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

Abstract

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, placebocontrolled, 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 hyperinsulinemiceuglycemic clamp (120 min, 120 mU/m 2 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 ϭ 0.0005) and increased plasma volume by 255 ml/1.73 m 2 (80 -430, P ϭ 0.007). Interestingly, the positive effect of rosiglitazone on glucose disposal correlated with change in foot volume (R 2 ϭ 0.53, P ϭ 0.001).CONCLUSIONS -Rosiglitazone improved insulin sensitivity but had no effect on NOdependent 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. Diabetes Care 29:581-587, 2006T hiazolidinedione (TZD) derivatives improve insulin sensitivity and hence are valuable in the treatment of type 2 diabetes (1). Important adverse effects are fluid retention and peripheral edema formation. The precise mechanism(s) of these adverse effects are unclear and probably are multifactorial (2).Although multiple factors are involved, the existence of an initial trigger or main mechanism could be of clinical importance. In theory, the initial trigger of fluid retention may originate either from kidney, heart, or peripheral circulation. As TZD treatment is associated with a reduction in blood pressure (3-6), a primary renal mechanism seems unlikely. A primary cardiac origin also seems improbable, because long-term studies with rosiglitazone have not revealed any negative effect on myocardial structure or function (7).The combination of blood pressure reduction, fluid retention, and edema formation is compatible with changes in the peripheral circulation resulting in capillary leakage. This may be induced by certain actions of TZDs, such as improved insulin-mediated vasodilatation, direct vasoa...

Microvascular Permeability in Diabetes and Insulin Resistance

“…The drugs also improve beta‐cell function and reduce blood pressure [ 82 ]. However, the use of TZDs is often associated with an adverse effect: fluid retention and peripheral edema, especially when used in combination with insulin [ 59 ]. In many cases, especially when patients have congestive heart disease, the risk of developing pulmonary edema limits its clinical utility [ 39 ].…”

“…On the other hand, peripheral microvascular leakage may contribute, at least partially, to the accumulation of fluid in tissues. The peripheral effects of TZDs are thought to occur through the augmented insulin effects on vasodilation, capillary recruitment, and hyperpermeability [ 59 , 67 , 69 ]. In addition, Rosiglitazone has been shown to increase transendothelial albumin flux in human pulmonary artery endothelial cells [ 39 ].…”

Autonomic neuropathy predisposes to rosiglitazone-induced vascular leakage in insulin-treated patients with type 2 diabetes: a randomised, controlled trial on thiazolidinedione-induced vascular leakage

“…This may be due to a combined effect of thiazolidinediones and insulin or to complications accompanying longstanding diabetes [9]. In a previous study in insulin-resistant people without diabetes, we found no evidence for adverse vascular effects of the combined use of rosiglitazone and insulin [20], suggesting that it is not insulin itself but probably complications associated with longstanding diabetes that render patients prone to oedema formation. Autonomic neuropathy is a typical complication of longstanding diabetes [21, 22].…”

Peroxisome Proliferator-Activated Receptor Gamma Agonists in Kidney Disease – Future Promise, Present Fears

“…It could be due to up-regulation of the epithelial sodium channel [68, 69], increased sympathetic nervous system activity or altered endothelial permeability [70, 71]. Fluid retention accounts for at least 75% of body weight gain in patients receiving TZDs [72, 73], and furthermore contributes to the increased incidence of congestive heart failure (see below).…”