HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Natali, A. Articles by Ferrannini, E. Search for Related Content PubMed PubMed Citation Articles by Natali, A. Articles by Ferrannini, E. Social Bookmarking                What's this?

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

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

	ABSTRACT

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS References

 
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 HbA_1c (–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-.

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, N^G-monomethyl-L-arginine • NEFA, nonesterified fatty acid • SNP, sodium nitroprusside • TNF-, tumor necrosis factor-

	INTRODUCTION

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS References

 
Cardiovascular disease is a major burden for patients with type 2 diabetes (1). Extensive and accelerated atherosclerosis is largely responsible for the excess cardiovascular morbidity and mortality that characterize diabetes (2). Endothelial dysfunction, an early and committed step in the development of atherosclerosis (3,4), is thought to be a major component of the vascular vulnerability of diabetic patients. Several studies have shown that endothelium-dependent reactivity of both conductance vessels (i.e., flow-mediated dilatation [5,6]) and resistance arteries (i.e., response to acetylcholine [ACh] or metacholine [7–9]) is impaired in type 2 diabetic patients. In these subjects, the vascular defect usually clusters with features of the metabolic syndrome (visceral obesity [10], hypertension [11], and abundance of small, dense LDL cholesterol particles [8]). Moreover, endothelial dysfunction in first-degree relatives of type 2 diabetic patients is more prominent in those with insulin resistance (6). Studies in transgenic animals indicate that endothelial dysfunction can be induced by disrupting the intracellular insulin-signaling pathway (12) and, conversely, that an insulin-resistant phenotype can be induced by experimental deprivation of endothelial nitric oxide (NO) synthase (13). Taken together, these findings suggest that in type 2 diabetes, insulin resistance and endothelial dysfunction may be related to one another in a causal manner. If this hypothesis is correct, then treatment of insulin resistance should result in a parallel improvement of endothelial function and, possibly, in a reduction of vascular complications. Thiazolidinediones, a new class of insulin-sensitizing agents, offer a unique investigative tool to assess the relation of insulin sensitivity to vascular reactivity. In an animal model of insulin resistance (14) and in normal rats chronically infused with angiotensin II (15), treatment with rosiglitazone has been shown to prevent deterioration of both insulin sensitivity and endothelial function.

Testing this hypothesis in patients, however, is complicated not only by the technical difficulty of measuring metabolic and vascular functions with valid techniques but also by the separate impact of hyperglycemia on either function. In an open study, addition of bedtime NPH insulin to metformin in type 2 diabetic patients achieved optimal glycemic control and improved endothelium-dependent but also endothelium-independent vasodilatation (16). In mild type 2 diabetic patients (17), low-dose metformin treatment improved endothelial function without changing fasting plasma glucose. In neither study, however, was insulin sensitivity directly measured.

Our aim was to compare the vascular effects of metformin and rosiglitazone in type 2 diabetes and to gain insight into the relationships between insulin resistance and endothelial dysfunction. Therefore, we undertook the present study in which changes in insulin sensitivity and vascular reactivity were measured with state-of-the-art techniques at similar levels of glycemic control (achieved with equipotent doses of metformin and rosiglitazone) in a placebo-controlled design.

	RESEARCH DESIGN AND METHODS

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS References

 
Type 2 diabetic patients were recruited from three clinics: one in London and two in Italy (Pisa and Naples). Patient inclusion criteria were 1) age 40–80 years, 2) fasting plasma glucose between 7.0 and 15.0 mmol/l, and 3) HbA_1c 10% after washout. Exclusion criteria were 1) women with childbearing potential; 2) BMI 35 kg/m²; 3) presence of clinically significant renal or hepatic disease, anemia, diabetic retinopathy or symptomatic neuropathy, New York Heart Association grades III-IV; cardiac failure, angina pectoris, or recent myocardial infarction; 4) change in dose of ACE inhibitors, ß-blockers, diuretics, statins, or fibrates in the 4 weeks before screening; and 5) current treatment with vitamins, nitrates, or calcium channel blockers. The control group consisted of 25 nondiabetic subjects, of whom 10 were selected to be hypertensive to match the hypertensive type 2 diabetic patients.

