The DOI matches its Crossref record; 45 of the 47 references it cites were found in a registry or an index; 1 of the 16 sources its claims cite were checked for support.
Improved endothelial function with metformin in type 2 diabetes mellitus
Open accessAbstract
Objectives This study was designed to assess the effect of metformin on impaired endothelial function in type 2 diabetes mellitus.Background Abnormalities in vascular endothelial function are well recognized among patients with type 2 (insulin-resistant) diabetes mellitus. Insulin resistance itself may be central to the pathogenesis of endothelial dysfunction. The effects of metformin, an antidiabetic agent that improves insulin sensitivity, on endothelial function have not been reported.Methods Subjects with diet-treated type 2 diabetes but without the confounding collection of cardiovascular risk factors seen in the metabolic syndrome were treated with metformin 500 mg twice daily (n = 29) or placebo (n = 15) for 12 weeks. Before and after treatment, blood flow responses to intraarterial administration of endothelium-dependent (acetylcholine), endothelium-independent (sodium nitroprusside) and nitrate-independent (verapamil) vasodilators were measured using forearm plethysmography. Whole-body insulin resistance was assessed on both occasions using the homeostasis model (HOMA-IR).Results Subjects who received metformin demonstrated statistically significant improvement in acetylcholine-stimulated flows compared with those treated with placebo (p = 0.0027 by 2-way analysis of variance), whereas no significant effect was seen on nitroprusside-stimulated (p = 0.27) or verapamil-stimulated (p = 0.40) flows. There was a significant improvement in insulin resistance with metformin (32.5% reduction in HOMA-IR, p = 0.01), and by stepwise multivariate analysis insulin resistance was the sole predictor of endothelium-dependent blood flow following treatment (r = -0.659, p = 0.0012).Conclusions Metformin treatment improved both insulin resistance and endothelial function, with a strong statistical link between these variables. This supports the concept of the central role of insulin resistance in the pathogenesis of endothelial dysfunction in type 2 diabetes mellitus. This has important implications for the investigation and treatment of vascular disease in patients with type 2 diabetes mellitus.
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TL;DR
In diet-treated type 2 diabetes patients without the clustered metabolic syndrome risk factors, 12 weeks of metformin improved endothelium-dependent forearm blood flow and insulin resistance compared with placebo. Post-treatment insulin resistance was the sole predictor of endothelium-dependent vasodilation, supporting a central role for insulin resistance in endothelial dysfunction.
Key findings
- Metformin significantly improved acetylcholine-stimulated forearm blood flow versus placebo (p = 0.0027 by two-way ANOVA), while no significant treatment effect was seen for sodium nitroprusside (p = 0.27) or verapamil (p = 0.40).
- Metformin produced a 32.5% reduction in HOMA-IR (p = 0.01), with no change in the placebo group; FFA also changed significantly (p = 0.019).
- After treatment, stepwise multivariate analysis found insulin resistance (logHOMA-IR) was the sole predictor of endothelium-dependent blood flow (r = −0.659, adjusted r² = 0.434, p = 0.0012).
- Glucose, HbA1c, weight, blood pressure, and cholesterol did not show significant treatment-attributable changes.
Methods
- Randomized, placebo-controlled study of patients with diet-controlled type 2 diabetes without other major cardiovascular risk factors; participants received metformin 500 mg twice daily (n = 29) or placebo (n = 15) for 12 weeks, with 44 subjects initially enrolled and 4 withdrawals.
- Forearm strain-gauge plethysmography measured blood flow responses to intraarterial acetylcholine (endothelium-dependent), sodium nitroprusside (endothelium-independent), and verapamil (nitrate-independent); whole-body insulin resistance was assessed by HOMA-IR.
- Main analyses used two-way repeated-measures ANOVA, ANCOVA, linear regression, and forward stepwise regression.
Limitations
- The paper states that oxidative balance/oxidative stress and LDL particle size were not measured, though these variables affect endothelial function and may be affected by metformin.
- Evident from the text: the study was small, baseline LDL cholesterol was significantly lower in the placebo group, and FFA levels showed a borderline baseline difference favoring placebo.
