Insulin modulates circulating endothelin-1 levels in humans

Wolpert, Howard; Steen, Stephen N.; Istfan, Nawfal W.; Simonson, Donald C.

doi:10.1016/0026-0495(93)90018-j

Cited by 85 publications

(52 citation statements)

References 24 publications

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“…Two recent studies have shown that plasma ET-1 concentrations were raised in obesity-associated hypertension and that obesity was a stronger determinant of circulating ET-1 levels than hypertension. 36,37 In support of this, weight loss due to caloric restriction has been shown to be accompanied by a marked decrease in ET-1 levels, in both obese 38 and nonobese subjects. 36 These observations suggest that obesity might be a factor that enhances the expression of the ET-1 gene, possibly through an upregulation by insulin, which is known to stimulate ET-1 production.…”

Section: Discussionmentioning

confidence: 77%

The Lys198Asn Polymorphism in the Endothelin-1 Gene Is Associated With Blood Pressure in Overweight People

et al. 1999

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Abstract-There is accumulating evidence that endothelin-1 plays an important role in vascular pathophysiology. Our objective was to examine whether molecular variations at the endothelin-1 locus were involved in susceptibility to myocardial infarction and variation in blood pressure. The entire coding sequence and 1.4 kb of the 5Ј flanking region were screened. Five polymorphisms were detected, which were genotyped in the ECTIM (Etude Cas-Témoin de l'Infarctus du Myocarde) Study, a multicenter study comparing 648 male patients who had survived a myocardial infarction and 760 population-based controls. The polymorphisms were not associated with myocardial infarction, nor did they contribute to blood pressure levels in the population at large. However, a G/T polymorphism predicting an Lys/Asn change (ET1/C198) strongly interacted (PϽ0.001) with body mass index in the determination of blood pressure levels. There was a steeper increase of blood pressure with body mass index in carriers of the T allele than in GG homozygotes. As a consequence, the T allele was associated with an increase of blood pressure in overweight subjects (body mass index Ն26 kg/m 2 ), while no significant effect was observed in lean subjects (body mass index Ͻ26 kg/m 2 ). To determine whether this finding could be replicated, the ET1/C198 was genotyped in the Glasgow Heart Scan Study, a population-based study including 619 men and 663 women. Subjects homozygous for the T allele had higher resting blood pressure levels than others (PϽ0.05). A similar interaction between the T allele and body mass index was observed on the maximum blood pressure achieved during a treadmill exercise test (PϽ0.001). In conclusion, results from 2 independent studies suggest that the ET1/C198 polymorphism is associated with blood pressure levels in overweight people. (Hypertension. 1999;33:1169-1174.) Key Words: genes Ⅲ endothelin Ⅲ myocardial infarction Ⅲ hypertension, genetic Ⅲ blood pressure Ⅲ body mass index Ⅲ obesity E ndothelin-1 (ET-1) is a powerful vasoconstrictor peptide produced by endothelial and smooth muscle cells. 1 It is found in a variety of tissues, where it acts as a modulator of vasomotor tone, cell proliferation, and hormone production (see References 2 and 3 for reviews). There is accumulating evidence from experimental and clinical data that ET-1 plays an important role in the pathophysiology of the vascular system. 3 ET-1 expression is enhanced in atherosclerosis and coronary endothelial dysfunction 4 -6 and may contribute to the rupture of active atherosclerotic plaques, leading to acute ischemic events. 7,8 Raised circulating concentrations of ET-1 have been observed in the acute phase of myocardial infarction (MI) 9 -11 and were related to an unfavorable prognosis after MI. 12 Congestive heart failure is also commonly associated with high ET-1 concentrations, 13-15 and long-term treatment with an endothelin-receptor antagonist has been reported to improve the survival of rats with chronic heart failure. 16 Because of its vasoconstrictor an...

