Elevated plasma endothelin-1 levels in diabetes mellitus

Schneider, Jochen G.; Tilly, N; Hierl, Thomas; Sommer, Ulrike; Hamann, Andreas; Dugi, Klaus A.; Leidig-Bruckner, G.; Kasperk, Christian

doi:10.1016/s0895-7061(02)03060-1

Cited by 147 publications

(98 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Earlier studies have shown that circulatory levels of ET-1 are increased in obesity. 10,[20][21][22][23][24] We have recently shown that s.c. adipose tissue, which is the major adipose region, might contribute to the elevated levels of ET-1 in the obese state. 10 This study shows that the expression of ET-1 mRNA is higher in s.c. adipose tissue compared with OM adipose tissue, whereas ETR expression is similar in the two depots .…”

Section: Discussionmentioning

confidence: 99%

Endothelin-1 stimulates human adipocyte lipolysis through the ETA receptor

et al. 2008

View full text Add to dashboard Cite

Objective: Levels of the vascular peptide endothelin-1 (ET-1) are significantly elevated in obesity. Adipose tissue-derived ET-1 attenuates insulin-mediated antilipolysis in human visceral adipocytes through the activation of the ET receptor B (ET B R), thereby linking ET-1 to insulin resistance. Whether ET-1 has direct effects on lipolysis in human adipocytes is not known. Research design and subjects: Endothelin-1 receptor (ETR) mRNA expression was determined by quatitative PCR in 130 nonobese and obese subjects. ET-1 mRNA in different adipose tissue regions was also assessed. ETR protein expression was analyzed by western blotting in 37 subjects. The effect of ET-1 on lipolysis was assessed in freshly isolated adipocytes and in vitro differentiated adipocytes from human donors. Results: Freshly isolated human adipocytes incubated with different concentrations of ET-1 showed no acute effect on lipolysis. In contrast, a 24 h incubation in primary cultures of human adipocytes resulted in a significant 50% increase in lipolysis. This effect was concentration dependent and could be mimicked by an agonist of the ET A receptor but not with a selective ET B R agonist. Adipocyte differentiation was not affected by any of the agonists. In subcutaneous (s.c.) adipose tissue from 19 nonobese and 18 obese subjects, the protein expression of ET A R was significantly higher in obese subjects whereas there was no difference in ET B R expression. Interestingly, the differences in protein expression were not observed at the mRNA level as ET A R expression was similar between lean and obese subjects. Conclusion: Long-term but not acute incubation of human adipocytes with ET-1 results in a significant increase in lipolysis. This appears to be mediated through the activation of ET A R, demonstrating a yet another receptor-specific effect of ET-1. In addition, the protein expression of ET A R is increased in s.c. adipose tissue in obesity, possibly through post-transcriptional mechanisms. An increased effect of ET-1 could be a mechanism that contributes to increased basal lipolysis in human obesity.

show abstract

Section: Discussionmentioning

confidence: 99%

Endothelin-1 stimulates human adipocyte lipolysis through the ETA receptor

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Because ET-1 plays a pathophysiologic role in various forms of cardiovascular disease (119), it has been suggested as a potential marker of endothelial dysfunction. Although plasma ET-1 levels are elevated in patients with symptomatic atherosclerosis (120), heart failure (121), cardiogenic shock (122), primary pulmonary hypertension (123), diabetes (124), and renal failure (125), plasma ET-1 does not reliably represent levels of tissue ET-1 production and has not been found to be elevated in patients with stage 1 hypertension (126). Plasma ET-1 has not proved to be a useful clinical measurement in most conditions.…”

Section: Assessment Of Endothelial Dysfunctionmentioning

confidence: 99%

Endothelial Dysfunction

Endemann¹

2004

Journal of the American Society of Nephrology

1,110

834

View full text Add to dashboard Cite

Abstract. Endothelial dysfunction is characterized by a shift of the actions of the endothelium toward reduced vasodilation, a proinflammatory state, and prothrombic properties. It is associated with most forms of cardiovascular disease, such as hypertension, coronary artery disease, chronic heart failure, peripheral artery disease, diabetes, and chronic renal failure. Mechanisms that participate in the reduced vasodilatory responses in endothelial dysfunction include reduced nitric oxide generation, oxidative excess, and reduced production of hyperpolarizing factor. Upregulation of adhesion molecules, generation of chemokines such as macrophage chemoattractant peptide-1, and production of plasminogen activator inhibitor-1 participate in the inflammatory response and contribute to a prothrombic state. Vasoactive peptides such as angiotensin II and endothelin-1; the accumulation of asymmetric dimethylarginine, an endogenous nitric oxide inhibitor; hypercholesterolemia; hyperhomocysteinemia; altered insulin signaling; and hyperglycemia can contribute to these different mechanisms. Detachment and apoptosis of endothelial cells (anoikis) are associated phenomena. Endothelial dysfunction is an important early event in the pathogenesis of atherosclerosis, contributing to plaque initiation and progression. Reductions in circulating endothelial progenitor cells that participate in regeneration of the endothelium participate in endothelial pathophysiology. The severity of endothelial dysfunction has been shown to have prognostic value for cardiovascular events.

