Metformin Improves Endothelial Vascular Reactivity in First-Degree Relatives of Type 2 Diabetic Patients With Metabolic Syndrome and Normal Glucose Tolerance LUIZ GUILHERME KRAEMER DE AGUIAR, MD LUCIANA R. BAHIA, MD NIVALDO VILLELA, MD, PHD CAMILA LAFLOR, MSC FERNANDO SICURO, MSC NICOLAS WIERNSPERGER, PHD DANIEL BOTTINO, MD, PHD ELIETE BOUSKELA, MD, PHD OBJECTIVE — Endothelial dysfunction is an early marker of atherosclerosis seen in type 2 diabetic subjects. Metformin is commonly used in the treatment of type 2 diabetes and has known vasculoprotective effects beyond its hypoglycemic ones. We aimed to investigate the vascular effects of metformin in first-degree relatives with metabolic syndrome of type 2 diabetic patients. RESEARCH DESIGN AND METHODS — The study included 31 subjects (age 38.3  7.6 years and BMI 36.3  5.2 kg/m 2 ), who were first-degree relatives of type 2 diabetic patients and who had metabolic syndrome and normal glucose tolerance. The subjects were randomly assigned 1:1 in a double-blind fashion to receive placebo (n = 15) or metformin (n = 16). Endothelial function was assessed by venous occlusion plethysmography, measuring forearm blood flow (FBF) and vascular resistance responses to three intra-arterial infusions of endothe- lium-dependent (acetylcholine 7.5, 15, and 30 g/min) and independent (sodium nitroprusside 2, 4, and 8 g/min) vasodilators. Weight, BMI, systolic and diastolic blood pressure, waist, and laboratory parameters (lipid profile and fasting plasma glucose [FPG]) were assessed at baseline and after treatment. RESULTS — The metformin and placebo groups did not differ in anthropometric, clinical, laboratory, and vascular measurements at baseline. The metformin group had decreased weight, BMI, systolic blood pressure, and FPG and improved lipid profile. Endothelium-dependent FBF responses were also improved, without any effect on endothelium-independent responses. There was no correlation between the improvement on FBF responses and the observed changes on anthropometric, clinical, and laboratory parameters. CONCLUSIONS — We concluded that metformin improved vascular endothelial reactivity in first-degree relatives with metabolic syndrome of type 2 diabetic patients, independently of its known antihyperglycemic effects. Diabetes Care 29:1083–1089, 2006 T he precocious and accelerated ath- erosclerosis seen in type 2 diabetes raised the question about pathoge- netic factors that initiate the development of vascular derangements in the pre- diabetic population. Metabolic syn- drome, a pre-diabetic state, comprises an array of cardiovascular risk factors such as abdominal obesity, dyslipidemia, hyper- tension, impaired glucose tolerance, and insulin resistance. Insulin resistance, the central abnormality for the pathogenesis of metabolic syndrome, is considered an independent risk factor for cardiovascular mortality in general (1) and in the diabetic population (2) in particular. The endothelium is an important lo- cus for the control of vascular function. It actively regulates vascular tone, perme- ability to leukocytes and macromole- cules, the balance between coagulation and fibrinolysis, composition of the sub- endothelial matrix, and proliferation of vascular smooth muscle cells. The great variety of beneficial functions attributed to the endothelium is mainly associated with nitric oxide (NO) bioavailability. In experimental studies of atherogenesis, the damage to the endothelium is the initiat- ing event. An early marker of endothelial dysfunction is the reduction of endothe- lium-dependent vasodilation due to re- duced bioavailability of NO (3). Endothelial dysfunction precedes and predicts clinical macrovascular dis- ease (4) and should be considered as a target for different therapeutic interven- tions. Endothelial function can be as- sessed, for clinical and research purposes, by measuring vascular reactivity to acetyl- choline (ACh), which directly stimulates NO production via muscarinic receptors. Abnormal vasomotor responses occur in the presence of traditional risk factors, such as hypercholesterolemia, hyperten- sion, smoking, diabetes, a low HDL cho- lesterol level, and hyperhomocysteinemia (5,6). Insulin resistance, obesity (7), and visceral fat accumulation (8) in nonobese men were associated with endothelial dysfunction, which was also observed in first-degree relatives of type 2 diabetic pa- tients (9,10). Several mechanisms that could impair endothelial function are as- sociated with insulin resistance. There is increasing evidence that hyperglycemia is only a worsening factor for endothelial dysfunction and not the triggering one. It is hypothesized that endotheliopathy pre- cedes type 2 diabetes (11). Therefore, comprehension of the mechanisms re- sponsible for impaired insulin action are fundamental to understand possible fa- vorable effects of insulin sensitizers. ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the Department of Physiological Sciences, Laborato ´ rio de Pesquisas em Microcirculac ¸a ˜o, State Uni- versity of Rio de Janeiro, Rio de Janeiro, Brazil. Address correspondence and reprint requests to L.G. Kraemer de Aguiar, Av. Sete de Setembro, 332 apto 601, CEP 24230-253, Nitero ´ i, RJ, Brazil. E-mail: gkraemer@ig.com.br. Received for publication 4 November 2005 and accepted in revised form 28 January 2006. Abbreviations: ACh, acetylcholine; FBF, forearm blood flow; FFA, free fatty acid; FPG, fasting plasma glucose; SNP, sodium nitroprusside. A table elsewhere in this issue shows conventional and Syste `me International (SI) units and conversion factors for many substances. DOI: 10.2337/dc05-2146 © 2006 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Cardiovascular and Metabolic Risk O R I G I N A L A R T I C L E DIABETES CARE, VOLUME 29, NUMBER 5, MAY 2006 1083 Downloaded from http://diabetesjournals.org/care/article-pdf/29/5/1083/562868/zdc00506001083.pdf by guest on 04 June 2022