Capillary endothelial but not lymphatic function is restored under rosiglitazone in Zucker Diabetic Fatty rats

Cosson, E.; Cohen-Boulakia, F; Tarhzaoui, K.; Dabiré, Hubert; Léger, Gérard; Charnaux, Nathalie; Lestrade, R.; Béhar, A.; Valensi, P.

doi:10.1016/j.mvr.2008.11.005

Cited by 8 publications

(4 citation statements)

References 44 publications

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“…All in all, the findings fit with the concept that defective counter-regulation of haemodynamic changes caused by autonomic neuropathy exaggerates vascular leakage induced by thiazolidinediones. In persons with no or mild autonomic neuropathy, rosiglitazone did not increase vascular leakage, which is in accordance with previous human [20] and preclinical [27] findings.…”

Section: Discussionsupporting

confidence: 92%

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

et al. 2010

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Aims/hypothesisThe mechanism of fluid-related complications caused by thiazolidinedione derivatives is unclear. One potential mechanism is thiazolidinedione-induced arterial vasodilatation, which results in vascular leakage and a fall in blood pressure, normally counterbalanced by sympathetic activation and subsequent renal fluid retention. We hypothesised that thiazolidinedione-induced vascular leakage will be particularly prominent in patients with autonomic neuropathy.MethodsWe conducted a randomised, double-blind, placebo-controlled, parallel study in 40 patients with type 2 diabetes on insulin treatment recruited from a university medical centre. The randomisation was performed by a central office using a randomisation schedule. Both treatment groups, placebo (n = 21) and rosiglitazone (n = 19), were stratified for sex and level of autonomic neuropathy as assessed by Ewing score (<2.5 or ≥2.5). We investigated the effects of 16 weeks of treatment with rosiglitazone 4 mg twice daily on vascular leakage (transcapillary escape rate of albumin, TERalb), body weight, extracellular volume and plasma volume.ResultsThirty-nine patients were included in the analysis. In patients with high Ewing scores (n = 16), rosiglitazone increased TERalb significantly (ΔTERalb: rosiglitazone +2.43 ± 0.45%/h, placebo −0.11 ± 0.15%/h, p = 0.002), while rosiglitazone had no effect in the patients with low Ewing scores (n = 23). Rosiglitazone-induced increases in TERalb and Ewing score at baseline were correlated (r = 0.65, p = 0.02). There was no correlation between Ewing score and rosiglitazone-induced changes in fluid variables. One subject was withdrawn from the study because of atrial fibrillation.Conclusions/interpretationRosiglitazone may increase vascular leakage in insulin-treated patients with type 2 diabetes with autonomic neuropathy. Autonomic neuropathy did not exaggerate rosiglitazone-induced fluid retention. Therefore, autonomic neuropathy should be considered as a risk factor for thiazolidinedione-induced oedema, not for thiazolidinedione-induced fluid retention.Trial registrationClinicalTrials.gov NCT00422955FundingGlaxoSmithKline

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Section: Discussionsupporting

confidence: 92%

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

et al. 2010

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“…In this study, rosiglitazone dose-dependently reduced the lymph vessel density of implanted gastric tumors and decreased expression of VEGF-C and VEGFR-3, common lymphangiogenic markers (Chen et al, 2013). Another study evaluated the impact of rosiglitazone on lymphatic function by using technetium-labelled albumin to measure albumin retention and uptake of interstitial albumin by lymphatics in hindquarters of Zucker Diabetic Fatty (ZDF) rats (Cosson et al, 2009). In previous studies the ratio of low and high frequency peaks (LF/ HF ratio) correlated with the half-life of the technetium-labelled albumin disappearance during lymphoscintigraphy (Cohen-Boulakia et al, 2000;Pecking et al, 2008); therefore, LF/HF ratio was used as a surrogate index of lymphatic uptake of albumin.…”

Section: Thiazodilinedionesmentioning

confidence: 99%

Drug-Related Lymphedema: Mysteries, Mechanisms, and Potential Therapies

Pal

Rahman

et al. 2022

Front. Pharmacol.