show abstract

“…Changes in blood flow correlate with changes in oxygen saturation (39) and reduced sural nerve endoneurial oxygen tension. These changes are potentiated by increased expression or action of vasoconstrictors such as endothelin and angiotensin and decreased activity of vasodilators such as prostacyclin, substance P, calcitonin gene-related peptide, endothelial-derived hyperpolarizing factor, and bradykinin (40). In particular, in patients with DPN there is disruption in vasomotion, the rhythmic contraction exhibited by arterioles and small arteries (19).…”

Section: Statisticsmentioning

confidence: 99%

Pioglitazone Treatment Improves Nitrosative Stress in Type 2 Diabetes

et al. 2006

View full text Add to dashboard Cite

OBJECTIVE -The purpose of this study was to determine the effect of 24 weeks of treatment with 45 mg/day pioglitazone on peripheral skin blood flow (SkBF) and skin nitric oxide (NO) production in vivo in patients with type 2 diabetes.RESEARCH DESIGN AND METHODS -This was a randomized, parallel, cross-over, double-blind, within-and between-subject study designed to compare vascular responses before and after treatment. We studied 12 subjects with type 2 diabetes (average age 58.6 Ϯ 30.8 years, HbA 1c 7.9 Ϯ 00.4%, BMI 31.3 Ϯ 1.2 kg/m 2 ). SkBF was measured using laser Doppler techniques in response to ischemia reperfusion and local skin warming, and NO production was assessed in vivo using an amperometric NO meter inserted directly into the skin. These measurements were performed before treatment and at 6 and 24 weeks.RESULTS -The SkBF response was not significantly improved after 24 weeks in either of the groups. NO production was significantly decreased in the pioglitazone-treated group in the basal condition (area under the curve 6.4 Ϯ 1.0 vs. 2.8 Ϯ 0.8, P Ͻ 0.01), after local heat stimulation at 40°C (12.9 Ϯ 2.2 vs. 5.7 Ϯ 1.7, P Ͻ 0.01), and after nociceptor stimulated flow with local heating at 44°C (36.4 Ϯ 6.3 vs. 16.6 Ϯ 3.4). Differences were not significant in the placebotreated group.CONCLUSIONS -Treatment of patients with type 2 diabetes with pioglitazone for 24 weeks reduced skin NO production, thus probably reducing nitrosative stress without a demonstrable effect on SkBF. Because nitrosative stress is considered to be a factor in the pathogenesis of neurovascular dysfunction, these findings warrant further investigation. Diabetes Care 29:869 -876, 2006W e have previously described both impaired peripheral vasoconstriction and vasodilatation in cutaneous vessels of people with diabetes, which strongly resembles the normal aging effects seen in peripheral vasculature (1). We have suggested both an endothelial and a neuronal component to these defects (2). The neuronal component is only activated at noxious temperatures (Ͼ40°C) or after tissue damage. Endothelial integrity is a major component under normal tissue demands for oxygenation after ischemia. Other investigators have also proposed the notion that there is specific damage to vascular endothelium and/or smooth muscle in diabetes, but localization of such a defect remains elusive.Insulin is a vasodilator hormone and facilitates endothelial release of nitric oxide (NO) and prostacyclin as well as upregulation of prostacyclin receptors on vascular smooth muscle (3). Resistance to the action of insulin could theoretically contribute to impaired neurovascular function. Jaap et al. (4) showed an endothelial or smooth muscle defect associated with insulin resistance that may precede the development of diabetes. We also showed that defective neurovascular function correlates with features of the metabolic syndrome, including insulin resistance, hypertension, dyslipidemia, and obesity (2). Diabetes is now recognized to be part of the metabolic syndrome an...

show abstract

Elevated plasma endothelin-1 levels in diabetes mellitus

Cited by 147 publications

References 31 publications

Endothelin-1 stimulates human adipocyte lipolysis through the ETA receptor

Endothelin-1 stimulates human adipocyte lipolysis through the ETA receptor

Endothelial Dysfunction

Pioglitazone Treatment Improves Nitrosative Stress in Type 2 Diabetes

Contact Info

Product

Resources

About