- Evident from the text: pretreatment sodium nitroprusside responses unexpectedly differed between groups, and the direct correlation between change in insulin resistance and improvement in endothelial response did not reach statistical significance.
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17 Own result · 10 Own method · 9 Not checked yet · 7 Own interpretation · 1 Supported so far · 1 No basis given
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There was a significant improvement in insulin resistance with metformin (32.5% reduction in HOMA-IR, p ϭ 0.01)”
- Also stated in: § Demographics. · plain
“Metformin produced a significant 32.5% drop in HOMA-IR, whereas no change was seen in the patients receiving placebo.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > RESULTS
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- Also stated in: § Demographics. · plain
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In the paper
“The inclusion of these variables with the change in BMI and in lipid variables in a multivariate model accounted for Ͼ95% of the variation in the change in endothelial response (p ϭ 0.005).”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Blood flow responses.
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In the paper
“by stepwise multivariate analysis insulin resistance was the sole predictor of endotheliumdependent blood flow following treatment (r ϭ Ϫ0.659, p ϭ 0.0012).”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > RESULTS
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In the paper
“After therapy with metformin, univariate ANOVA revealed an effect of logHOMA-IR (p ϭ 0.06) and of body mass index (BMI) (p ϭ 0.007) on endothelial responses.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Blood flow responses.
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In the paper
“Of note, no relationship with LDL cholesterol, ambient glucose, Hb A1c or FFA level was evident.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Blood flow responses.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“whereas no significant effect was seen on nitroprusside-stimulated (p ϭ 0.27) or verapamil-stimulated (p ϭ 0.40) flows.”
- Also stated in: § Blood flow responses. · plain
“across all doses there was no statistically significant treatment effect relative to placebo (p ϭ 0.27).”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > RESULTS
plain- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Blood flow responses. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Metformin treatment resulted in statistically significant improvements only in HOMA-IR and FFA levels compared to placebo”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Verapamil-induced, nitrateindependent flows were not different between groups either before or after treatment (p ϭ 0.40, Fig. 3).”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Blood flow responses.
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In the paper
“In the present study, the direct correlation between the change in IR and the improvement in endothelial response did not achieve statistical significance”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > DISCUSSION
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In the paper
“but the combination of changes in IR, lipids, FFAs and BMI was able to account for the vast majority of the change in endothelial response.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 13
- The quote only partly states this claim. 2
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In the paper
“Also, in ex-vivo preparations of vascular smooth muscle, a direct vasodilating action of metformin has been reported, possibly due to altered calcium handling (35,37,38).”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > DISCUSSION
What the sources say
- Not checked yetcites [35] Abbasi, 1998, Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin, Diabetes Care source
- Not checked yetcites [37] Bhalla, 1996, Vascular effects of metformin. Possible mechanisms for its antihypertensive action in the spontaneously hypertensive rat, Am J Hypertens source
- Supportedcites [38] Dominguez, 1996, Effects of metformin on tyrosine kinase activity, glucose transport, and intracellular calcium in rat vascular smooth muscle, Endocrinology source
The Introduction reports that metformin attenuates contraction of isolated rat tail artery rings and describes this as evidence of direct effects on vascular tissue. The paper's calcium results and Discussion report an attenuated thrombin-induced calcium rise in cultured vascular smooth muscle cells and suggest that this may help explain reduced vascular contraction. The proposed calcium mechanism is appropriately qualified as possible. (LLM, conf=0.88)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Subjects who received metformin demonstrated statistically significant improvement in acetylcholine-stimulated flows compared with those treated with placebo (p ϭ 0.0027 by 2-way analysis of variance)”
- Also stated in: § DISCUSSION · plain
“In patients with IR and type 2 DM, three months of treatment with metformin improved endotheliumdependent vascular responses, whereas vascular responses of patients treated with placebo remained unchanged.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > RESULTS
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In the paper
