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Dual Endothelin Receptor Blockade Acutely Improves Insulin Sensitivity in Obese Patients with Insulin Resistance and Coronary Artery Disease

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Dual Endothelin Receptor Blockade Acutely Improves Insulin Sensitivity in Obese Patients with Insulin Resistance and Coronary Artery Disease Emerging Treatments and Technologies ORIGINAL ARTICLE Dual Endothelin Receptor Blockade Acutely Improves Insulin Sensitivity in Obese Patients With Insulin Resistance and Coronary Artery Disease 1 2 GUNVOR AHLBORG, MD, PHD ADRIAN GONON, MD, PHD The vascular responses to ET-1 are 2 2 ALEXEY SHEMYAKIN, MD JOHN PERNOW, MD, PHD mediated via two receptor subtypes: ET 2 A FELIX B¨OHM, MD, PHD and ETB receptors (10,11). Both types of receptors are located on vascular smooth muscle cells and mediate vasoconstric- OBJECTIVE — Endothelin (ET)-1 is a vasoconstrictor and proinflammatory peptide that may tion. The ETB receptor is also located on inhibit glucose uptake. The objective of the study was to investigate if ET (selective ETA and dual endothelial cells and mediates vasodilata- ϩ ETA ETB) receptor blockade improves insulin sensitivity in patients with insulin resistance and tion by stimulating release of NO and coronary artery disease. prostacyclin. Early reports show that Ϯ ET-1 interferes with glucose metabolism RESEARCH DESIGN AND METHODS — Seven patients (aged 58 2 years) with as indicated by a drop in splanchnic glu- insulin resistance and coronary artery disease completed three hyperinsulinemic-euglycemic clamp protocols: a control clamp (saline infusion), during ET receptor blockade (BQ123), and cose production and peripheral glucose A utilization during ET-1 infusion in during combined ETA (BQ123) and ETB receptor blockade (BQ788). Splanchnic blood flow (SBF) and renal blood flow (RBF) were determined by infusions of cardiogreen and p- healthy subjects (12). Ferri et al. (4) dem- aminohippurate. onstrated a negative correlation between total glucose uptake and circulating ET-1 RESULTS — Total-body glucose uptake (M) differed between the clamp protocols with the levels in non–insulin-dependent diabe- highest value in the BQ123ϩBQ788 clamp (P Ͻ 0.05). The M value corrected by insulin was tes. The notion that ET-1 modulates insu- higher in the BQ123ϩBQ788 than in the control clamp (P Ͻ 0.01) or the BQ123 clamp (P Ͻ lin sensitivity was supported by the 0.05). There was no difference between the control clamp and the BQ123 clamp. Mean arterial demonstration that ET-1 reduces insulin pressure did not change during the control clamp, whereas it decreased during both the BQ123 sensitivity in healthy volunteers (13). (P Ͻ 0.01) and BQ123ϩBQ788 (P Ͻ 0.05) clamps. RBF increased and renal vascular resistance decreased in the BQ123ϩBQ788 clamp (P Ͻ 0.05) but not in the BQ123 clamp. There was no Furthermore, the ET-1 precursor, big change in SBF in either clamp. ET-1, reduces insulin sensitivity via an ac- tion mediated by the ETA receptor in ϩ CONCLUSIONS — Dual ETA ETB receptor blockade acutely enhances insulin sensitivity healthy subjects (14). However, no study in patients with insulin resistance and coronary artery disease, indicating an important role for has investigated whether endogenous endogenous ET-1. ET-1 contributes to reduced insulin sen- sitivity in patients with insulin resistance. Diabetes Care 30:591–596, 2007 The present study was therefore designed to investigate the impact of ET-1 receptor nsulin resistance is a key component of resistant states such as type 2 diabetes (4), blockade on insulin sensitivity in patients the metabolic syndrome and is associ- obesity (5), essential hypertension (6), with insulin resistance and coronary ar- I ated with increased cardiovascular risk and coronary artery disease (7) are asso- tery disease. Since ETB receptors on vas- (1). Impairment of endothelial function, ciated with elevated plasma levels of the cular smooth muscle have been shown to characterized by reduced bioactivity of endothelium-derived vasoconstrictor and be upregulated in atherosclerosis (15) ϩ nitric oxide (NO), is an early finding in proinflammatory peptide endothelin and dual ETA ETB receptor blockade patients with insulin resistance (2) and (ET)-1 (8,9). Furthermore, insulin may (but not selective ETA receptor blockade) type 2 diabetes (3). Besides the negative directly stimulate the secretion of ET-1 improves endothelial function in subjects effects on NO availability, insulin- from endothelial cells (8). with insulin resistance (16), we compared ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● the effects of selective ETA and dual ET ϩET receptor antagonism on insulin 1 A B From the Department of Laboratory Medicine, Division of Clinical Physiology, Karolinska Institutet, Stock- sensitivity. holm, Sweden; and the 2Department of Medicine, Division of Cardiology, Karolinska