JACC
HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK
QUICK SEARCH:   [advanced]


     

J Am Coll Cardiol, 2001; 37:1344-1350
© 2001 by the American College of Cardiology Foundation
This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mather, K. J.
Right arrow Articles by Anderson, T. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mather, K. J.
Right arrow Articles by Anderson, T. J.

CLINICAL STUDY: ENDOTHELIAL FUNCTION

Improved endothelial function with metformin in type 2 diabetes mellitus

Kieren J. Mather, MD*, Subodh Verma, MD, PhD{dagger} and Todd J. Anderson, MD{ddagger}

* Division of Endocrinology and Metabolism, Indiana University, Indianapolis, Indiana, USA
{dagger} Division of Cardiac Surgery, University of Toronto, Toronto, Canada
{ddagger} Division of Cardiology, University of Calgary, Calgary, Canada

Manuscript received August 11, 2000; revised manuscript received November 17, 2000, accepted December 21, 2000.

Reprint requests and correspondence: Dr. Todd J. Anderson, Division of Cardiology, Faculty of Medicine, University of Calgary, c849, 1403 29th Street NW, Calgary, Alberta T2N 2T9, Canada.
todd.anderson{at}crha-health.ab.ca

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.

Abbreviations and Acronyms
  Ach = acetylcholine
  ANCOVA = analysis of covariance
  ANOVA = analysis of variance
  BMI = body mass index
  CV = coefficient of variation
  DM = diabetes mellitus
  FBF = forearm blood flow
  FFA = free fatty acid
  HOMA-IR = homeostasis model assessment of insulin resistance
  IR = insulin resistance
  LDL = low density lipoprotein
  SNP = sodium nitroprusside
  VER = verapamil




This article has been cited by other articles:


Home page
 Endocr. Rev.Home page
R. Muniyappa, M. Montagnani, K. K. Koh, and M. J. Quon
Cardiovascular Actions of Insulin
Endocr. Rev., August 1, 2007; 28(5): 463 - 491.
[Abstract] [Full Text] [PDF]

Home page
 HeartHome page
T H Schindler, A D Facta, J O Prior, J Cadenas, W A Hsueh, M J Quinones, and H R Schelbert
Improvement in coronary vascular dysfunction produced with euglycaemic control in patients with type 2 diabetes
Heart, March 1, 2007; 93(3): 345 - 349.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
S. Jadhav, W. Ferrell, I. A. Greer, J. R. Petrie, S. M. Cobbe, and N. Sattar
Effects of Metformin on Microvascular Function and Exercise Tolerance in Women With Angina and Normal Coronary Arteries: A Randomized, Double-Blind, Placebo-Controlled Study
J. Am. Coll. Cardiol., September 5, 2006; 48(5): 956 - 963.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
I. J. Goldberg and H. M. Dansky
Diabetic Vascular Disease: An Experimental Objective
Arterioscler. Thromb. Vasc. Biol., August 1, 2006; 26(8): 1693 - 1701.
[Abstract] [Full Text] [PDF]

Home page
 Hum ReprodHome page
E. Diamanti-Kandarakis, T. Paterakis, K. Alexandraki, C. Piperi, A. Aessopos, I. Katsikis, N. Katsilambros, G. Kreatsas, and D. Panidis
Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin
Hum. Reprod., June 1, 2006; 21(6): 1426 - 1431.
[Abstract] [Full Text] [PDF]

Home page
 Diabetes CareHome page
L. G. K. de Aguiar, L. R. Bahia, N. Villela, C. Laflor, F. Sicuro, N. Wiernsperger, D. Bottino, and E. Bouskela
Metformin Improves Endothelial Vascular Reactivity in First-Degree Relatives of Type 2 Diabetic Patients With Metabolic Syndrome and Normal Glucose Tolerance
Diabetes Care, May 1, 2006; 29(5): 1083 - 1089.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
J.-a Kim, M. Montagnani, K. K. Koh, and M. J. Quon
Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction: Molecular and Pathophysiological Mechanisms
Circulation, April 18, 2006; 113(15): 1888 - 1904.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
A. Natali, E. Toschi, S. Baldeweg, D. Ciociaro, S. Favilla, L. Sacca, and E. Ferrannini
Clustering of insulin resistance with vascular dysfunction and low-grade inflammation in type 2 diabetes.
Diabetes, April 1, 2006; 55(4): 1133 - 1140.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
J. B. Meigs, C. J. O'Donnell, G. H. Tofler, E. J. Benjamin, C. S. Fox, I. Lipinska, D. M. Nathan, L. M. Sullivan, R. B. D'Agostino, and P. W.F. Wilson
Hemostatic Markers of Endothelial Dysfunction and Risk of Incident Type 2 Diabetes: The Framingham Offspring Study
Diabetes, February 1, 2006; 55(2): 530 - 537.
[Abstract] [Full Text] [PDF]