“without significant changes in body mass index, blood pressure or cholesterol levels.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Treatment effects on glucose (0.5 mmol/l reduction) and weight (1.5 kg) were small and did not achieve statistical significance.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Demographics.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Although the change in response at peak dose was statistically significant for metformin-treated subjects compared with their baseline (p ϭ 0.01), across all doses there was no statistically significant treatment effect relative to placebo (p ϭ 0.27).”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Blood flow responses.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“At baseline, univariate ANOVA revealed no effect of any metabolic or anthropomorphic parameters on endothelial responses, and similarly by ANCOVA there were no significant interactions of these effects on baseline responses.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Blood flow responses.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Following therapy, linear regression analyses revealed dependencies of endothelium-dependent responses following therapy on BMI (r ϭ Ϫ0.43, p ϭ 0.007), logHOMA-IR (r ϭ Ϫ0.486, p ϭ 0.017) (Fig. 4) and high density lipoprotein cholesterol (r ϭ 0.34, p ϭ 0.036).”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Blood flow responses.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Baseline endothelium-independent nitrate responses were unexpectedly higher in the group who received placebo, but at the end of treatment this difference was abolished (Fig. 2).”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Blood flow responses.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Abnormalities in endothelium-dependent vascular responses, perhaps the earliest demonstrable alteration in vascular health, have been found among patients with type 2 DM (2,3).”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > RESULTS
What the sources say
- Not checked yetcites [2] McVeigh, 1992, Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus, Diabetologia source
- Not checked yetcites [3] Williams, 1996, Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus, J Am Coll Cardiol source
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In the paper
“Medication compliance was Ͼ95% by pill count.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Demographics.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“This trial was designed and performed in accordance with the principles of the Declaration of Helsinki and was approved by our University's Ethical Review Board.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Patients.
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In the paper
“We did not undertake any measure of oxidative balance or oxidative stress, nor was LDL particle size measured.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Study limitations.
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In the paper
“Written informed consent was obtained after the purpose, nature and potential risks of the interventions were explained to the subjects.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Patients.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In fact, metformin has recently been reported to have antioxidant effects (34) in addition to the known favorable effects on circulating lipids (10) and FFAs (35).”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > DISCUSSION
What the sources say
- Not checked yetcites [34] Faure, 1999, An insulin sensitizer improves the free radical defence system potential and insulin sensitivity in high fructose-fed rats, Diabetes source
- Not checked yetcites [10] Bailey, 1996, Metformin, N Engl J Med source
- Not checked yetcites [35] Abbasi, 1998, Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin, Diabetes Care source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“End point measures including blood flow data analyses were blinded to patient name, treatment assignment and treatment timing.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Patients.
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In the paper
“Insulin resistance is felt to be central to the pathogenesis of the metabolic syndrome (Syndrome X), a clustering of traditional cardiovascular risk factors in patients with type 2 DM (8).”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > RESULTS
What the sources say
- Not checked yetcites [8] Reaven, 1988, Role of insulin resistance in human disease, Diabetes source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Subjects assigned to metformin and placebo were well matched for degree of obesity and level of glycemic control, and both the fasting insulin level and the calculated index of IR indicated equivalent degrees of IR.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Demographics.
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In the paper
“Four subjects withdrew from the study before the second set of measurements, two of whom had been assigned to receive metformin therapy.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Demographics.
plainn = 4- Asserted: passes — The authors put it forward as true.
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In the paper
“Flow data analysis was performed at a later date by investigators blind to patient name, study day and treatment assignment.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Vascular responses.
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In the paper
“The level of low density lipoprotein (LDL) cholesterol was significantly lower in the group who received placebo.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Demographics.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Again, ANCOVA revealed no interactions, suggesting that the chance imbalances between groups, particularly with regard to LDL cholesterol, did not influence the results.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Blood flow responses.
hedged- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Metformin treatment improved both insulin resistance and endothelial function, with a strong statistical link between these variables.”