This was a multicenter, randomized, double-blind, parallel-group, placebo-controlled study. After a 4-week, single-blind placebo run-in period, eligible patients underwent 24-h ambulatory blood pressure monitoring (ABPM) followed by test procedures (week 0). Patients were then randomized to rosiglitazone (4 mg b.i.d.), metformin (500 mg t.i.d.), or placebo and entered a 16-week treatment period. To maintain study blindness, all patients received two capsules three times a day throughout the study; the dose of no other concomitant medication was changed. Patients returned at 4-week intervals for measurements of plasma glucose and body weight. At week 16, patients repeated 24-h ABPM and test procedures. On test days, only the experimental therapy was regularly assumed. The Ethics Review Committee of each participating institution approved the study.

Vascular reactivity (forearm blood flow [FBF] by the perfused forearm technique plus venous occlusion plethysmography) and insulin sensitivity (by the euglycemic insulin clamp technique) were measured during a single study session. All procedures were carefully standardized: the same strain-gauge plethysmograph (EC4; Hokanson, Bellevue, WA) and test chemicals were used in all centers, and a training session was attended by all investigators before the beginning of the study. A teflon cannula (21 gauge) was inserted into the brachial artery of the nondominant arm and used for drug infusion and intra-arterial blood pressure/heart rate monitoring via a pressure transducer connected to a monitor. Another catheter was inserted into an antecubital vein for systemic insulin (40 mU · min^–1 · m^–2) and glucose infusion. After baseline blood sampling, at time –180 min a primed-continuous (0.05 mg · min^–1 · kg^–1) infusion of 6,6-²H-glucose was started and maintained until the end of the clamp. Once FBF had stabilized (at least 30 min after cannulation), FBF was measured at the end of each of five 5-min steps of intra-arterial ACh infusion (0.15, 0.45, 1.5, 4.5, and 15 µg · min^–1 · dl^–1 of forearm tissue). After another rest period, FBF was measured at the end of each of three 5-min steps of intra-arterial sodium nitroprusside (SNP) (1, 2, and 4 µg · min^–1 · dl^–1). Three blood samples were obtained to measure plasma 6,6-²H-glucose enrichment, glucose, insulin, and free fatty acids (nonesterified fatty acid [NEFA]) concentration 10, 5, and 1 min before the insulin infusion was started (time 0). Glucose infusion was started only when plasma glucose concentration reached 6.0 mmol/l. Blood samples for 6,6-²H-glucose enrichment were taken every 20 min throughout the clamp. Blood samples for plasma insulin and NEFA were taken at time 0, 80, 100, and 120 min. FBF was measured at 60 and 120 min and then again at 125 min after a 5-min intra-arterial infusion of N^G-monomethyl-L-arginine (L-NMMA) (100 µg · min^–1 · dl^–1).

Assays
Plasma 6,6-²H-glucose enrichment was assayed in Pisa, as previously described (18). HbA_1c, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and routine blood chemistry were assayed at SmithKline Beecham Central Clinical Laboratories. Insulin (human insulin-specific radioimmunoassay kit; Linco), NEFA (Wako Chemical), interleukin-6 (ELISA kit; R&D Systems), tumor necrosis factor- (TNF-) (ELISA kit; R&D Systems), and C-reactive protein (High Sensitive UL-CRP; Wako Chemical) were assayed in London.

Calculations
Plethysmographic recordings were analyzed centrally by the same investigator (A.N.) who was blinded to the randomization code and the metabolic results. FBF was expressed as absolute value and as percent change from baseline. Because during local SNP infusion a slight but consistent drop in intra-arterial blood pressure was observed in most patients, impedance (i.e., blood flow x 100 divided by mean blood pressure) was used for the calculation of percent SNP-induced increments above baseline. The slope of the dose-response curves of percent increments above baseline values versus the log of the nominal drug infusion rates was obtained using least-squares linear regression of each individual’s data points. If the correlation coefficient of the fit was <0.7, the slope was not calculated and the study discarded. The effect of L-NMMA was calculated as percent change relative to the clamp FBF. Insulin sensitivity was calculated as the mean glucose infusion rate between 80 and 120 min corrected for the concomitant plasma glucose changes and expressed as metabolic glucose (M value) in mg · min^–1 · kg fat-free mass^–1 (19). Fasting endogenous glucose production (EGP) was calculated as the 6,6-²H-glucose infusion rate divided by the steady-state plasma 6,6-²H-glucose enrichment. During the clamp, glucose rate of appearance (R_a) was calculated using a two-compartment model (20). EGP during the clamp was obtained as the mean R_a of the last 40 min minus the mean exogenous glucose infusion during the same time period.