Home page
 ANN INTERN MEDHome page
J. P.H. van Wijk, E. J.P. de Koning, M. C. Cabezas, J. op't Roodt, J. Joven, T. J. Rabelink, and A. I. Hoepelman
Comparison of Rosiglitazone and Metformin for Treating HIV Lipodystrophy: A Randomized Trial
Ann Intern Med, September 6, 2005; 143(5): 337 - 346.
[Abstract] [Full Text] [PDF]

Home page
 Vasc MedHome page
K. Sydow, C. E Mondon, and J. P Cooke
Insulin resistance: potential role of the endogenous nitric oxide synthase inhibitor ADMA
Vascular Medicine, May 1, 2005; 10(2_suppl): S35 - S43.
[Abstract] [PDF]

Home page
 Clin. DiabetesHome page
B. Kimmel and S. E. Inzucchi
Oral Agents for Type 2 Diabetes: An Update
Clin. Diabetes, April 1, 2005; 23(2): 64 - 76.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
A. Gallo, G. Ceolotto, P. Pinton, E. Iori, E. Murphy, G. A. Rutter, R. Rizzuto, A. Semplicini, and A. Avogaro
Metformin Prevents Glucose-Induced Protein Kinase C-{beta}2 Activation in Human Umbilical Vein Endothelial Cells Through an Antioxidant Mechanism
Diabetes, April 1, 2005; 54(4): 1123 - 1131.
[Abstract] [Full Text] [PDF]

Home page
 HeartHome page
S Jadhav, J Petrie, W Ferrell, S Cobbe, and N Sattar
Insulin resistance as a contributor to myocardial ischaemia independent of obstructive coronary atheroma: a role for insulin sensitisation?
Heart, December 1, 2004; 90(12): 1379 - 1383.
[Abstract] [Full Text] [PDF]

Home page
 Vasc MedHome page
D. J Collinson, R. Rea, and R. Donnelly
Masterclass series in peripheral arterial disease: Vascular risk: diabetes
Vascular Medicine, November 1, 2004; 9(4): 307 - 310.
[PDF]

Home page
 J Am Coll CardiolHome page
S. Fazel, R. D. Weisel, and S. Verma
A novel technique to assess flow-mediated vasodilation
J. Am. Coll. Cardiol., October 6, 2004; 44(7): 1478 - 1480.
[Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. E. Caballero, A. Delgado, C. A. Aguilar-Salinas, A. N. Herrera, J. L. Castillo, T. Cabrera, F. J. Gomez-Perez, and J. A. Rull
The Differential Effects of Metformin on Markers of Endothelial Activation and Inflammation in Subjects with Impaired Glucose Tolerance: A Placebo-Controlled, Randomized Clinical Trial
J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3943 - 3948.
[Abstract] [Full Text] [PDF]

Home page
 Diabetes CareHome page
A. Natali, S. Baldeweg, E. Toschi, B. Capaldo, D. Barbaro, A. Gastaldelli, J. S. Yudkin, and E. Ferrannini
Vascular Effects of Improving Metabolic Control With Metformin or Rosiglitazone in Type 2 Diabetes
Diabetes Care, June 1, 2004; 27(6): 1349 - 1357.
[Abstract] [Full Text] [PDF]

Home page
 JAMAHome page
J. B. Meigs, F. B. Hu, N. Rifai, and J. E. Manson
Biomarkers of Endothelial Dysfunction and Risk of Type 2 Diabetes Mellitus
JAMA, April 28, 2004; 291(16): 1978 - 1986.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
V. Fonseca, C. Desouza, S. Asnani, and I. Jialal
Nontraditional Risk Factors for Cardiovascular Disease in Diabetes
Endocr. Rev., February 1, 2004; 25(1): 153 - 175.
[Abstract] [Full Text] [PDF]

