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Diabetes Care 27:1349-1357, 2004
© 2004 by the American Diabetes Association, Inc.

Pathophysiology/Complications
Original Article

Vascular Effects of Improving Metabolic Control With Metformin or Rosiglitazone in Type 2 Diabetes

Andrea Natali, MD1, Stephanie Baldeweg, MD2, Elena Toschi, MD1, Brunella Capaldo, MD3, Daniele Barbaro, MD4, Amalia Gastaldelli, PHD1, John S. Yudkin, MD2 and Ele Ferrannini, MD1

1 Department of Internal Medicine and C.N.R. Institute of Clinical Physiology, University of Pisa, Pisa, Italy
2 Department of Medicine, University College, London, U.K.
3 Department of Internal Medicine, "Federico II" University, Naples, Italy
4 Livorno General Hospital, Livorno, Italy

Address correspondence and reprint requests to Dr. Andrea Natali, Department of Internal Medicine, Via Roma, 67, 56100 Pisa, Italy. E-mail: anatali{at}ifc.cnr.it

OBJECTIVE—The aim of this study was to test whether vascular reactivity is modified by improving metabolic control and peripheral insulin resistance in type 2 diabetes.

RESEARCH DESIGN AND METHODS—In a randomized, double-blind design, we assigned 74 type 2 diabetic patients to rosiglitazone (8 mg/day), metformin (1,500 mg/day), or placebo treatment for 16 weeks and measured insulin sensitivity (euglycemic insulin clamp), ambulatory blood pressure, and forearm blood flow response to 1) intra-arterial acetylcholine (ACh), 2) intra-arterial nitroprusside, 3) the clamp, and 4) blockade of nitric oxide (NO) synthase.

RESULTS—Compared with 25 nondiabetic subjects, patients had reduced insulin sensitivity (30 ± 1 vs. 41 ± 3 µmol · min–1 · kg fat-free mass–1; P < 0.001) and reduced maximal response to ACh (586 ± 42 vs. 883 ± 81%; P < 0.001). Relative to placebo, 16 weeks of rosiglitazone and metformin similarly reduced fasting glucose (–2.3 ± 0.5 and –2.3 ± 0.5 mmol/l) and HbA1c (–1.2 ± 0.3 and –1.6 ± 0.3%). Insulin sensitivity increased with rosiglitazone (+6 ± 3 µmol · min–1 · kg fat-free mass–1; P < 0.01) but not with metformin or placebo. Ambulatory diastolic blood pressure fell consistently (–2 ± 1 mmHg; P < 0.05) only in the rosiglitazone group. Nitroprusside dose response, clamp-induced vasodilatation, and NO blockade were not affected by either treatment. In contrast, the slope of the ACh dose response improved with rosiglitazone (+40% versus baseline, P < 0.05, +70% versus placebo, P < 0.005) but did not change with either metformin or placebo. This improvement in endothelium-dependent vasodilatation was accompanied by decrements in circulating levels of free fatty acids and tumor necrosis factor-{alpha}.

CONCLUSIONS—At equivalent glycemic control, rosiglitazone, but not metformin, improves endothelium dependent vasodilatation and insulin sensitivity in type 2 diabetes.

Abbreviations: ABPM, ambulatory blood pressure monitoring • ACh, acetylcholine • eNOS, endothelial nitric oxide synthase • EGP, endogenous glucose production • FBF, forearm blood flow • L-NMMA, NG-monomethyl-L-arginine • NEFA, nonesterified fatty acid • SNP, sodium nitroprusside • TNF-{alpha}, tumor necrosis factor-{alpha}


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