Statistical analysis
Data are expressed as mean ± SD. Group comparisons were performed by ANOVA or ² test, as appropriate. The effect of each treatment on continuous variables was calculated as the difference between week 16 and week 0 by paired Student’s t test or ANOVA for repeated measures. Differences between treatment-induced changes were assessed by an ANCOVA model including center and baseline value as covariates. When the model yielded a significant treatment effect, comparisons were calculated by applying paired contrasts. Confidence interval calculations and regression analysis were done using standard procedures.

	RESULTS

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS References

 
Seventy percent of the screened patients were randomized. As expected, the drop-out rate was slightly, although not significantly (P = 0.3), higher in the placebo (29%) than in the metformin (13%) or rosiglitazone (17%) groups. In comparison with completers, drop-out patients had similar age, sex distribution, BMI, insulin sensitivity, endothelial function, and diabetes duration but worse metabolic control, as indicated by higher fasting plasma glucose and HbA_1c levels at week 0 (11.7 ± 2.8 vs. 9.9 ± 2.1 mmol/l, P < 0.003, and 8.4 ± 1.4 vs. 7.7 ± 1.0%, P < 0.03, respectively). Among completers, six patients did not have evaluable vascular tests due to poor correlation coefficient of the data fit (see RESEARCH DESIGN AND METHODS) at either examination and were therefore excluded from analysis. At randomization, type 2 diabetic patients in the three groups were similar for metabolic control and most other clinical characteristics (Table 1), although patients in the placebo group had a greater BMI and a shorter disease duration. Compared with type 2 diabetic patients, control subjects had a similar sex distribution (20 men), age (54 ± 7 years), BMI (27.7 ± 3.3 kg/m²), and prevalence of hypertension (40%). Similar were also the vascular responses to SNP and to the clamp, whereas insulin sensitivity (41 ± 3 vs. 30 ± 1 µmol · min^–1 · kg fat-free mass^–1, P < 0.001) and the maximal response to ACh (883 ± 81 vs. 586 ± 42%, P < 0.001) were significantly higher (Fig. 1).

View larger version (32K): [in this window] [in a new window]   Figure 1— FBF responses to ACh and SNP (A) and insulin sensitivity and clamp-induced changes in blood flow (B) in 25 nondiabetic subjects (Controls) and 74 type 2 diabetic patients (T2D).

Basal FBF was similar in all groups and unaffected by treatment (Table 3). At week 0, the vascular responses to ACh and SNP were similar in the three groups. Neither placebo nor metformin induced significant changes in the vascular response to ACh. In contrast, a significantly greater vasodilatation in response to ACh was observed in the patients treated with rosiglitazone (Fig. 2). This difference was statistically significant both when analyzed by repeated measures ANOVA (P = 0.002 for the ACh dose-by-week interaction) and by paired Student’s t test on the slopes of the dose-response curves or on maximal FBF responses (+166 ± 78%, P < 0.05). Quantitatively, rosiglitazone treatment was associated with a slope increase of 108 FBF units, which represents a 40% increment above pretreatment values. When compared with placebo and adjusted for baseline value and center, the net effect of rosiglitazone on the dose-response slope was even greater (+70%, P < 0.005).

View larger version (23K): [in this window] [in a new window]   Figure 2— FBF percent increments above baseline in response to stepwise intra-arterial infusions of ACh (A) and sodium-nitroprusside (B) before (- - - -) and after (——) 16 weeks of treatment with placebo, metformin, and rosiglitazone.

At week 0, fasting plasma insulin, interleukin-6, and C-reactive protein concentrations were similar in the three groups (Table 4), and none of the treatments were associated with changes in these parameters. With treatment, both fasting plasma NEFA and TNF- concentrations showed a tendency to decrease in the rosiglitazone group.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS References

 
The present study design, using full doses of rosiglitazone and intermediate dosage of metformin, successfully achieved comparable lowering of fasting plasma glucose in insulin-resistant type 2 diabetic patients with endothelial dysfunction. Metabolic and vascular changes could thus be compared across treatments on equal grounds of glucose toxicity. The main findings were that, relative to placebo, rosiglitazone, but not metformin, enhanced insulin sensitivity by 30%, reduced EGP by 13%, and improved endothelium-dependent vasodilatation of resistance arteries by 70%. Rosiglitazone also induced a modest fall in arterial blood pressure (more evident for diastolic and nighttime blood pressure).