Home page
 Arch Intern MedHome page
S. R. Salpeter, E. Greyber, G. A. Pasternak, and E. E. Salpeter
Risk of Fatal and Nonfatal Lactic Acidosis With Metformin Use in Type 2 Diabetes Mellitus: Systematic Review and Meta-analysis
Arch Intern Med, November 24, 2003; 163(21): 2594 - 2602.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
S. Verma, M. R. Buchanan, and T. J. Anderson
Endothelial Function Testing as a Biomarker of Vascular Disease
Circulation, October 28, 2003; 108(17): 2054 - 2059.
[Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
M. E. Widlansky, N. Gokce, J. F. Keaney Jr, and J. A. Vita
The clinical implications of endothelial dysfunction
J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1149 - 1160.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
M. A. Creager, T. F. Luscher, F. Cosentino, and J. A. Beckman
Diabetes and Vascular Disease: Pathophysiology, Clinical Consequences, and Medical Therapy: Part I
Circulation, September 23, 2003; 108(12): 1527 - 1532.
[Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
M. Guazzi, G. Tumminello, M. Matturri, and M. D. Guazzi
Insulin ameliorates exercise ventilatory efficiency and oxygen uptake in patients with heart failure-type 2 diabetes comorbidity
J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1044 - 1050.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
S. Verma, S.-H. Li, C.-H. Wang, P. W.M. Fedak, R.-K. Li, R. D. Weisel, and D. A.G. Mickle
Resistin Promotes Endothelial Cell Activation: Further Evidence of Adipokine-Endothelial Interaction
Circulation, August 12, 2003; 108(6): 736 - 740.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
C.-H. Wang, R. D. Weisel, P. P. Liu, P. W.M. Fedak, and S. Verma
Glitazones and Heart Failure: Critical Appraisal for the Clinician
Circulation, March 18, 2003; 107(10): 1350 - 1354.
[Full Text] [PDF]

Home page
 Diabetes CareHome page
B. A. Kingwell, M. Formosa, M. Muhlmann, S. J. Bradley, and G. K. McConell
Type 2 Diabetic Individuals Have Impaired Leg Blood Flow Responses to Exercise: Role of endothelium-dependent vasodilation
Diabetes Care, March 1, 2003; 26(3): 899 - 904.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
J. C. Baldi, J. L. Aoina, H. C. Oxenham, W. Bagg, and R. N. Doughty
Reduced exercise arteriovenous O2 difference in Type 2 diabetes
J Appl Physiol, March 1, 2003; 94(3): 1033 - 1038.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Coll. Nutr.Home page
G. D. Kolovou, D. Ch. Daskalova, S. A. Iraklianou, E. N. Adamopoulou, N. D. Pilatis, G. C. Hatzigeorgiou, and D. V. Cokkinos
Postprandial Lipemia in Hypertension
J. Am. Coll. Nutr., February 1, 2003; 22(1): 80 - 87.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
S. Verma and T. J. Anderson
Fundamentals of Endothelial Function for the Clinical Cardiologist
Circulation, February 5, 2002; 105(5): 546 - 549.
[Full Text] [PDF]

Home page
 Cardiovasc ResHome page
I.J.A.M Jonkers, M.A van de Ree, A.H.M Smelt, F.H.A.F de Man, H Jansen, A.E Meinders, A van der Laarse, and G.J Blauw
Insulin resistance but not hypertriglyceridemia per se is associated with endothelial dysfunction in chronic hypertriglyceridemia
Cardiovasc Res, February 1, 2002; 53(2): 496 - 501.
[Abstract] [Full Text] [PDF]

Home page
 JAMAHome page
S. E. Inzucchi
Oral Antihyperglycemic Therapy for Type 2 Diabetes: Scientific Review
JAMA, January 16, 2002; 287(3): 360 - 372.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
S. Verma, S. R. Raj, L. Shewchuk, K. J. Mather, and T. J. Anderson
Cyclooxygenase-2 Blockade Does Not Impair Endothelial Vasodilator Function in Healthy Volunteers: Randomized Evaluation of Rofecoxib Versus Naproxen on Endothelium-Dependent Vasodilatation
Circulation, December 11, 2001; 104(24): 2879 - 2882.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
N. N. Chan
Improved endothelial function with metformin in type 2 diabetes mellitus
J. Am. Coll. Cardiol., December 1, 2001; 38(7): 2131 - 2131.
[Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
K. Mather, S. Verma, and T. Anderson
Improved endothelial function with metformin in type 2 diabetes mellitus: Reply
J. Am. Coll. Cardiol., December 1, 2001; 38(7): 2131 - 2132.
[Full Text] [PDF]


HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK
Copyright © 2001 by the American College of Cardiology Foundation.