Endothelin‐1 in the pathophysiology of obesity and insulin resistance

Jenkins, Haley N.; Rivera‐Gonzalez, Osvaldo; Gibert, Yann; Speed, Joshua S.

doi:10.1111/obr.13086

Cited by 24 publications

(18 citation statements)

References 83 publications

(213 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Insulin was initially believed to be a vasodilator because of its activation on NO secretion (30,31). However, in recent studies, insulin-induced vasodilation was confirmed to be impaired in insulin-resistant patients, and patients with obesity or insulin resistance have elevated ET-1 concentrations in the blood (32,33). The mechanism underlying the direct vascular effect of insulin on endothelial cells remains controversial.…”

Section: Discussionmentioning

confidence: 99%

Pathological Hyperinsulinemia and Hyperglycemia in the Impaired Glucose Tolerance Stage Mediate Endothelial Dysfunction Through miR-21, PTEN/AKT/eNOS, and MARK/ET-1 Pathways

et al. 2021

View full text Add to dashboard Cite

BackgroundImpaired glucose tolerance (IGT) is an important prediabetic stage characterized by elevated concentrations of glucose and insulin in the blood. The pathological hyperglycemia and hyperinsulinemia in IGT may regulate the expression of microRNA-21 (miR-21) and affect the downstream insulin signaling pathways, leading to endothelial cell dysfunction and early renal damage.MethodsThe individual and combined effects of insulin and glucose were investigated using human glomerular endothelial cells (HGECs). The expression levels of miR-21, and PTEN/AKT/eNOS and MAPK/ET-1 pathway proteins in the treated cells were measured. The levels of nitric oxide (NO) and endothelin-1 (ET-1) secreted by the cells were also measured. The role of miR-21 in mediating the regulatory effects of insulin and glucose was assessed by overexpression/inhibition of this miRNA using mimics/inhibitor.ResultsHigh (>16.7 mmol/L) concentration of glucose upregulated the expression of miR-21, leading to the activation and inhibition of the PTEN/AKT/eNOS and MAPK/ET-1 pathways, and upregulation of NO and downregulation of ET-1 secretion, respectively. High (>25 ng/mL) concentration of insulin downregulated the expression of miR-21, and lead to the activation of the MAPK/ET-1 and inhibition of the PTEN/AKT/eNOS pathway, thereby upregulating the expression of ET-1 and downregulating the secretion of NO. MiR-21 was observed to play a key role by directly controlling the activation of the insulin signaling pathways when the cells were cotreated with different concentrations of insulin and glucose. The expression of miR-21 was found to be dependent on the relative concentration of insulin and glucose. Under simulated conditions of the IGT stage (8.3 mmol/L glucose + 50 ng/mL insulin), the inhibitory effect of high insulin concentration on miR-21 expression in the cells attenuated the activation by high glucose concentration, resulting in the downregulation of miR-21, upregulation of ET-1 and downregulation of NO secretion.ConclusionTaken together, these results indicate that high insulin and glucose concentrations regulate the secretory function of glomerular endothelial cells in opposite ways by regulating the expression of miRNA-21. Pathological concentrations of insulin and glucose in the IGT stage may lead to a decrease in miR-21 expression, thereby disordering the secretion of vasoactive factors, resulting in renal tubule ischemia.

show abstract

Section: Discussionmentioning

confidence: 99%

Pathological Hyperinsulinemia and Hyperglycemia in the Impaired Glucose Tolerance Stage Mediate Endothelial Dysfunction Through miR-21, PTEN/AKT/eNOS, and MARK/ET-1 Pathways

et al. 2021

View full text Add to dashboard Cite

show abstract

“…First, IR is correlated with endothelial dysfunction and atherosclerosis. IR is characterised by reduced phosphatidylinositol 3-kinase (PI3-K)/Akt pathway activity and increased expression of mitogen-activated protein kinase (MAPK) pathways; the disequilibrium between the two signals causes endothelial dysfunction, reduced nitric oxide (NO) production in endothelial cells, and increased endothelin-1 (ET-1) production, which may initiate oxidative stress, inflammatory cascade, and early stage atherosclerosis, [16][17][18][19] promote the development of CSVD, and accelerate cognitive impairment. Elevated levels of inflammatory cytokines are closely associated with IR.…”

Section: Discussionmentioning

confidence: 99%

Increased insulin resistance is associated with vascular cognitive impairment in Chinese patients with cerebral small vessel disease