- Also stated in: § Conclusions. · plain
“In our group of patients with type 2 DM and IR but without other metabolic abnormalities, we found that treatment with metformin resulted in improved IR and improved endothelial function.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > RESULTS
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- Also stated in: § Conclusions. · plain
In the paper
“Despite a clear improvement in insulin sensitivity with treatment, no improvement in insulin-mediated or agonist-stimulated vasodilation was seen.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > DISCUSSION
What the sources say
- Not checked yetcites [32] Tack, 1998, Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone, Diabetologia source
boosted- Asserted: passes — The authors put it forward as true.
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In the paper
“A direct metformin effect in vascular endothelial cells is also possible, and supported by recent findings in insulin-resistant rats (36).”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > DISCUSSION
What the sources say
- Not checked yetcites [36] Katakam, 2000, Metformin improves vascular function in insulin-resistant rats, Hypertension source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, an important effect of IR per se on endothelial function is suggested by the fact that a relationship was not evident at baseline but was brought out by metformin therapy, which concurrently improved insulin sensitivity and endothelial function.”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
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The paper relies on this without support.
The effects of altering insulin resistance with metformin on endothelial function in humans have not been previously reported.
“The effects of altering IR with metformin on endothelial function in humans have not been previously reported.”
“The effects of metformin, an antidiabetic agent that improves insulin sensitivity, on endothelial function have not been reported.”
The paper relies on this without support.
No evidence links alterations in antioxidant, lipid, or FFA parameters with improvements in vascular function separate from improvements in insulin resistance.
“However, no evidence links alterations in these parameters with improvements in vas-cular function separate from improvements in IR, and therefore the hypothesis of the central role of IR remains plausible.”
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In the citing paper
“Mather et al. reported that compared to placebo, metformin improved endothelium-dependent, but not endothelium-independent vasodilation thus highlighting the primary dysfunction in blood flow was not the vascular smooth muscle response but was secondary to endothelial dysfunction (106).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [106]
In the citing paper
“Based on critical reviews of the literature, the answer appears to be “yes”, although the clinical data could be interpreted as secondary to metformin’s actions to enhance insulin sensitivity and lower blood glucose levels (34, 106, 173).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [106]
In the citing paper
“Mather et al. reported that metformin has no effect on endothelium dependent blood flow but has a significant effect on endothelium independent blood flow and insulin resistance reduction [89].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [89]
In the citing paper
“Many different mechanisms, beyond glycemic control, have been implicated in vascular protection induced by metformin such as improvements in the inflammatory pathway [86], coagulation [87], oxidative stress and glycation [88-92], endothelial dysfunction [88-90], haemostasis [88,91-93], insulin resistance improvement [94], lipid profiles [95,96], and fat redistribution [97,98].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [89]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“| Parameter | (n ؍ 15) | (n ؍ 28) | | Age (yrs) | 54.8 (2.6) | 50.7 (1.8) | | Gender (M/F) | 11/4 | 15/14 |”
§ Endothelial Function Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus > Conclusions.
Reported 28 · recomputed 29
Citations
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Metadata
- Authors
- Mather, K. J., Verma, S., & Anderson, T. J.
- Affiliations
- Indiana University Indianapolis (US)
- University of Toronto (CA)
- University of Calgary (CA)
- Corresponding author
- Anderson, Todd J
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2001-04
- Volume
- 37
- Issue
- 5
- Pages
- 1344-1350
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W2114391822
- Cited by
- 513
- References
- 47
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 15 · 2023: 10 · 2022: 15 · 2021: 17 · 2020: 19 · 2019: 18 · 2018: 18 · 2017: 27 · 2016: 13 · 2015: 23 · 2014: 20 · 2013: 25 · 2012: 25
- FWCI
- 17.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- Alberta Heritage Foundation for Medical Research
- Topics
- Health Sciences › Medicine › Physiology (medical) › 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
- metformin, endothelial dysfunction, type 2 diabetes, insulin resistance, acetylcholine-induced vasodilation, forearm blood flow, HOMA-IR, insulin-sensitizing drugs, vascular disease
- MeSH terms
- Blood Flow Velocity, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Endothelium, Vascular, Female, Forearm, Humans, Hypoglycemic Agents, Insulin Resistance, Male, Metformin, Middle Aged, Plethysmography, Vasodilation
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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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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