine, sodium nitroprusside and L-NMMA did not differ between the obese and lean group, nor between both treatment periods in the obese individuals. In conclusion, in insulin resistant obese subjects, endothelial vascular function is normal despite impaired vasodilator responses to insulin. Troglitazone improved insulin sensitivity but it had no effects on endothelium-dependent and -independent vascular responses. These data do not support an association between insulin resistance and endothelial function.

AI snapshot

Written from the paper’s full text.

TL;DR

In obese, insulin-resistant, normotensive adults, insulin-induced forearm vasodilatation was blunted compared with lean controls, but endothelium-dependent and endothelium-independent vascular responses were preserved. Troglitazone modestly improved insulin sensitivity without restoring insulin-mediated vasodilatation or altering endothelial function.

Key findings

  • Obese subjects were insulin resistant: whole-body glucose uptake was 26.8 ± 3.0 vs 53.9 ± 4.3 mmol × kg⁻¹ × min⁻¹ in lean subjects (p < 0.001). Insulin-induced forearm blood flow increased 10.1 ± 11.3% in obese vs 66.5 ± 23.0% in lean subjects (p = 0.04).
  • Vascular responses to acetylcholine, sodium nitroprusside, and L-NMMA were not different between lean and obese subjects and were not affected by troglitazone.
  • Troglitazone improved whole-body glucose uptake to 31.9 ± 3.3 mmol × kg⁻¹ × min⁻¹ (p = 0.028) and insulin-induced forearm glucose uptake to 2.31 ± 0.69 mmol × dl⁻¹ × min⁻¹ (p = 0.006 vs placebo), but did not change insulin-induced vasodilatation (2.2 ± 4.9%, p = NS vs placebo).
  • No significant correlation was observed between vascular responses to acetylcholine and insulin sensitivity (r = 0.20, p = NS); the correlation between insulin-induced change in blood flow and whole-body glucose uptake was r = 0.39 (p = 0.056).

Methods

  • Randomized, placebo-controlled, double-blind crossover trial in 15 obese healthy volunteers (BMI 27–36 kg/m², age 25–50 years, normotensive) and 13 age- and sex-matched lean controls; treatment was troglitazone 400 mg/day or placebo for 8 weeks with a 2-week washout. Vascular responses were assessed in 13 obese subjects.
  • Forearm blood flow was measured by venous occlusion plethysmography during intra-arterial acetylcholine, sodium nitroprusside, and L-NMMA, plus a euglycaemic hyperinsulinaemic clamp (insulin 430 pmol × m⁻² × min⁻¹ for 120 min); 24-h ambulatory blood pressure was also monitored.
  • Analyses used paired and unpaired t tests, repeated measures ANOVA, and Spearman correlations; significance was set at p < 0.05.

Limitations

  • The paper states that it cannot exclude that a more pronounced increase in insulin sensitivity might result in greater insulin-mediated vasodilatation, and that no pharmacological therapy currently achieves this target.
  • The paper notes the study duration may have been relatively short, troglitazone effects were modest and variable between individuals, and a full dose-response curve of insulin on blood flow could not be constructed.
  • Evident from the text: the sample was small (15 obese, 13 lean; vascular responses in 13 obese), one obese subject was excluded from the troglitazone portion after surgery/complications and 6.4 kg weight loss, and one subject had near syncope during a clamp but her data were included.

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

Integrity signals

Registry

Crossref · 10.1007/s001250050948

Cites

42 of 42 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 27 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Vascular responses to sodium nitroprusside were similar between obese and lean subjects.

    “responses to endothelium-dependent as well as independent vasodilators were absolutely similar with those in the lean group.”
    Quote in the paperSubstantial claim
  • Findingown data

    Troglitazone did not affect the absolute or relative vascular responses to nitroprusside.

    “Troglitazone did not affect the absolute or relative vascular responses to nitroprusside (Fig. 2, lower panel).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Acetylcholine induced a dose-dependent increase in forearm blood flow in the experimental arm.

    “Acetylcholine induced a dose-dependent increase in FBF in the experimental arm.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Sodium nitroprusside induced a dose-dependent increase in forearm blood flow in the experimental arm.