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Section: Discussionmentioning

confidence: 77%

The Lys198Asn Polymorphism in the Endothelin-1 Gene Is Associated With Blood Pressure in Overweight People

et al. 1999

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“…Therefore, the present investigation does not support the concept that insulin influences local or systemic ET-1 generation, release, or vasoconstrictor action. Given that hyperinsulinemia was present in the subjects under study at systemic doses over 6 h in protocol 1 and that BQ-123 alone was equally effective under placebo, an acute counterregulatory potential of ET-1 on vascular tone, which could have been missed in previous studies due to the short infusion period used (Wolpert et al, 1993;Metsä rinne et a., 1994;Katsumori et al, 1996), is very unlikely. Therefore, our results suggest that data from animal experiments showing markedly elevated plasma ET-1 levels in hyperinsulinemic rats (Hu et al, 1993) cannot be extrapolated to humans.…”

Section: Discussionmentioning

confidence: 99%

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confidence: 81%

“…In addition, hyperinsulinemia elevates plasma ET-1 levels in rats (Hokanson et al, 1975), suggesting increased production and/or secretion of ET-1. This effect of insulin on circulating ET-1 levels was confirmed in obese patients (Wolpert et al, 1993) and type II diabetic patients but was not seen in healthy subjects during a standard glucose tolerance test (Leyva et al, 1997) or during mild hyperinsulinemia (Metsä rinne et al, 1994).We decided to rechallenge the question of whether insulin may stimulate ET-1 release in healthy subjects for several reasons. On the one hand, studies of the effect of hyperinsulinemia on circulating ET-1 levels may be of limited value since ET-1 is predominantly a paracrine modulator of vascular tone (Webb, 1997).…”

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confidence: 94%

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Specific Endothelin ET_A Receptor Antagonism Does Not Modulate Insulin-Induced Hemodynamic Effects in the Human Kidney, Eye, or Forearm

Rab

Dallinger²,

Polak³

et al. 2004

J Pharmacol Exp Ther

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There is evidence that hyperinsulinemia may stimulate endothelin-1 (ET-1) generation or release, which may affect diabetic vascular complications. BQ-123, a specific ET A receptor antagonist, was used to investigate if insulin-induced vascular effects are influenced by an acute ET-1 release. Two randomized, placebo-controlled, double-blind, cross-over studies were performed. In protocol 1, 12 healthy subjects received, on separate study days, infusions of BQ-123 (60 g/min for 30 min) during placebo clamp conditions, BQ-123 during euglycemic hyperinsulinemia (3 mU/kg/min for 390 min), or placebo during euglycemic hyperinsulinemia. Fundus pulsation amplitude (FPA) was measured to assess pulsatile choroidal blood flow, and mean flow velocity (MFV) of the ophtalmic artery was measured by color Doppler imaging. In protocol 2, eight healthy subjects received, on separate study days, intra-arterial infusions of BQ-123 (32 g/min for 120 min) during placebo or insulin clamp. Forearm blood flow was measured with bilateral plethysmography, expressing the ratio of responses in the intervention arm and in the control arm. Insulin alone increased FPA (ϩ10%, p Ͻ 0.001) and forearm blood flow (ϩ19%). BQ-123 increased FPA, MFV, and forearm blood flow ratio in the absence and presence of exogenous insulin, but this effect was not different between normo-and hyperinsulinemic conditions. ET-1 plasma concentrations were not affected by insulin. In conclusion, these data do not support the concept that hyperinsulinemia increases ET-1 generation in healthy subjects. Our results, however, cannot necessarily be extrapolated to diabetic and obese subjects.It has been reported that plasma endothelin-1 (ET-1) concentrations are significantly increased in some patients with type I (Takahashi et al., 1990) and type II diabetes mellitus (Laurenti et al., 1997), which may contribute to the vascular complications in diabetes. Several studies demonstrated that insulin can stimulate ET-1 release in endothelial cell cultures (Metsä rinne et al., 1994;. In addition, hyperinsulinemia elevates plasma ET-1 levels in rats (Hokanson et al., 1975), suggesting increased production and/or secretion of ET-1. This effect of insulin on circulating ET-1 levels was confirmed in obese patients (Wolpert et al., 1993) and type II diabetic patients but was not seen in healthy subjects during a standard glucose tolerance test (Leyva et al., 1997) or during mild hyperinsulinemia (Metsä rinne et al., 1994).We decided to rechallenge the question of whether insulin may stimulate ET-1 release in healthy subjects for several reasons. On the one hand, studies of the effect of hyperinsulinemia on circulating ET-1 levels may be of limited value since ET-1 is predominantly a paracrine modulator of vascular tone (Webb, 1997). Hence, ET-1 plasma concentrations do not necessarily predict the level of vascular ET-1 activity. Furthermore, ET-1 concentrations are subject to considerable within-subject variability (Jilma et al., 1997). Thus, determination of ET-1 plasma lev...