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The lymphatic circulation is an important component of the circulatory system in humans, playing a critical role in the transport of lymph fluid containing proteins, white blood cells, and lipids from the interstitial space to the central venous circulation. The efficient transport of lymph fluid critically relies on the rhythmic contractions of collecting lymph vessels, which function to “pump” fluid in the distal to proximal direction through the lymphatic circulation with backflow prevented by the presence of valves. When rhythmic contractions are disrupted or valves are incompetent, the loss of lymph flow results in fluid accumulation in the interstitial space and the development of lymphedema. There is growing recognition that many pharmacological agents modify the activity of ion channels and other protein structures in lymph muscle cells to disrupt the cyclic contraction and relaxation of lymph vessels, thereby compromising lymph flow and predisposing to the development of lymphedema. The effects of different medications on lymph flow can be understood by appreciating the intricate intracellular calcium signaling that underlies the contraction and relaxation cycle of collecting lymph vessels. For example, voltage-sensitive calcium influx through long-lasting (“L-type”) calcium channels mediates the rise in cytosolic calcium concentration that triggers lymph vessel contraction. Accordingly, calcium channel antagonists that are mainstay cardiovascular medications, attenuate the cyclic influx of calcium through L-type calcium channels in lymph muscle cells, thereby disrupting rhythmic contractions and compromising lymph flow. Many other classes of medications also may contribute to the formation of lymphedema by impairing lymph flow as an off-target effect. The purpose of this review is to evaluate the evidence regarding potential mechanisms of drug-related lymphedema with an emphasis on common medications administered to treat cardiovascular diseases, metabolic disorders, and cancer. Additionally, although current pharmacological approaches used to alleviate lymphedema are largely ineffective, efforts are mounting to arrive at a deeper understanding of mechanisms that regulate lymph flow as a strategy to identify novel anti-lymphedema medications. Accordingly, this review also will provide information on studies that have explored possible anti-lymphedema therapeutics.

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“…[19][20][21] Microangiopathy also affects endothelial function with increased capillary permeability to large proteins and molecules in diabetic patients, a feature that can be seen by the transcapillary escape rate of radiolabelled albumin. 22,23 Removal and drainage of interstitial albumin appears to be delayed in diabetic patients, suggesting a defect in lymphatic function due to overflow saturation of the lymph pumps. 22 Hence, although diabetes does not cause direct damage to the lymphatic vessels, the processes of normal interstitial fluid homeostasis are affected with the increase in transport capacity that overwhelms the drainage system.…”

Section: Diabetic Microangiopathy and Lymphedemamentioning

confidence: 99%

“…10 Peripheral limb edema is a feature of DFU and despite the lack of an estimate of its incidence or prevalence in DFU, it has been identified as a significant risk factor for amputation in patients with DFU. 11,12 Diabetes, however, has been identified as a comorbidity in 23.5% of patients with lymphedema in a multicenter study of 1,000 patients…”

Section: Introductionmentioning

confidence: 99%

Diabetic foot ulcers in conjunction with lower limb lymphedema: pathophysiology and treatment procedures

Kanapathy¹,

Portou²,

Tsui³

et al. 2015

CWCMR

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Diabetic foot ulcers (DFUs) are complex, chronic, and progressive wounds, and have a significant impact on morbidity, mortality, and quality of life. A particular aspect of DFU that has not been reviewed extensively thus far is its management in conjunction with peripheral limb edema. Peripheral limb edema is a feature of diabetes that has been identified as a significant risk factor for amputation in patients with DFU. Three major etiological factors in development of lymphedema with concurrent DFU are diabetic microangiopathy, failure of autonomic regulation, and recurrent infection. This review outlines the pathophysiology of lymphedema formation in patients with DFU and highlights the cellular and immune components of impaired wound healing in lymphedematous DFU. We then discuss the principles of management of DFU in conjunction with lymphedema.

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Capillary endothelial but not lymphatic function is restored under rosiglitazone in Zucker Diabetic Fatty rats

Cited by 8 publications

References 44 publications

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

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

Drug-Related Lymphedema: Mysteries, Mechanisms, and Potential Therapies

Diabetic foot ulcers in conjunction with lower limb lymphedema: pathophysiology and treatment procedures

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