    “Infusion of sodium nitroprusside induced a dosedependent increase in FBF in the experimental arm.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Responses to L-NMMA in the obese group were not different from those in lean subjects.

    “Responses in the obese group were not different from those in lean subjects and were not affected by troglitazone.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 22
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 20

  • May combine two claims.

    Findingown data

    Troglitazone did not affect the absolute or relative vascular responses to acetylcholine.

    “The absolute or relative vascular responses were not different between lean and obese, nor were they affected by troglitazone (Fig. 2, upper panel).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    The changes under these strictly double-blind placebo-controlled conditions were modest and largely variable between individuals.

    “However the changes under these strictly double-blind placebo-controlled conditions were modest and largely variable between individuals.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Troglitazone decreased mean ambulatory 24-h diastolic blood pressure (84.5 ± 1.2 to 81.5 ± 1.6 mmHg, p = 0.041).

    “Mean ambulatory 24-h diastolic blood pressure decreased during treatment with troglitazone, mean ambulatory 24-h systolic blood pressure did not change (Table 2).”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    The number of subjects in our study was larger than in Steinberg's study.

    “The number of subjects in our study was larger than in Steinberg's study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Obese group had higher plasma triglycerides and NEFA and lower HDL-cholesterol than lean group.

    “Mean plasma triglycerides (TG) and NEFA levels were higher, and HDL-cholesterol levels lower in the obese group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Troglitazone did not change baseline arterial norepinephrine concentration nor the insulin-induced absolute or percentual increase in norepinephrine.

    “Treatment with troglitazone did not change baseline arterial NE concentration nor the insulin-induced absolute or percentual increase in NE (all p = NS vs. placebo) (Table 3).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Troglitazone treatment was associated with slight decrements in NEFA (from 0.61 ± 0.07 to 0.47 ± 0.05 mmol/l, p = 0.06).

    “Troglitazone treatment was associated with slight decrements in NEFA (from 0.61 ± 0.07 to 0.47 ± 0.05 mmol × l ±1 , p = 0.06)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Total cholesterol, HDL-cholesterol and triglyceride concentrations did not significantly change with troglitazone.

    “total cholesterol, HDL-cholesterol and TG concentrations did not significantly change.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Eight weeks of treatment with troglitazone improved total-body as well as forearm insulin-mediated glucose uptake and tended to lower fasting insulin concentration.

    “Eight weeks of treatment with Troglitazone improved total-body as well as forearm insulin-mediated glucose uptake and tended to lower fasting insulin concentration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Responses in blood pressure and heart rate to insulin were not different between obese and lean subjects and were not influenced by troglitazone.

    “Responses in blood pressure and heart rate to insulin were not different between the two groups and were not influenced by troglitazone.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Obese group had higher weight, fat percentage and waist/hip ratio than lean group.

    “There was a clear difference with respect to weight, fat percentage and waist/hip ratio.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Ambulatory diastolic blood pressure decreased slightly, and elevated NEFA levels showed a tendency to improve.

    “Furthermore, ambulatory diastolic blood pressure decreased slightly, and elevated NEFA lev-els showed a tendency to improve.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Insulin infusion increased systolic blood pressure and pulse pressure in both groups.

    “Insulin infusion increased systolic but not diastolic blood pressure in both groups.As a result, pulse pressure increased significantly (Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Obese subjects in our group exhibited well known features of the insulin resistance syndrome, with insulin sensitivity clearly different from lean subjects.

    “Obese subjects in our group exhibited well known features of the insulin resistance syndrome [38], with insulin sensitivity clearly different from lean subjects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38]

      Not checked in the free run.

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

    Findingown data

    Obese group had higher mean office diastolic blood pressure than lean group.

    “Although all individuals were normotensive, mean office diastolic blood pressure was higher in the obese group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In NIDDM and hypertension, impaired endothelial function has been reported.

    “in NIDDM [10,11] and hypertension [12], an impaired endothelial function has been reported.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10]

      Not checked in the free run.

    • cites [11]

      Not checked in the free run.

    • cites [12]

      Not checked in the free run.

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

    Premisecitation

    Recent reports claim a reduced vasodilator response to metacholine and not to sodium nitroprusside in insulin resistant obese individuals, indicating a specific defect in endothelial-dependent vasodilatation.