Institutet, Stockholm, Sweden. Address correspondence and reprint requests to John Pernow, Department of Cardiology, Karolinska RESEARCH DESIGN AND University Hospital, Solna, S-171 76 Stockholm, Sweden. E-mail: [email protected]. METHODS — Seven patients (aged Received for publication 22 September 2006 and accepted in revised form 9 December 2006. Ϯ Ϯ 2 Abbreviations: ET, endothelin; MAP, mean arterial blood pressure; PAH, p-aminohippurate; RBF, renal 58 2 years, BMI 31.7 2.6 kg/m ) with blood flow; SBF, splanchnic blood flow. a previous history of impaired glucose tol- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion erance and coronary artery disease were factors for many substances. recruited. Impaired glucose tolerance was DOI: 10.2337/dc06-1978 defined as fasting blood glucose Ͻ6.1 © 2007 by the American Diabetes Association. Ն The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby mmol/l and a blood glucose 7.8 mmol/l marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 2 h after an oral glucose loading (75 g). DIABETES CARE, VOLUME 30, NUMBER 3, MARCH 2007 591 Endothelin blockade improves insulin sensitivity Patients were classified as having diabetes tional uptake, F (equal to the arterio- Calculations and statistics if fasting blood glucose was Ն6.1 mmol/l venous difference divided by the arterial The total-body glucose uptake (M;mg⅐ Ϫ Ϫ (on at least on two occasions) or blood concentration), of cardiogreen and PAH kg 1 ⅐ min 1) was calculated during three glucose concentration was Ն11.1 mmol/l were not influenced by the infusion of the 20-min sampling periods from 60 to 120 2 h after an oral glucose loading. Based on ET-1 blockers (17) or the clamp proce- min during the clamp (i.e., 60–80, 80– these criteria, five patients were classified dure (14). As there was no change in the F 100, and 100–120 min). This means that as having diabetes and two as having im- values, a constant F value of 0.8 for car- the first sampling was made during ET paired glucose tolerance. Coronary artery diogreen and 0.9 for PAH was used in the receptor blockade on the occasions when disease was defined as a history of previ- present study. antagonists were administered. The M ous myocardial infarction or significant Insulin, dissolved in 0.9% saline and value was then corrected for the mean of coronary stenosis verified by coronary an- blood, was infused at a rate correspond- the two plasma insulin values obtained giography. The patients were taking aspi- ing to 804 mU/m2 body surface area dur- during each period to calculate the M/I rin (n ϭ 7), statins (n ϭ 6), fibrates (n ϭ ing the first 8 min, followed by 40 mU/m2 value, which represents a measure of in- 1), ACE inhibitors (n ϭ 5), ␤-blockers per min for 112 min. Fasting blood glu- sulin sensitivity. Splanchnic and renal (n ϭ 7), and oral antidiabetic agents (n ϭ cose level was maintained by adjusting vascular resistance were calculated as 5). Average total, LDL, and HDL choles- the infusion rate of a 20% glucose solu- MAP divided by SBF or RBF, respectively, terol levels were 4.0 Ϯ 0.3, 2.3 Ϯ 0.3, and tion. Arterial blood samples were taken and measured 60 min into the clamp, i.e., 0.9 Ϯ 0.1 mmol/l, respectively. Average every 5 min for determination of blood before administration of the antagonists serum creatinine was 87 Ϯ 5 ␮mol/l. The glucose. Arterial samples for plasma insu- (baseline), and thereafter every 20 min. A subjects were informed of the nature, pur- lin, cardiogreen, PAH, and hematocrit two-way ANOVA with repeated measures pose, and possible risk involved in the were collected at 60, 80, 100, and 120 on two factors was used to analyze the study before giving informed consent. min of the clamp procedure. data. The factors were clamp (three levels) The investigation was carried out in ac- In the control clamp, an infusion of and time (three to four levels). The inter- cordance with the Declaration of Helsinki saline was started at 60 min into the action in the ANOVA refers to the statis- and was approved by the ethics commit- clamp and was maintained for 15 min. In tical test of whether the effect of one tee of the Karolinska Institute. the BQ123 clamp, the ETA receptor an- factor, as measured by differences in the The study consisted of three different tagonist BQ123 was infused at a rate of 5 response averages, is different for differ- Ϫ Ϫ hyperinsulinemic-euglycemic clamp pro- nmol ⅐ kg 1 ⅐ min 1. In the combined ent levels of the other factor. In the case of ϩ tocols: 1) a control clamp with saline in- BQ123 BQ788 clamp, the ETB receptor significant interaction, post hoc interac- fusion, 2) a clamp with infusion of the antagonist BQ788 was infused at a rate of tion tests were performed between each Ϫ Ϫ ET receptor antagonist BQ123, and 3)a 4 nmol ⅐ kg 1 ⅐ min 1 together with pair of the clamp conditions across the A Ϫ Ϫ clamp with a combined infusion of BQ123 (5 nmol ⅐ kg 1 ⅐ min 1).
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