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Enhancement of Muscle Glucose Uptake by the Vasopeptidase Inhibitor, Omapatrilat, Is Independent of Insulin Signaling and the AMP Kinase Pathway

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Enhancement of Muscle Glucose Uptake by the Vasopeptidase Inhibitor, Omapatrilat, Is Independent of Insulin Signaling and the AMP Kinase Pathway 441 Enhancement of muscle glucose uptake by the vasopeptidase inhibitor, omapatrilat, is independent of insulin signaling and the AMP kinase pathway Victor Wong, Linda Szeto, Kristine Uffelman, I George Fantus and Gary F Lewis Department of Medicine, Division of Endocrinology and Metabolism and the Department of Physiology, University of Toronto, Toronto, Ontario, Canada (Requests for offprints should be addressed to G F Lewis who is now at Toronto General Hospital, EN11-229, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada; Email: [email protected]) Abstract Omapatrilat (OMA), a vasopeptidase inhibitor (VPI), P!0$01). Immunoprecipitation and Western blot analysis of presently being tested in clinical trials for its anti- insulin receptor substrate 1 (IRS-1) revealed no changes in hypertensive properties, inhibits both angiotensin-converting protein mass with OMA treatment. OMA did not enhance enzyme and neutral endopeptidase, and raises tissue basal or insulin-stimulated IRS-1 tyrosine phosphorylation bradykinin levels. Recent studies from our laboratory and or its subsequent association with the p85 regulatory subunit those of others have demonstrated that VPIs enhance muscle of phosphatidylinositol 3-kinase. Under basal and insulin- glucose uptake in animal models, and this effect is mediated stimulated conditions, OMA treatment did not alter the by the bradykinin–nitric oxide pathway. The mechanism of protein mass or the phosphorylation of Akt/protein kinase the effect of OMA on muscle glucose uptake, however, is B, p42/44 extracellular signal-regulated kinase or adenosine presently unknown. To investigate the effect of OMA on monophosphate-activated protein kinase, or GLUT4 protein insulin signaling, soleus muscle was isolated 2 or 5 min after expression. We conclude that the ability of OMA to enhance an i.v. bolus of insulin or saline from male Zucker fatty rats whole body and specifically muscle glucose uptake in Zucker (8–10 weeks of age), following a 5-day treatment period of fatty rats is not mediated by enhancing insulin or AMPK oral OMA (15 mg/kg per day) or drug vehicle (placebo). signaling. Future studies should examine whether hemo- OMA resulted in significantly lower systolic blood pressure dynamic effects of the drug, independent of insulin signaling, compared with the placebo-treated group (84$4G enhance glucose uptake in insulin-resistant skeletal muscle. 7$52 mmHg in OMA vs 112G2$18 mmHg in controls, Journal of Endocrinology (2006) 190, 441–450 Introduction both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP; Floras 2002). The consequence of dual Insulin resistance is a major pathogenic factor for type-2 inhibition of NEP and ACE is a synergistic reduction in diabetes mellitus and is associated with a cluster of vasoconstriction and enhancement of vasodilation, thereby atherosclerotic cardiovascular disease risk factors (Reaven serving to reduce blood pressure (BP) more effectively than 1988). These risk factors include, but are not limited to, ACE inhibitors (ACEI). Of the VPIs, the most advanced in its hypertension, dyslipidemia, endothelial dysfunction, pro- development as a therapeutic agent is omapatrilat (OMA), coagulant and pro-inflammatory states, abdominal obesity, although its clinical development has been curtailed severely by and hepatic steatosis, a complex that has collectively been a high incidence of serious side effects, including angioedema termed the metabolic syndrome. The close link between (Rouleau et al. 2000, Guthrie & Reeves 2002, Lapointe & insulin resistance and the development of cardiovascular Rouleau 2002). We recently showed that OMA enhances complications suggests either a direct or an indirect causal muscle glucose uptake in Zucker fatty rats and these results mechanism and emphasizes the need to develop therapeutic have been confirmed by others using another VPI, mixanpril strategies that improve insulin sensitivity and its (Arbin et al. 2003, Wang et al. 2003). By using two independent co-morbidities. methods, euglycemic hyperinsulinemic clamp and insulin- Vasopeptidase inhibitors (VPIs) are new therapeutic agents bolus-mediated 2-deoxyglucose tissue uptake, our laboratory that are being developed for the treatment of hypertension and has previously demonstrated enhancement of whole body heart failure (Floras 2002). They act primarily by blocking and muscle glucose uptake by OMA (Wang et al. 2003). Journal of Endocrinology (2006) 190, 441–450 DOI: 10.1677/joe.1.06396 0022–0795/06/0190–441 q 2006 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/27/2021 08:15:09PM via free access 442 V WONG and others $ OMA and mechanism of insulin sensitization The insulin-sensitizing effects of OMA are blocked by Animals bradykinin B receptor antagonist (ecatibant-140) and nitric 2 Obese (fa/fa) Zucker male rats (Charles River Laboratories, oxide synthase inhibitor (Danser et