    “Recent reports indeed claim a reduced vasodilator response to metacholine and not to sodium nitroprusside in insulin resistant obese individuals indicating a specific defect in endothelial-dependent vasodilatation [13].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13]

      Not checked in the free run.

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

    Study design and conductown data

    There was a two week wash-out period between treatment periods.

    “Between both treatment periods there was a two week wash-out period.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    Statistical analyses were only performed after prior verification of appropriateness by exclusion of period or sequence effects.

    “Statistical analyses were only performed after prior verification of appropriateness by exclusion of period or sequence effects [22].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Obesity represents a situation of pure insulin resistance, with the advantage that changes in insulin sensitivity are not confounded by changes in blood glucose concentrations (glucose toxicity).

    “In this study, obesity represents a situation of ªpureº insulin resistance, with the advantage that changes in insulin sensitivity are not confounded by changes in blood glucose concentrations (ªglucose toxicityº) [37].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37]

      Not checked in the free run.

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

    Premisecitation

    In uncomplicated NIDDM, no correlation was observed between an index of in vivo NO generation and insulin sensitivity.

    “Recently, in uncomplicated NIDDM, no correlation was observed between an index of in vivo NO generation and insulin sensitivity [32].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32]

      Not checked in the free run.

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

    Study design and conductnone given

    Identical changes occurred when forearm vascular resistance instead of forearm blood flow was used for analyses.

    “Identical changes occurred when FVR instead of FBF was used for analyses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Troglitazone improves metabolic parameters related to insulin sensitivity, but does not change the effect of insulin on vascular tone nor on endothelial function.

    “Troglitazone improves metabolic parameters related to insulin sensitivity, but it does not change the effect of insulin on vascular tone nor on endothelial function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Steinberg's study population had higher blood pressure values than ours, possibly explaining part of the observed differences.

    “Their study population (although strictly speaking normotensive), had higher blood pressure values (mean arterial pressure (MAP) » 100 mmHg) than ours (MAP » 92.5 mmHg), possibly explaining part of the observed differences [12].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12]

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The absence of a specific defect in vascular endothelial function in obese, insulin-resistant subjects suggests that alternative mechanisms may be responsible for insulin-mediated vasodilatation.

    “The absence of a specific defect in vascular endothelial function in obese, insulin-resistant subjects, despite a diminished insulin-induced vasodilatation, suggests that alternative mechanisms may be responsible for insulin-mediated vasodilatation.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Hypercholesterolaemia is firmly associated with disturbed endothelial function.

    “hypercholesterolaemia, a disorder that is firmly associated with disturbed endothelial function [33]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33]

      Not checked in the free run.

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

    Study design and conductown data

    Drug compliance was more than 95%.

    “Troglitazone was well tolerated, drug compliance was more than 95 %.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    During infusion of acetylcholine, nitroprusside and L-NMMA, intra-arterial blood pressure remained stable throughout.

    “During infusion of acetylcholine, nitroprusside and L-NMMA infusions, intra-arterial blood pressure remained stable throughout (data not shown).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The treatment code was broken only after completion of all analyses.

    “The subjects, pharmacists and investigators were not aware of the treatment code which was broken only after completion of all analyses.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Compliance was monitored by pill counts and diary records.

    “Compliance was monitored by pill counts and diary records.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To avoid interference with previously administered vasodilator drugs, changes in forearm blood flow in the control arm were used for statistical evaluation of the effect of insulin on blood flow.

    “To avoid interference with the previously administered vasodilator drugs in the experimental arm (see Fig. 1, schedule of the protocol), changes in FBF in the control arm were used for statistical evaluation of the effect of insulin on blood flow.”
    Quote in the paperSubstantial claim

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

    Interpretationown data

    The increase in forearm glucose uptake may reflect a specific beneficial drug effect on skeletal muscle glucose uptake.

    “perhaps reflecting a specific beneficial drug effect on skeletal muscle glucose uptake.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The study was a randomised, placebo-controlled, double-blind crossover trial.

    “we performed a randomised, placebo-controlled, double-blind crossover trial with troglitazone in obese individuals characterised by insulin resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Steinberg et al. used metacholine instead of acetylcholine as endothelial-dependent vasodilator, which may not be purely nitric oxide dependent.