The results on insulin sensitivity stand in partial contrast with those of Inzucchi et al. (21) who, in a smaller, non-placebo-controlled study, reported a 13 and 45% increase of insulin sensitivity with metformin and troglitazone, respectively, and a 15% decrease in EGP with metformin only. That study, however, used threefold higher insulin infusion rates (120 vs. 40 mU · min^–1 · m^–2 in our study) for longer time periods (5 vs. 3 h), thereby achieving supraphysiological insulin levels. In addition, a higher metformin dose (2.0 vs. 1.5 g/day) was used in more severely hyperglycemic patients (15 vs. 10 mmol/l), thereby inducing a larger plasma glucose drop (–3.2 vs. –1 mmol/l). In our patients, treatment with metformin was associated with an 11% increase in fasting glucose clearance (from 137 ± 25 to 150 ± 30 ml/min, P < 0.04), which was not seen with either rosiglitazone (136 ± 23 to 138 ± 29 ml/min) or placebo (147 ± 25 to 153 ± 30 ml/min). Metabolic studies using metformin in type 2 diabetes have yielded conflicting data, with some reporting a modest enhancement of insulin-mediated glucose disposal (22,23), some reporting no change (24,25), and some reporting an effect only on fasting glucose clearance (26,27). As for rosiglitazone, the only other placebo-controlled trial in type 2 diabetes published thus far (28) found an 11% decline in fasting EGP and a 25% increment in insulin-stimulated glucose clearance on a 40-mU · min^–1 · m^–2 clamp, similar to the present results.

The blood pressure-lowering effect observed in the rosiglitazone group was small but consistent across 24-h monitoring (Table 2), office diastolic blood pressure (from 85 ± 9 to 82 ± 11 mmHg, P = 0.06), and intra-arterial mean blood pressure readings (from 96 ± 11 to 91 ± 10 mmHg, P = 0.023). Although the study was not designed to evaluate the mechanisms of this hypotensive effect, the absence of treatment-induced changes in baseline FBF (Table 3) and 24-h heart rate (Table 2) implies an action on systemic vascular resistance. In fact, ACh-stimulated, but not SNP-induced, vasodilatation was markedly enhanced by rosiglitazone, indicating improved endothelial function of resistance vessels.

Although the pattern of correlations in the whole dataset on baseline data indicated that Ach vasodilatation, clamp vasodilatation, and insulin sensitivity were all interrelated, the effect of rosiglitazone was not associated with detectably different vascular responses to insulin infusion or with its NO-dependent component (L-NMMA coinfusion). This apparent discrepancy is explained by considering that graded ACh infusion explores acute agonist-dependent vasodilatation over a wide range (7–10 times the baseline FBF), whereas euglycemic insulin infusion elicits a modest decrease in vascular tone in a dose-dependent fashion in which large responses are only seen at supraphysiological insulin concentrations (29). Moreover, ACh and insulin affect vascular tone through different mediators (NO, prostaglandins, and hyperpolarizing factor for ACh, mostly NO, and endothelin-1 for insulin [30,31]) and activate endothelial NO synthase (eNOS) through different pathways (calcium for ACh and protein kinase B-dependent phosphorylation for insulin [32]).

At baseline, insulin sensitivity and ACh-induced dilatation were related variables, and the effect of the treatment with rosiglitazone was to improve both. With respect to the slope of the regression line of baseline data, the mean absolute improvement in maximal ACh-indexed vasodilation was relatively more pronounced than expected on the bases of the mean change in insulin sensitivity (108 ± 52 vs. 64 ± 15%). Moreover, among the individual changes, the association was weak (r = 0.22, P = 0.07); therefore, although glucose metabolism and eNOS share common signaling steps, we should consider that the corresponding ED₅₀s are widely different (0.1 and 100 nmol/l, respectively [32,33]) and that the effects of rosiglitazone on the endothelium might be transduced through other pathways. From the comparison between the treatments, we can estimate that 30–40% of the improvement in endothelial function was due to the improved glycemic control, because the adjusted changes in ACh-induced vasodilatation were consistently smaller when rosiglitazone was compared with metformin than placebo. In fact, the chronic hyperglycemia of the placebo group was associated with a tendency to deterioration, which was only prevented by metformin and effectively reversed by rosiglitazone (Fig. 2). Rosiglitazone could influence endothelial function by reducing circulating NEFA (28), which in high concentrations impair endothelial function in vivo (34), or by reducing the production of proinflammatory cytokines, as suggested by in vitro (35) and recent in vivo (36) studies. Although the present study was not powered to detect these effects, we did observe some decrease in circulating NEFA and TNF- levels as well as reciprocal associations between treatment-induced changes in TNF- levels and changes in ACh-induced vasodilatation. However, the baseline- and center-adjusted effect of rosiglitazone was not attenuated when each of the candidate variables was entered into the ANCOVA model. Finally, another possible mediator of this cross-talk between insulin action and endothelium might be represented by asymmetric dimethylarginine, a natural inhibitor of eNOS, whose plasma concentrations in nondiabetic subjects have recently been shown to correlate inversely with insulin sensitivity and to be significantly reduced by rosiglitazone (37).