al. 2000, Wang et al. 2003). Saint Constant, Quebec, Canada) were studied at the age of Following on from our previous observations (Wang et al. 8–10 weeks, as this is the time when Zucker fa/farats progress 2003), the present study was designed to investigate whether from insulin-resistance to mild glucose intolerance. Limited the previously demonstrated OMA-induced improvement in studies were also performed in two leanstrains ( fa/K and K/K) muscle glucose uptake is mediated by enhanced insulin for comparison. The rats were housed in the Animal Care signaling via known pathways of insulin signaling in skeletal Facility of the Toronto General Hospital. They were exposed muscle. Our results demonstrate that OMA does not affect to a 12 h light:12 h darkness cycle and fed rat chow (Purina insulin-signaling molecules under basal or insulin-stimulated 5001, 4$5% fat, Ralston Purina Co., St Louis, MO, USA) and conditions. Furthermore, the enhancement of muscle water ad libitum. All procedures were approved by the Animal glucose uptake by OMA treatment cannot be attributed to Care Committee of the University Health Network, adenosine monophosphate-activated protein kinase a University of Toronto. (AMPKa) activation or to an increase in total GLUT4 protein expression. Surgery and animal handling After 3 days of adaptation to the facility, the rats were anesthetized by i.p. injection of ketamine:xylazine:acepro- Materials and Methods mazine (20:2:1 mg/ml, 1 ml/g body weight) and an indwel- ling catheter was inserted in the right internal jugular vein for Materials i.v. administration of the insulin or saline bolus. The catheter Polyethylene (PE-50) catheters were obtained from Cay Adams was tunneled subcutaneously and exteriorized to the back of (Aronson et al. 1997a), and each was extended with a segment of the neck. All surgeries (vessel cannulation) were performed silastic tubing (length 3 cm, internal diameter 0$05 cm) from under sterile conditions. The catheters were filled with a Dow Corning Co. (Midland, MI, USA). OMA was obtained mixture of 60% polyvinylpyrrolidone and heparin from Bristol-Myers Squibb (#186716-01, Lot9B10310 CA, (1000 USP/ml) to maintain patency for 5 days and closed at Princeton, NJ, USA). Human insulin was obtained from Eli the end with a metal pin. The catheters were flushed with Lilly and heparin from Organon (Toronto, Ont., Canada). saline once during the 5-day treatment of either OMA or Protease inhibitors used in this study such as aprotinin, placebo, on day 3. leupeptin, okadaic acid, phenylmethylsulfonyl fluoride (PMSF), E64, and pepstatin were obtained from Sigma. All Treatment of rats and muscle preparations electrophoresis and transfer processes were carried out in XCell The obese Zucker rats were randomized to receive oral SureLock Novex Mini-Cell and XCell II Blot module obtained gavage of either OMA (15 mg/kg per day) diluted in saline from Invitrogen. Nitrocellulose membranes were purchased (nZ12) or drug vehicle only (control, nZ12), once daily, for from Schleicher and Schuell Bioscience (Keene, NH, USA). a period of 5 days. This is the same dose of the drug used in Anti-phospho-tyrosine antibody was purchased from Santa our previous studies (Wang et al. 2003), in which we Cruz Biotechnology, Inc. (Santa Cruz, CA, USA). Agarose- demonstrated an insulin-sensitizing effect of OMA. All conjugated anti-insulin receptor substrate-1 (anti-IRS-1) and animals were given free access to regular chow and water anti-p85 subunit of phosphatidylinositol 3-kinase (PI3K) throughout the 5-day treatment period. On the third day of antibodies were purchased from Upstate Biotechnology, Inc. the study, systolic BP was measured by tail cuff in lightly (Lake Placid, NY, USA). Anti-AKT, anti-phospho-AKT anesthetized rats (approximately two-thirds of the anesthetic (Ser473), anti-phospho-AKT (Thr308), anti-AMPKa, anti- dosage for surgery as mentioned earlier), 6 h before their oral phospho AMPKa (Thr172), anti-extracellular signal-regulated treatment. Immediately afterwards, the catheter was flushed kinase 1 and 2 (anti-ERK1/2) mitogen-activated protein kinase with saline and filled with polyvinylpyrrolidone and heparin (MAPK; p44/p48) and anti-phospho-ERK1/2 MAPK admixture to maintain patency for the remaining days of the (Thr202/Tyr204), anti-acetyl CoA carboxylase (ACC), and treatment. Blood samples were obtained from the tail vein anti-phospho-ACC(Ser79) antibodieswere from Cell Signaling after an overnight fast (food was removed at 1800 h after the Technology, Inc. (Beverly, MA, USA). Rabbit polyclonal anti- final dose of treatments on day 5). Insulin (50 U/kg) was GLUT4 antibody was a generous gift from Dr Amira Klip administered as an i.v. bolus through the venous catheter to (Hospital for Sick Children, Toronto, Ont., Canada). Horse- nZ12 OMA-treated and nZ12 placebo-treated rats. Six radish peroxidase (HRP)-conjugated anti-mouse or anti-rabbit animals in each of these two treatment groups had muscle immunoglobulin G (IgG) was purchased from Cell Signaling biopsies performed 2-min post-i.v. insulin bolus for Technology,Inc. Enhanced chemiluminescence (ECL) reagents assessment of IRS-1 activation, whereas six animals in each were obtained from Amersham.
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