    “Steinberg et al. used metacholine instead of acetylcholine as endothelial-dependent vasodilator, which may not be purely nitric oxide dependent [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30]

      Not checked in the free run.

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

    Interpretationcitation

    These treatment results of troglitazone are consistent with earlier studies in humans.

    “These treatment results of troglitazone are consistent with earlier studies in humans [15±17].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15±17]

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    There were no sequence or period effects during the trial.

    “There were no sequence or period effects during the trial; mean weight change, fasting plasma glucose/insulin, lipid levels, insulin sensitivity and blood pressure were comparable during the first and second period of the trial.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The role of ATP-dependent potassium channels and Na+-K+-ATPase has been reported as alternative mechanisms for insulin-induced vasodilatation.

    “the role of ATP-dependent potassium channels [35] and Na + -K + -ATPase [36] has been reported as alternative mechanisms for insulin-induced vasodilatation”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35]

      Not checked in the free run.

    • cites [36]

      Not checked in the free run.

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

    Study design and conductown data

    Coefficients of plasma glucose variation during the last 30 min of the clamp were 3.1 ± 0.4% in obese and 4.4 ± 0.7% in lean subjects.

    “Coefficients of plasma glucose variation during the last 30 min of the clamp were 3.1 ± 04 % in obese and 4.4 ± 0.7 % in lean subjects.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    Although baseline forearm blood flow was not significantly different between groups, it tended to be higher in the obese group; responses to drugs were also expressed as percentage increase above baseline to compensate.

    “Although baseline FBF was not significantly different between both groups, FBF tended to be higher in the obese group.To compensate for these possible differences in baseline flow, responses to drugs were also expressed as percentage increase above baseline [23].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23]

      Not checked in the free run.

39 of 39

  • The authors state this as an assumption.

    Whole blood glucose equals (1 - 0.3 × haematocrit) × plasma blood glucose.

    “Assuming that whole blood glucose = (1±0.3´haematocrit) ´plasma blood glucose [20]”
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?

  • In one prior publication, troglitazone given to obese insulin-resistant subjects improved insulin sensitivity but did not improve insulin-mediated or agonist-stimulated vasodilation.

    “Despite a clear improvement in insulin sensitivity with treatment, no improvement in insulin-mediated or agonist-stimulated vasodilation was seen.”

    From Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus (2001) · cites this paper as [32]

Cites

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Related

Authors
Tack, C. J. J., Ong, M. K. E., Lutterman, J. A., & Smits, P.
Affiliations
Radboud University Nijmegen (NL)
ORCID
Tack, C. J. J.
Venue
Diabetologia
Publisher
Springer Science and Business Media LLC
Published
1998-04-21
Volume
41
Issue
5
Pages
569-576
ISSN
  • 0012-186X (ISSN-L)
  • 1432-0428
DOI
10.1007/s001250050948
OpenAlex
W2040855107
Semantic Scholar
9797f8f079c36c2855b3d263a5af040730aefdb6
Cited by
177
References
37
Citations by year
2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 1 · 2017: 1 · 2015: 4 · 2014: 5 · 2013: 10 · 2012: 2
FWCI
6.75
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Diabetologia (publishedVersion)
  • PubMed (publishedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
Keywords
insulin resistance, obesity, troglitazone, endothelial function, nitric oxide, forearm blood flow, acetylcholine, sodium nitroprusside, L-NMMA, glucose uptake, blood pressure, neurohumoral response, hyperinsulinemia
MeSH terms
Troglitazone, Acetylcholine, Adult, Analysis of Variance, Blood Glucose, Cardiovascular System, Chromans, Dose-Response Relationship, Drug, Double-Blind Method, Endothelium, Vascular, Enzyme Inhibitors, Fasting, Female, Forearm, Hemodynamics, Humans, Hyperinsulinism, Hypoglycemic Agents, Insulin, Insulin Resistance, Lipids, Male, Middle Aged, Nitroprusside, Obesity, Reference Values, Regional Blood Flow, Thiazoles, Vasodilation, Vasodilator Agents, Glucose Clamp Technique, Biomarkers, Case-Control Studies, Cross-Over Studies, omega-N-Methylarginine, Thiazolidinediones

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