Although the precise mechanisms of rosiglitazone action on endothelial function in vivo remain only suggestive, the potential benefit is of clinical interest. Aside from its vasodilatatory effects, the endothelium has many antiatherogenic properties: it limits smooth muscle cell proliferation (38), reduces platelet aggregability (39), and prevents monocyte chemotaxis (40). More importantly, an impaired endothelium-mediated dilatation of coronary (41) or forearm vessels (42,43) has been shown to predict subsequent cardiovascular events. If one considers the additional effect on insulin sensitivity, blood pressure, and hematocrit together with the evidence that thiazolidinediones suppress the proliferation and migration of vascular smooth muscle cells (44,45) and inhibit metalloproteases and macrophages activation (46), then the antiatherosclerotic potential of these compounds could be noteworthy. Preliminary evidence has shown that, in patients with type 2 diabetes, progression of carotid artery atherosclerosis might be reversed by treatment with thiazolidinediones (47,48).

	Acknowledgments

 
The study was supported by a grant from GlaxoSmithKline. We thank Sara Burchielli for her technical assistance.

	Footnotes

 
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

Received for publication November 7, 2003. Accepted for publication March 1, 2004.

	References

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS References

 

1. Howard B, Rodriguez B, Bennet P, Harris M, Hamman R, Kuller L, Pearson T, Wylie-Roset J: Prevention Conference VI: diabetes and cardiovascular disease: Writing Group I: epidemiology. Circulation 105:e132–e137, 2002[Free Full Text]
   
2. Natali A, Vichi S, Landi P, Severi S, L’Abbate A, Ferrannini E: Coronary atherosclerosis in type II diabetes: angiographic findings and clinical outcome. Diabetologia 43:632–641, 2000[Medline]
   
3. Vane JR, Anggard EE, Botting RM: Regulatory functions of the vascular endothelium. N Engl J Med 323:27–36, 1990[Medline]
   
4. Quyyumi AA: Endothelial function in health and disease: new insights into the genesis of cardiovascular disease. Am J Med 105:32S–39S, 1998[Medline]
   
5. Enderle M, Benda N, Schmuelling R, Haering H, Pfohl M: Preserved endothelial function in IDDM patients, but not in NIDDM patients, compared with healthy subjects. Diabetes Care 21:271–277, 1998[Abstract]
   
6. Balletshofer B, Ritting K, Enderle M, Volk A, Maerker E, Jacob S, Matthaei S, Rett K, Haring H: Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance. Circulation 101:1780–1784, 2000[Abstract/Free Full Text]
   
7. Williams S: Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 27:567–574, 1996[Abstract]
   
8. Makimattila S, Liu M-L, Vakkilainen J, Shlenzka A, Lahdenpera S, Syvanne M, Mantysaary M, Summanen P, Bergholm R, Taskinen M-R, Yki-Jarvinen H: Impaired endothelium-dependent vasodilation in type 2 diabetes: relation to LDL size, oxidized LDL, and antioxidants. Diabetes Care 22:973–981, 1999[Abstract]
   
9. Heitzer T, Krohn K, Albers S, Meinertz T: Tetrahydropterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with type 2 diabetes mellitus. Diabetologia 43:1435–1438, 2000[Medline]
   
10. Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron A: Obesity insulin resistance is associated with endothelial dysfunction: implication for the syndrome of insulin resistance. J Clin Invest 97:2061–2610, 1996
    
11. Preik M, Kelm M, Rosen P, Tschope D, Strauer B: Additive effect of coexistent type 2 diabetes and arterial hypertension on endothelial dysfunction in resistance arteries of human forearm vasculature. Angiology 51:545–554, 2000
    