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“…Participation of insulin in the modulation of plasma ET-1 levels was suspected. 28,29 It is also known that a higher concentration of serum insulin is observed in obese subjects. 30,31 Thus, FBS was included in the analysis to adjust for the confounding factor of insulin resistance of subjects.…”

Section: Various Measurements and Survey Of Life Habitsmentioning

confidence: 99%

The Lack of Relationship between an Endothelin-1 Gene Polymorphism (Ala288Ser) and Incidence of Hypertension: A Retrospective Cohort Study among Japanese Workers

Kaetsu

Kishimoto

Osaki

et al. 2004

Journal of Epidemiology

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BACKGROUND: Some case-control association studies revealed the relationship between some endothelin-1 (ET-1) gene polymorphisms and blood pressure. Because no report was available about the relationship between any ET-1 gene polymorphism and incidence of hypertension, we examined the relationship between novel ET-1 gene polymorphism (G862T / Ala288Ser in exon 5) and incidence of hypertension by a retrospective cohort study. METHODS: The subjects were Japanese workers at a company in Shimane Prefecture in Japan. The polymorphism with genome DNA extracted from the blood of the workers was analyzed using the polymerase chain reaction confronting two pair primers method. According to the results of two regular health checkups with a 6-year interval, the study population was divided into two groups by blood pressure and antihypertensive treatment in 1998, after excluding people who had hypertension in 1992. RESULTS: There were 133 (93 males and 40 females) incidences of hypertension observed among the study population of 922 (540 males and 382 females). In the univariate analysis, odds ratios o Ala/Ser and Ser/Ser against Ala/Ala were 0.98 (95% confidence interval [CI]): 0.7-1.4) and 0.79 (95% CI: 0.4-1.6), respectively. In the multivariate analysis adjusted for sex, age, body mass index, serum total cholesterol, fasting blood sugar, and smoking and drinking habits, odds ratios for Ala/Ser and Ser/Ser against Ala/Ala were 0.97 (95% CI: 0.7-1.4) and 0.75 (95% CI: 0.4-1.5), respectively. CONCLUSIONS: The ET-1 gene polymorphism in this study did not seem to be associated with the incidence of hypertension among the Japanese workers.

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Insulin modulates circulating endothelin-1 levels in humans

Cited by 85 publications

References 24 publications

The Lys198Asn Polymorphism in the Endothelin-1 Gene Is Associated With Blood Pressure in Overweight People

The Lys198Asn Polymorphism in the Endothelin-1 Gene Is Associated With Blood Pressure in Overweight People

Specific Endothelin ET_A Receptor Antagonism Does Not Modulate Insulin-Induced Hemodynamic Effects in the Human Kidney, Eye, or Forearm

The Lack of Relationship between an Endothelin-1 Gene Polymorphism (Ala288Ser) and Incidence of Hypertension: A Retrospective Cohort Study among Japanese Workers

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Insulin modulates circulating endothelin-1 levels in humans

Cited by 85 publications

References 24 publications

The Lys198Asn Polymorphism in the Endothelin-1 Gene Is Associated With Blood Pressure in Overweight People

The Lys198Asn Polymorphism in the Endothelin-1 Gene Is Associated With Blood Pressure in Overweight People

Specific Endothelin ETA Receptor Antagonism Does Not Modulate Insulin-Induced Hemodynamic Effects in the Human Kidney, Eye, or Forearm

The Lack of Relationship between an Endothelin-1 Gene Polymorphism (Ala288Ser) and Incidence of Hypertension: A Retrospective Cohort Study among Japanese Workers

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Specific Endothelin ET_A Receptor Antagonism Does Not Modulate Insulin-Induced Hemodynamic Effects in the Human Kidney, Eye, or Forearm