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Fluid Retention and Vascular Effects of Rosiglitazone in Obese, Insulin-Resistant, Nondiabetic Subjects

¹ Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
² Department of Pharmacology-Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
³ GlaxoSmithKline, Harlow, U.K.

Address correspondence and reprint requests to Alexander J.M. Rennings, MD, Department of Pharmacology-Toxicology 149, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, Netherlands. E-mail: a.rennings{at}aig.umcn.nl

OBJECTIVE—The use of thiazolidinedione (TZD) derivatives is associated with fluid retention, especially when combined with insulin. Because TZDs improve the metabolic effect of insulin, they may also reverse the blunted vascular response to insulin. We hypothesize that improvement of the action of insulin on vascular tone or permeability is the key mechanism of TZD-related fluid retention.

RESEARCH DESIGN AND METHODS—In a randomized, double-blind, placebo-controlled, cross-over study in 18 obese, nondiabetic subjects with features of the metabolic syndrome, we investigated the effects of a 12-week treatment with 4 mg rosiglitazone twice a day on glucose disposal, hemodynamics (including forearm vasoconstrictor response to nitric oxide [NO]), synthase inhibition by N-monomethyl-L-arginine-acetate (L-NMMA), vascular permeability (transcapillary escape rate of albumin), and plasma volume during a hyperinsulinemic-euglycemic clamp (120 min, 120 mU/m² per min).

RESULTS—As expected, rosiglitazone increased the glucose infusion rate during clamping. However, neither vascular permeability nor forearm blood flow response to hyperinsulinemia or L-NMMA was affected by rosiglitazone. Compared with placebo, rosiglitazone decreased diastolic blood pressure by 5 mmHg (95% CI 2.35–6.87, P = 0.0005) and increased plasma volume by 255 ml/1.73 m² (80–430, P = 0.007). Interestingly, the positive effect of rosiglitazone on glucose disposal correlated with change in foot volume (R² = 0.53, P = 0.001).

CONCLUSIONS—Rosiglitazone improved insulin sensitivity but had no effect on NO-dependent vasodilatation in the forearm or vascular permeability in obese, insulin-resistant, nondiabetic subjects. As such, TZD-related fluid retention was not caused by improvement of the vascular actions of insulin. Nonetheless, rosiglitazone-induced improvement in insulin sensitivity appears to be correlated to edema formation.

Abbreviations: ANP, atrial natriuretic peptide • DBP, diastolic blood pressure • FBF, forearm blood flow • GIR, glucose infusion rate • L-NMMA, N^G-monomethyl-L-arginine • PPAR, peroxisome proliferator–activated receptor • SBP, systolic blood pressure • TERalb, transcapillary escape rate of labeled albumin • TZD, thiazolidinedione

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