12. Abe H, Yamada N, Kamata K, Kuwaki T, Shimada M, Osuga J, Shionori F, Yahagy N, Kadowaki T, Tamemoto H, Ishibashi S, Yazaki Y, Makuuki M: Hypertension, hypertriglycemia, and impaired endothelium-dependent vascular relation in mice lacking insulin receptor substrate-1. J Clin Invest 101:1784–1788, 1998[Medline]
    
13. Shankar RR, Wu Y, Shen HQ, Zhu JS, Baron AD: Mice with gene disruption of both endothelial and neuronal nitric oxide synthase exhibit insulin resistance. Diabetes 49:684–687, 2000[Abstract]
    
14. Walker AB, Chattington PD, Buckingam RE, Williams G: The thiazolidinedione rosiglitazone (BRL-49653) lowers blood pressure and protects against impairment of endothelial function in Zucker fatty rats. Diabetes 48:1448–1451, 1999[Abstract]
    
15. Diep QN, El Mabrouk M, Cohn JS, Endemann D, Amiri F, Virdis A, Neves MF, Schiffrin EL: Structure, endothelial function, cell growth, and inflammation in blood vessels of angiotensin II-infused rats: role of peroxisome proliferator-activated receptor-. Circulation 105:2296–2302, 2002[Abstract/Free Full Text]
    
16. Vehkavaara S, Makimattila S, Schlenzka A, Vakkilainen J, Westerbacka J, Yki-Jarvinen: Insulin therapy improves endothelial function in type 2 diabetes. ArteriosclerThromb Vasc Biol 20:545–550, 2000[Abstract/Free Full Text]
    
17. Mather K, Verma S, Anderson T: Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol 37:1344–1350, 2001[Abstract/Free Full Text]
    
18. Wolfe RR: Radioactive and Stable Isotope Tracers in Biomedicine: Principles and Practice of Kinetic Analysis. New York, Wiley, 1992
    
19. DeFronzo RA, Tobin JD, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214–E223, 1979
    
20. Mari A: Estimation of the rate of appearance in the non-steady state with a two-compartment model. Am J Physiol 263:E400–E415, 1992
    
21. Inzucchi SE, Maggs DG, Spollett GR, Page SL, Rife FS, Walton V, Shulman GI: Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 338:867–872, 1998[Abstract/Free Full Text]
    
22. Dorella M, Giusto M, Da Tos V, Campagnolo M, Palatini P, Rossi G, Ceolotto G, Felice M, Semplicini A, Del Prato S: Improvement of insulin sensitivity by metformin treatment does not lower blood pressure of nonobese insulin-resistant hypertensive patients with normal glucose tolerance. J Clin Endocrinol Metab 81:1568–1574, 1996[Abstract]
    
23. Prager R, Schernthaner G, Graf H: Effect of metformin on peripheral insulin sensitivity in non insulin dependent diabetes mellitus. Diabetes Metab 12:346–350, 1986
    
24. DeFronzo RA, Barzilai N, Simonson DC: Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects. J Clin Endocrinol Metab 73:1294–1301, 1991[Abstract]
    
25. Cusi K, Consoli A, DeFronzo RA: Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 81:4059–4067, 1996[Abstract/Free Full Text]
    
26. Abbasi F, Carantoni M, Chen YD, Reaven GM: Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin. Diabetes Care 21:1301–1305, 1998[Abstract]
    
27. Hother-Nielsen O, Schmitz O, Andersen PH, Beck-Nielsen H, Pedersen O: Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes. Acta Endocrinol (Copenh) 120:257–265, 1989[Medline]
    
28. Miyazaki Y, Glass L, Triplitt C, Matsuda M, Cusi K, Mahankali A, Mahankali S, Mandarino LJ, DeFronzo RA: Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in type II diabetic patients. Diabetologia 44:2210–2219, 2001[Medline]
    
29. Utriainen T, Malmstrom R, Yki-Jarvinen H: Methodological aspects, dose-response characteristics and causes of interindividual variation in insulin stimulation of limb blood flow in normal subjects. Diabetologia 38:555–564, 1995[Medline]
    
30. Trovati M, Masucco P, Mattiello L, Cavalot F, Mularoni E, Hahn A, Anfossi G: Studies on the influence of insulin on cyclic adenosine monophosphate in human vascular smooth muscle cells: dependence on cyclic guanosine mono-phosphate and modulation of catecholamine effects. Diabetologia 39:1156–1164, 1996[Medline]
    