Guo

Zhu

et al. 2021

Psychogeriatrics

View full text Add to dashboard Cite

Background The aim of this study was to investigate the association between insulin resistance (IR) and vascular cognitive impairment (VCI) in patients with cerebral small vessel disease (CSVD). Methods A total of 275 CSVD patients were enrolled in this retrospective case–control study. The homeostatic model assessment of insulin resistance (HOMA‐IR) was used to measure the index of insulin resistance. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Spearman's correlation coefficient was used to evaluate the correlation between HOMA‐IR and MoCA score. The variance inflation factor (VIF) was used to detect collinearity between variables. Multivariate logistic regression analysis was employed to confirm whether HOMA‐IR is an independent risk factor for VCI in CVSD. Finally, receiver operating characteristic (ROC) curve analysis was conducted to assess the diagnostic value of HOMA‐IR in VCI. Results Of the 275 patients, 164 displayed VCI. VCI patients showed a significantly higher level of HOMA‐IR compared to non‐VCI patients (P < 0.001). HOMA‐IR was negatively correlated with the MoCA score (r = −0.593, P < 0.001). After adjusting for potential confounding variables, using HOMA‐IR quartile 1 (<1.11) as the reference, HOMA‐IR quartile 3 (1.71–2.50) and quartile 4 (≥2.50) were independently associated with the occurrence of VCI; for each one unit increase in the HOMA‐IR, the risk of VCI increased by 177.3% (odds ratio 2.773, 95% confidence interval: 1.050–7.324, P = 0.040) and 444.3% (odds ratio 5.443, 95% confidence interval: 2.109–14.050, P < 0.001), respectively. According to the ROC curve, the optimal cut‐off point of HOMA‐IR in predicting VCI was 1.55, and the area under the curve was 0.744, with a sensitivity of 71.3% and a specificity of 69.4%. Conclusion This study demonstrated that increased IR is significantly associated with VCI in CSVD patients.

show abstract

“…ET-1 is the most potent vasoconstrictor substance identified, and it is widely distributed in cardiovascular and neural tissues, and the increased peripheral vascular resistance in essential hypertension may be related to its excessive production ( 10 ). NO is a gaseous biological messenger molecule that is widely involved in a variety of physiological and pathological processes in the body, and is considered to be a regulatory mediator in the regulation of vascular tone and maintenance of BP stability ( 11 , 12 ). The aim of this study was to investigate the relationship between the expression of serum ET-1 and NO levels and BP changes in patients with different degrees of BP in ESRD treated with HD after action endovenous fistula surgery and their correlation.…”

Section: Introductionmentioning

confidence: 99%

Correlation of NO and ET-1 Levels with Blood Pressure Changes in Hemodialysis Patients after Arteriovenous Fistula Surgery

Sun

2022

Front. Surg.

View full text Add to dashboard Cite

Hemodialysis (HD) is the most common renal replacement therapy for patients with end-stage renal disease (ESRD) and can significantly reduce mortality and improve the quality of life of patients. The occurrence of intradialytic hypotension and intradialytic hypertension are important risk factors for death and disability during dialysis in patients with ESRD, yet their etiology remains unclear, and some studies suggest that nitric oxide (NO) and endothelin-1 (ET-1) may play an important role in these hemodynamic alterations. For this purpose we examined the changes in NO and ET-1 levels during hemodialysis in 30 patients on maintenance hemodialysis (MHD) after arteriovenous fistula surgery. Thirty dialysis patients were divided into group I (stable blood pressure during dialysis), group II (Intradialytic hypotension) and group III (Intradialytic hypertension) according to the change of blood pressure (BP) during hemodialysis, with 10 cases in each group. BP of MHD patients were measured Pre-dialysis (Pre-D), at 1 h of dialysis (1h-D), at 2 h of dialysis (Mid-D, 2h-D), at 3 h of dialysis (3h-D), and at the end of dialysis (Post-D); and blood samples were taken from the arterial end at Pre-D, Mid-D, and Post-D to measure NO and ET-1 levels. The results of the analysis showed that as dialysis proceeded and ended, the NO levels in the three groups gradually decreased, with significant differences compared with those before dialysis (p < 0.05); the ET-1 levels in group III gradually increased, with significant differences compared with those before dialysis (p < 0.05), while the increasing trend of ET-1 levels in group I and group II was not significant. The increasing trend of MAP in group I was not significant (p > 0.05); MAP in group II showed a gradual decrease and MAP in group III showed an increasing trend, and the difference between MAP after dialysis and before dialysis was significant (p < 0.05). Correlation analysis showed a significant positive correlation between ET-1 levels and MAP in Group III at Mid-D (r = 0.847, p = 0.002). This shows that serum ET-1 and NO levels are significantly higher than normal in MHD patients after arteriovenous endovascular fistula surgery, and both ET-1 and NO levels are changing during dialysis, and there may be a link between their changes and blood pressure changes. It is suggested that the blood pressure fluctuations that occur during dialysis in MHD patients may be related to endothelial cell dysfunction.

show abstract

Endothelin‐1 in the pathophysiology of obesity and insulin resistance

Cited by 24 publications

References 83 publications

Pathological Hyperinsulinemia and Hyperglycemia in the Impaired Glucose Tolerance Stage Mediate Endothelial Dysfunction Through miR-21, PTEN/AKT/eNOS, and MARK/ET-1 Pathways

Pathological Hyperinsulinemia and Hyperglycemia in the Impaired Glucose Tolerance Stage Mediate Endothelial Dysfunction Through miR-21, PTEN/AKT/eNOS, and MARK/ET-1 Pathways

Increased insulin resistance is associated with vascular cognitive impairment in Chinese patients with cerebral small vessel disease

Correlation of NO and ET-1 Levels with Blood Pressure Changes in Hemodialysis Patients after Arteriovenous Fistula Surgery

Contact Info

Product

Resources

About