31. Cardillo C, Nambi SS, Kilcoyne CM, Choucair WK, Katz A, Quon MJ, Panza JA: Insulin stimulates both endothelin and nitric oxide activity in the human forearm. Circulation 100:820–825, 1999[Abstract/Free Full Text]
    
32. Zeng G, Nystrom FH, Ravichandran LV, Cong LN, Kirby M, Mostowski H, Quon MJ: Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation 101:1539–1545, 2000[Abstract/Free Full Text]
    
33. Cong LN, Chen H, Li Y, Zhou L, McGibbon MA, Taylor SI, Quon MJ: Physiological role of Akt in insulin-stimulated translocation of GLUT4 in transfected rat adipose cells. Mol Endocrinol 11:1881–1890, 1997[Abstract/Free Full Text]
    
34. Steinberg HO, Tarshoby M, Monestel R, Hook G, Cronin J, Johnson A, Bayazeed B, Baron AD: Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest 100:1230–1239, 1997[Medline]
    
35. Marx N, Kehrle B, Kohlhammer K, Grub M, Koenig W, Hombach V, Libby P, Plutzky J: PPAR activators as antiinflammatory mediators in human T lymphocytes: implications for atherosclerosis and transplantation-associated arteriosclerosis. Circ Res 90:703–710, 2002[Abstract/Free Full Text]
    
36. Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI: Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 106:679–684, 2002[Abstract/Free Full Text]
    
37. Stuhlinger MC, Abbasi F, Chu JW, Lamendola C, McLaughlin TL, Cooke JP, Reaven GM, Tsao PS: Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA 287:1420–1426, 2002[Abstract/Free Full Text]
    
38. Garg U, Hassid A: Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 83:1774–1777, 1989
    
39. Ikeda H, Takajo Y, Murohara T, Ichiki K, Adachi H, Haramaki N, Katoh A, Imaizumi T: Platelet-derived nitric oxide and coronary risk factors. Hypertension 35:904–907, 2000[Abstract/Free Full Text]
    
40. Bath P, Hassall D, Gladwin A, Palmer R, Martin J: Nitric oxide and prostacyclin: divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro. Arterioscler Thromb Vasc Biol 11:254–260, 1991[Abstract/Free Full Text]
    
41. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A: Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 101:948–954, 2000[Abstract/Free Full Text]
    
42. Perticone F, Ceravolo R, Pujia A, Ventura G, Iacopino S, Scozzafava A, Ferraro A, Chello M, Mastroroberto P, Verdecchia P, Schillaci G: Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation 104:191–196, 2001[Abstract/Free Full Text]
    
43. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T: Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 104:2673–2678, 2001[Abstract/Free Full Text]
    
44. Marx N, Schonbeck U, Lazar MA, Libby P, Plutzky J: Peroxisome proliferator-activated receptor activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res 83:1097–1103, 1998[Abstract/Free Full Text]
    
45. Law RE, Meehan WP, Xi XP, Graf K, Wuthrich DA, Coats W, Faxon D, Hsueh WA: Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia. J Clin Invest 98:1897–1905, 1996[Medline]
    
46. Wakino S, Law RE, Hsueh WA: Vascular protective effects by activation of nuclear receptor PPAR. J Diabetes Complications 16:46–49, 2002[Medline]
    
47. Minamikawa J, Tanaka S, Yamauchi M, Inoue D, Koshiyama H: Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 83:1818–1820, 1998[Abstract/Free Full Text]
    
48. Koshiyama H, Shimono D, Kuwamura N, Minamikawa J, Nakamura Y: Rapid communication: inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 86:3452–3456, 2001[Abstract/Free Full Text]
    

CiteULike

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				S. S Lund, L. Tarnow, C. D A Stehouwer, C. G Schalkwijk, T. Teerlink, J. Gram, K. Winther, M. Frandsen, U. M Smidt, O. Pedersen, et al. Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes Eur. J. Endocrinol., May 1, 2008; 158(5): 631 - 641. [Abstract] [Full Text] [PDF]

				J. G. Boyle, P. J. Logan, M.-A. Ewart, J. A. Reihill, S. A. Ritchie, J. M. C. Connell, S. J. Cleland, and I. P. Salt Rosiglitazone Stimulates Nitric Oxide Synthesis in Human Aortic Endothelial Cells via AMP-activated Protein Kinase J. Biol. Chem., April 25, 2008; 283(17): 11210 - 11217. [Abstract] [Full Text] [PDF]

				F. Desjardins, B. Sekkali, W. Verreth, M. Pelat, D. De Keyzer, A. Mertens, G. Smith, M.-C. Herregods, P. Holvoet, and J.-L. Balligand Rosuvastatin increases vascular endothelial PPAR{gamma} expression and corrects blood pressure variability in obese dyslipidaemic mice Eur. Heart J., January 1, 2008; 29(1): 128 - 137. [Abstract] [Full Text] [PDF]

				M. Fernandez, C. Triplitt, E. Wajcberg, A. A. Sriwijilkamol, N. Musi, K. Cusi, R. DeFronzo, and E. Cersosimo Addition of Pioglitazone and Ramipril to Intensive Insulin Therapy in Type 2 Diabetic Patients Improves Vascular Dysfunction by Different Mechanisms Diabetes Care, January 1, 2008; 31(1): 121 - 127. [Abstract] [Full Text] [PDF]

				E. Wajcberg, A. Sriwijitkamol, N. Musi, R. A. DeFronzo, and E. Cersosimo Relationship between Vascular Reactivity and Lipids in Mexican-Americans with Type 2 Diabetes Treated with Pioglitazone J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1256 - 1262. [Abstract] [Full Text] [PDF]

				A. Balasubramanyam, D. Hinnen, and W. Polonsky Cardiovascular Event Prevention in the Person With Type 2 Diabetes: Case Examples for Identifying and Treating Multiple Risks The Diabetes Educator, July 1, 2006; 32(Supplement_5): 163S - 173S. [Full Text] [PDF]

				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]

				A. Basu, M. D. Jensen, F. McCann, D. Mukhopadhyay, M. J. Joyner, and R. A. Rizza Effects of pioglitazone versus glipizide on body fat distribution, body water content, and hemodynamics in type 2 diabetes. Diabetes Care, March 1, 2006; 29(3): 510 - 514. [Abstract] [Full Text] [PDF]

				A. J.M. Rennings, P. Smits, M. W. Stewart, and C. J. Tack Fluid retention and vascular effects of rosiglitazone in obese, insulin-resistant, nondiabetic subjects. Diabetes Care, March 1, 2006; 29(3): 581 - 587. [Abstract] [Full Text] [PDF]

				A. Gastaldelli, Y. Miyazaki, M. Pettiti, E. Santini, D. Ciociaro, R. A. DeFronzo, and E. Ferrannini The Effect of Rosiglitazone on the Liver: Decreased Gluconeogenesis in Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 806 - 812. [Abstract] [Full Text] [PDF]

				A. P. M. Viljanen, K. A. Virtanen, M. J. Jarvisalo, K. Hallsten, R. Parkkola, T. Ronnemaa, F. Lonnqvist, P. Iozzo, E. Ferrannini, and P. Nuutila Rosiglitazone Treatment Increases Subcutaneous Adipose Tissue Glucose Uptake in Parallel with Perfusion in Patients with Type 2 Diabetes: A Double-Blind, Randomized Study with Metformin J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6523 - 6528. [Abstract] [Full Text] [PDF]

				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]

				F. Pistrosch, K. Herbrig, B. Kindel, J. Passauer, S. Fischer, and P. Gross Rosiglitazone Improves Glomerular Hyperfiltration, Renal Endothelial Dysfunction, and Microalbuminuria of Incipient Diabetic Nephropathy in Patients Diabetes, July 1, 2005; 54(7): 2206 - 2211. [Abstract] [Full Text] [PDF]

				A. Natali, E. Toschi, S. Baldeweg, A. Casolaro, S. Baldi, A. M. Sironi, J. S. Yudkin, and E. Ferrannini Haematocrit, type 2 diabetes, and endothelium-dependent vasodilatation of resistance vessels Eur. Heart J., March 1, 2005; 26(5): 464 - 471. [Abstract] [Full Text] [PDF]

				Y. Miyazaki, E. De Filippis, M. Bajaj, E. Wajcberg, L. Glass, C. Triplitt, E. Cersosimo, L. J Mandarino, and R. A Defronzo Predictors of improved glycaemic control with rosiglitazone therapy in type 2 diabetic patients: a practical approach for the primary care physician The British Journal of Diabetes & Vascular Disease, January 1, 2005; 5(1): 28 - 35. [Abstract] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed