Peptides 51 (2014) 26–30

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Angiotensin 1–7 improves insulin sensitivity by increasing skeletal muscle glucose uptake in vivo Omar Echeverría-Rodríguez a , Leonardo Del Valle-Mondragón b , Enrique Hong a,∗ a Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Sede Sur, Mexico City, Mexico b Departamento de Farmacología, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City, Mexico

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Article history: Received 12 September 2013 Received in revised form 14 October 2013 Accepted 15 October 2013 Available online 31 October 2013 Keywords: Renin–angiotensin system (RAS) Angiotensin-converting enzyme 2 (ACE2) Angiotensin 1–7 Mas receptor Skeletal muscle Glucose uptake

a b s t r a c t The renin–angiotensin system (RAS) regulates skeletal muscle insulin sensitivity through different mechanisms. The overactivation of the ACE (angiotensin-converting enzyme)/Ang (angiotensin) II/AT1 R (Ang II type 1 receptor) axis has been associated with the development of insulin resistance, whereas the stimulation of the ACE2/Ang 1–7/MasR (Mas receptor) axis improves insulin sensitivity. The in vivo mechanisms by which this axis enhances skeletal muscle insulin sensitivity are scarcely known. In this work, we investigated whether rat soleus muscle expresses the ACE2/Ang 1–7/MasR axis and determined the effect of Ang 1–7 on rat skeletal muscle glucose uptake in vivo. Western blot analysis revealed the expression of ACE2 and MasR, while Ang 1–7 levels were detected in rat soleus muscle by capillary zone electrophoresis. The euglycemic clamp exhibited that Ang 1–7 by itself did not promote glucose transport, but it increased insulin-stimulated glucose disposal in the rat. In a similar manner, captopril (an ACE inhibitor) enhanced insulin-induced glucose uptake and this effect was blocked by the MasR antagonist A-779. Our results show for the first time that rat soleus muscle expresses the ACE2/Ang 1–7/MasR axis of the RAS, and Ang 1–7 improves insulin sensitivity by enhancing insulin-stimulated glucose uptake in rat skeletal muscle in vivo. Thus, endogenous (systemic and/or local) Ang 1–7 could regulate insulin-mediated glucose transport in vivo. © 2013 Elsevier Inc. All rights reserved.

1. Introduction Skeletal muscle is the predominant site for glucose disposal in the postprandial state, and insulin-stimulated glucose uptake in this tissue represents the most important process for maintaining glucose homeostasis [6]. In insulin resistance states such as obesity, hypertension, and type 2 diabetes, insulin-induced glucose transport is markedly decreased in skeletal muscle, due to an impaired expression and functionality of the insulin signaling pathway [11]. The mechanisms underlying skeletal muscle insulin resistance are multifactorial. Of paramount importance, the RAS regulates skeletal muscle insulin sensitivity through different mechanisms. The overactivation of the classical pathway of RAS, the ACE/Ang II/AT1 R axis, has been associated with the development of insulin resistance in skeletal muscle [11,14]. In contrast, recent studies

∗ Corresponding author at: Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Sede Sur, Czda. de los Tenorios No. 235, Col. Granjas Coapa, Del. Tlalpan, C.P. 14330 México D.F., Mexico. Tel.: +52 55 5483 2864; fax: +52 55 5483 2863. E-mail addresses: [email protected], [email protected] (E. Hong). 0196-9781/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.peptides.2013.10.022

show that the stimulation of the novel pathway of the RAS, the ACE2/Ang 1–7/MasR axis, acts in the opposite way, i.e. it improves skeletal muscle insulin sensitivity [10,21,25]. The in vivo mechanisms by which the ACE2/Ang 1–7/MasR axis improves skeletal muscle insulin sensitivity have not been extensively characterized, even though it is known that skeletal muscle expresses ACE2 [8] and MasR [18], suggesting that Ang 1–7 could be locally synthesized. At the functional level, the i.v. administration of Ang 1–7 in normal rats stimulates the phosphorylation of the insulin signaling effector Akt (protein kinase B) in skeletal muscle, liver, and adipose tissue (insulin target tissues) [18]. Furthermore, in fructose-fed rats, Ang 1–7 infusion reverts insulin resistance by restoring the decreased activation of the insulin signaling pathway, including insulin receptor, IRS-1 (insulin receptor substrate 1), PI3K (phosphatidylinositide 3-kinase), and Akt, in the insulin target tissues [10]. It has been also observed that Ang 1–7 reduces Ang II-induced insulin resistance by increasing the phosphorylation of Akt in isolated rat skeletal muscle [21]. In addition, Ang 1–7 increases the protein expression of GLUT4 (glucose transporter 4) in both skeletal muscle from ACE2 knockout mice, and in C2CI2 myotubes [25]. These results clearly indicate that Ang 1–7 positively regulates the insulin signaling in skeletal muscle. In support

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of this contention, recent reports exhibit that Ang 1–7 stimulates glucose uptake in both 3T3-L1 adipocytes [16] and C2C12 myotubes [25]. Considering the above findings, we hypothesized that Ang 1–7 would improve insulin sensitivity by regulating skeletal muscle glucose disposal in vivo. We aimed to investigate whether rat soleus muscle expresses the ACE2/Ang 1–7/MasR axis, and to determine the effect of Ang 1–7 on glucose uptake in rat skeletal muscle in vivo. 2. Materials and methods 2.1. Animals Eight weeks-old male Wistar rats (weighing 250–300 g) were used for this study and were provided by our animal facility. The animals were maintained under controlled conditions of light/dark cycles (12/12 h), temperature (22 ± 1 ◦ C), and humidity (50 ± 10%), and were fed with standard laboratory diet and water ad libitum. All experimental procedures were conducted in accordance with our Federal Regulations [19], which follow the Guidelines for Care and Use of Laboratory Animals, and were approved by our Institutional Ethics Committee (CICUAL, Protocol 127-03). 2.2. Collection of tissue Six rats were killed by decapitation and samples of skeletal muscle (soleus) were collected. The samples were immediately frozen in liquid nitrogen and stored at −70 ◦ C for later analysis. 2.3. Quantification of Ang II and Ang 1–7

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films (Kodak, USA). The bands were quantified by densitometry employing the UVP EpiChemi System with the Labworks 4.5 software. The results are expressed by the relationship protein/actin in units of relative density. 2.5. Glucose uptake The hyperinsulinemic euglycemic clamp was used to determine the effect of Ang 1–7 on glucose uptake in vivo [17]. After an overnight fast, the rats were anesthetized with ketamine (100 mg/kg, i.m.) and xylazine (10 mg/kg, i.m.). One third of each dose was administered when was required. The animals were placed under a heating lamp to ensure euthermia and the trachea was cannulated, and then connected to an air pump (Searle Bioscience; 56 strokes/min; stroke/volume: 20 ml/kg) to maintain continuous ventilation. Polyethylene tubes were placed into: (1) right carotid artery for blood pressure recording (Grass Instrument Co., model 7, Quincy, MA, USA); (2) left and right jugular veins for infusions of insulin (4 mU/kg/min; HUMULIN® R, Eli Lilly Co., IN, USA) and glucose (25%, w/v, variable infusion rate), respectively; (3) left and right femoral veins for infusions of saline (0.02 ml/min), Ang 1–7 (67 ng/kg/min; Sigma–Aldrich Co., St. Louis, MO, USA), Ang 1–7 in the absence (0–70 min) and presence (70–120 min) of insulin, captopril (30 ␮g/kg/min; donated by TEVA Pharmaceuticals, Mexico), or captopril + A-779 (30 ␮g/kg/min; Bachem, PA, USA); and (4) left femoral artery to take blood samples. When the animals presented stable hemodynamic parameters and anesthesia (for 15–30 min), the blood glucose was determined (baseline level) using a glucometer (Accu-Check Active, Roche, Mannheim, Germany). Then rats were subjected to the following protocols (Fig. 1). In the protocol A, they received systemic infusions of saline or Ang 1–7; while the rats of the protocol B received infusions of saline, captopril, or captopril + A-779. After 30 min, blood glucose was measured and insulin infusion was started (for 120 min). In the case of Ang 1–7 per se, insulin was infused at min 70 (Fig. 1A). Blood glucose concentrations were determined every 10 min during 2 h. Glucose solution was infused at a variable rate to maintain baseline blood glucose levels. Glucose infusion rate (mg/kg/min) was calculated to evaluate insulin sensitivity.

Simultaneous determination of both Ang II and Ang 1–7 was performed in soleus muscle by capillary zone electrophoresis coupled with photodiode-array detection (CZE-PDA) [26]. The samples (∼30 mg) were homogenized in a cold mixture of methanol (500 ␮l) and phosphate buffer (500 ␮l, pH 7.4, 50 mM), and centrifuged at 13 000 rpm for 15 min at 4 ◦ C. The pellets were discarded and the supernatants (300 ␮l) were diluted with NaOH (1:1, 0.1 M) and incubated for 3 h at 4 ◦ C. The samples (200 ␮l) were diluted (1:10) in a cold mixture (1:1) of methanol and perchloric acid (5%, w/v). The pH of the mixture was adjusted to 2.0 ± 0.1 and centrifuged at 13 000 rpm for 15 min at 4 ◦ C. The supernatants (100 ␮l) were passed through a Sep-Pak Classic C-18 cartridge (Waters Corporation, Milford, MA, USA) and mixed with 10 ␮l of a solution (1:1:1) of water–methanol–acetic acid (1%, w/v). The samples were filtered with a nitrocellulose membrane (0.22 ␮m) and analyzed by CZE-PDA (P/ACETM MDQ, Beckman Coulter, Fullerton, CA, USA).

Results are expressed as means ± SEM. The euglycemic clamp data were examined employing the two-way ANOVA followed by the Student–Newman–Keuls post hoc test. The effect of Ang 1–7 on the glucose infusion rate in the absence (0–70 min) and presence (70–120 min) of insulin was analyzed using the one-way RM ANOVA. Statistical significance was set at P < 0.05.

2.4. Western blot

3. Results

Forty micrograms of proteins were extracted from rat soleus muscle (∼150 mg of tissue), separated on SDS-PAGE (10%), and transferred on PVDF membranes. The membranes were incubated overnight at 4 ◦ C with the following primary antibodies: monoclonal mouse anti-ACE2 (1:1000 dilution; Millipore, cat. no. MAB5676), polyclonal goat anti-Mas R (1:1000 dilution; Santa Cruz Biotechnology, cat. no. sc-54848), or monoclonal mouse anti-actin (load control; 1:10 000 dilution; Millipore, cat. no. MAB1501R). Then the membranes were incubated 1 h at room temperature with their corresponding secondary antibody: goat anti-Mouse (1:5000 dilution; Jackson ImmunoResearch, cat. no. 115-035-003), rabbit anti-goat (1:5000 dilution; Jackson ImmunoResearch, cat no. 305035-003), or goat anti-Mouse (1:10 000 dilution). After incubation, the blots were visualized using a chemiluminescence kit (Immobilon Western, Millipore, MA, USA) and exposed to photographic

3.1. Skeletal muscle expresses the ACE2/Ang 1–7/Mas axis of the RAS

2.6. Statistical analysis

Western blot analysis revealed the expression of ACE2 and MasR in rat soleus muscle (Fig. 2A and B). In addition, capillary zone electrophoresis allowed the detection of Ang II and Ang 1–7 levels in muscle tissue (Fig. 2C). 3.2. Ang 1–7 increases skeletal muscle glucose uptake in vivo Acute infusion of Ang 1–7 (67 ng/kg/min) increased the insulininduced glucose infusion rate in comparison with the saline infusion (Fig. 3A). Ang 1–7 infusion by itself, i.e. in the absence of insulin (0–70 min), did not stimulate glucose disposal (Fig. 3A), that is, the glucose infusion rate was not different to zero

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Fig. 2. Skeletal muscle expresses the ACE2/Ang 1–7/MasR axis of the RAS. (A) Representative immunoblots and (B) protein expression of ACE2 and MasR in rat soleus muscle. (C) Concentrations of Ang II and Ang 1–7 in rat soleus muscle. Data are presented as means ± SEM of 6 animals per group.

(P > 0.05). However, when the insulin infusion was started (min 70), the glucose removal markedly increased, which was higher (at 110–120 min) than the saline infusion (Fig. 3A). None of the treatments significantly modified the blood glucose (Fig. 3B) neither blood pressure (Fig. 3C). Since ACE inhibitors increase Ang 1–7 levels in both plasma and tissues [3,30], we investigated whether the ACE inhibitor captopril could stimulate glucose transport through the endogenous generation of Ang 1–7. In a similar manner to Ang 1–7, acute infusion of captopril (30 ␮g/kg/min) increased insulin-induced glucose uptake rate compared to the saline infusion (Fig. 4A). This effect was blocked by infusion of the MasR antagonist A-779 (30 ␮g/kg/min) (Fig. 4A). Captopril infusion did not change blood glucose levels (Fig. 4B); however, it decreased blood pressure in comparison with the saline infusion (Fig. 4C). 4. Discussion The ACE2/Ang 1–7/MasR axis of the RAS represents a novel therapeutic target to decrease insulin resistance in disorders such as obesity, hypertension, and type 2 diabetes [5]. The in vivo

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mechanisms by which the activation of this axis enhances insulin sensitivity remain unknown. In this work we show that Ang 1–7 improved insulin sensitivity by increasing insulin-stimulated glucose uptake in vivo. The hyperinsulinemic euglycemic clamp is considered the gold standard for measuring the insulin action in vivo, due to that approximately 80% of insulin-induced whole-body glucose transport occurs in skeletal muscle [17]. Using this procedure, this study documented that Ang 1–7 by itself did not stimulate glucose uptake, but it increased insulin-mediated glucose disposal in rats, without exhibiting changes in both the blood glucose and pressure. Therefore, our results suggest that Ang 1–7 enhances insulin-stimulated glucose uptake predominantly in rat skeletal muscle in vivo. The role of Ang 1–7 on glucose uptake has not been completely elucidated. Some studies indicated that the systemic elevation of Ang 1–7 in rats increases insulin-induced glucose removal in isolated adipocytes [22]; whereas, in adipocytes from MasR deficient mice decrease insulin-dependent glucose transport [23]. In addition, Ang 1–7 partially reverses Ang II-induced insulin resistance in isolated rat skeletal muscle [21]. These findings suggest that Ang 1–7 could modulate glucose uptake. Recent studies confirmed this

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Fig. 3. Ang 1–7 increases insulin-stimulated glucose uptake in vivo. (A) Effect of acute infusions of either saline or Ang 1–7 on the glucose infusion rate induced by insulin (4 mU/kg/min, 0–120 min). (A) Influence of Ang 1–7 on glucose disposal in the absence (0–70 min) and presence (70–120 min) of insulin. () Changes in both (B) blood glucose and (C) blood pressure during the euglycemic clamps. Data are presented as means ± SEM of 6–11 rats per group. *P < 0.001 vs. saline; # P < 0.001 vs. Ang 1–7 without insulin min 70; & P < 0.05 vs. corresponding saline.

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Fig. 4. Captopril enhances insulin sensitivity through Ang 1–7. (A) Effect of acute infusions of saline, captopril, or captopril + A-779 on the glucose infusion rate induced by insulin (4 mU/kg/min, 0–120 min). () Changes in both (B) blood glucose and (C) blood pressure throughout the euglycemic clamps. Data are presented as means ± SEM of 7–11 rats per group. *P < 0.001 vs. saline; # P < 0.001 vs. captopril.

idea, showing that Ang 1–7 per se does not promote glucose disposal, but it increases insulin-mediated glucose uptake in C2C12 myotubes [25]. These in vitro observations are consistent with our results in vivo. To our knowledge, this paper is the first in evaluating the effect of Ang 1–7 on glucose transport in vivo. In contrast to these findings, Liu et al. [16] found that Ang 1–7 promotes glucose uptake under both baseline and insulin-mediated conditions in 3T3-L1 cells. One possible explanation to this discrepancy is that compared with primary adipocytes, the cultured cells have a reduced capacity to intracellularly sequester GLUT4 in the basal state and, consequently, increased basal activities and blunted insulin responses could be observed [2]. Also, glucose disposal is stimulated 20–30-fold by insulin in rat adipocytes, but only 4–8-fold in 3T3-L1 adipocytes. This reflects, in part, more abundant GLUT1 in 3T3-L1 cells, and therefore, an increased insulin-independent glucose transport [2]. Therefore, these events could explain why Ang 1–7 by itself stimulates glucose removal in 3T3-L1 cells [16]. Ang 1–7 activates critical effectors of the insulin signaling pathway. At proximal level, Ang 1–7 stimulates the phosphorylation of IRS-1 and Akt in human endothelial cells [27], skeletal muscle, adipose tissue, and heart from rat [9,18]. In addition, Ang 1–7 is able to revert insulin resistance by restoring decreased activation of the insulin signaling under in vivo [10] and ex vivo [21] conditions. At distal level, Ang 1–7 promotes the phosphorylation of PI3KC2A, TBCD1D1, and TBCD1D4 in human endothelial cells [27]. Interestingly, these kinases participate in the GLUT4 translocation to the plasma membrane in response to insulin stimulation [7,15]. In this work we found that Ang 1–7 promoted glucose uptake in an insulindependent manner (Fig. 3A). Considering those findings, our results suggest that Ang 1–7 increases skeletal muscle glucose disposal in vivo, possibly by amplifying the insulin signaling. It remains to be investigated: What part of this pathway is amplified by Ang 1–7? An additional mechanism by which Ang 1–7 improved skeletal muscle glucose transport in vivo could involve microvascular actions. Insulin in order to act on muscle must relax precapillary arterioles, which increases microvascular perfusion and expands the endothelial exchange surface area for promoting its transendothelial transport into muscle interstitium [1]. In insulinsensitive rats, i.v. administration of losartan (an AT1 R antagonist) increases insulin-induced microvascular perfusion, although acute infusion of PD123319 (an AT2 R blocker) abolishes this effect [4]. In addition, losartan reverses both the decreased insulin-mediated microvascular perfusion and –glucose removal in insulin-resistant rats [29]. AT1 R antagonists, like losartan, raise plasma concentrations of Ang 1–7 [30]. However, those studies did not evaluate the possible role of Ang 1–7 on microvascular perfusion. Taking into consideration this observation and further that: (1) Ang

1–7 induces vasodilatation in microvessels through MasR [20]; (2) Ang 1–7 increases insulin-stimulated glucose uptake in vivo (Fig. 3A); and (3) insulin-mediated microvascular recruitment precedes skeletal muscle glucose disposal in vivo [28], we hypothesized that in this study Ang 1–7 increased insulin sensitivity in vivo probably by enhancing skeletal muscle microvascular perfusion. It has been postulated that ACE inhibitors improve insulin sensitivity by decreasing the production of Ang II, and/or increasing the systemic and local concentrations of bradykinin [13]. However, ACE inhibitors also raise plasma and tissues levels of Ang 1–7 [3,30], and recent studies show that Ang 1–7 reduces insulin resistance [10,21,25]. In this work we indicated that the ACE inhibitor captopril enhanced insulin-induced glucose uptake in rat skeletal muscle in vivo, and this effect was blocked by the MasR antagonist A-779. Considering that the main actions of Ang 1–7 are mediated through MasR [16,20,21], our results suggest that captopril improved skeletal muscle insulin sensitivity through endogenous (blood and/or skeletal muscle) formation of Ang 1–7. This observation could explain, at least in part, why the RAS blockade, with either ACE inhibitors or AT1 R antagonists, augments insulin sensitivity and reduces the incidence of type 2 diabetes in prediabetic individuals [11]. Hence, this study provides a novel mechanism by which ACE inhibitors enhance insulin sensitivity. We observed that captopril improved insulin sensitivity through Ang 1–7. However, it has been indicated that the beneficial action of captopril on insulin-stimulated glucose uptake in isolated rat skeletal muscle is mediated by bradykinin [12]. This apparent contradiction could be explained because some actions of ACE inhibitors can be blocked by B2 receptor antagonists [12], and some bradykinin-mediated effects are attenuated by MasR blockers [20]. These observations illustrate the intricate relationship between Ang and kinin receptors, suggesting common interactions of signaling pathways or heterodimerization [24]. Therefore, we do not discard the possibility that other types of receptors could be involved in these responses. Captopril infusion decreased the blood pressure in the euglycemic clamp. Considering that ACE inhibitors rise endogenous concentrations of both Ang 1–7 and bradykinin, it is possible that the systemic elevation of these peptides contributed to decrease the blood pressure. In conclusion, this work shows for the first time that rat soleus muscle expresses the ACE2/Ang 1–7/MasR axis of the RAS, and Ang 1–7 improves insulin sensitivity by increasing insulin-stimulated glucose uptake in rat skeletal muscle in vivo. These findings suggest that endogenous (systemic and/or local) Ang 1–7 could regulate the insulin sensitivity in vivo, modulating the glucose transport mainly in postprandial states (where insulin concentrations are higher) than in fasting conditions.

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Acknowledgments The authors thank Drs. Rafael Villalobos-Molina and Mónica Lamas-Gregori for the critical review of the manuscript, Miguel Ángel Rosas-Lezama and Gerardo Rivera for the technical assistance, and Héctor Vázquez for the bibliographic search. Omar Echeverría-Rodríguez received a Ph.D. fellowship (203772) from CONACyT (Consejo Nacional de Ciencia y Tecnología, México). This work was supported by ICyTDF (Instituto de Ciencia y Tecnología del Distrito Federal, México). Grants PICDS 08-24 and 270-2011. References [1] Barrett EJ, Wang H, Upchurch CT, Liu Z. Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature. Am J Physiol Endocrinol Metab 2011;301:E252–63. [2] Bogan JS. Regulation of glucose transporter translocation in health and diabetes. Annu Rev Biochem 2012;81:507–32. [3] Campbell DJ, Kladis A, Duncan AM. Effects of converting enzyme inhibitors on angiotensin and bradykinin peptides. Hypertension 1994;23:439–49. [4] Chai W, Wang W, Dong Z, Cao W, Liu Z. Angiotensin II receptors modulate muscle microvascular and metabolic responses to insulin in vivo. Diabetes 2011;60:2939–46. [5] Chhabra KH, Chodavarapu H, Lazartigues E. Angiotensin converting enzyme 2: a new important player in the regulation of glycemia. IUBMB Life 2013;65:731–8. [6] DeFronzo RA, Gunnarsson R, Björkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest 1985;76:149–55. [7] Falasca M, Hughes WE, Dominguez V, Sala G, Fostira F, Fang MQ, et al. The role of phosphoinositide 3-kinase C2alpha in insulin signaling. J Biol Chem 2007;282:28226–36. [8] Fernandes T, Hashimoto NY, Oliveira EM. Characterization of angiotensinconverting enzymes 1 and 2 in the soleus and plantaris muscles of rats. Braz J Med Biol Res 2010;43:837–42. ˜ MC, Pena ˜ C, Turyn D, Dominici FP. Angiotensin[9] Giani JF, Gironacci MM, Munoz (1–7) stimulates the phosphorylation of JAK2, IRS-1 and Akt in rat heart in vivo: role of the AT1 and Mas receptors. Am J Physiol Heart Circ Physiol 2007;293:H1154–63. ˜ [10] Giani JF, Mayer MA, Munoz MC, Silberman EA, Höcht C, Taira CA, et al. Chronic infusion of angiotensin-(1–7) improves insulin resistance and hypertension induced by a high-fructose diet in rats. Am J Physiol Endocrinol Metab 2009;296:E262–71. [11] Henriksen EJ, Prasannarong M. The role of the renin–angiotensin system in the development of insulin resistance in skeletal muscle. Mol Cell Endocrinol 2013;378:15–22. [12] Henriksen EJ, Jacob S. Effects of captopril on glucose transport activity in skeletal muscle of obese Zucker rats. Metabolism 1995;44:267–72. [13] Henriksen EJ, Jacob S. Modulation of metabolic control by angiotensin converting enzyme (ACE) inhibition. J Cell Physiol 2003;196:171–9. ˜ S, del-Rio-Navarro BE, [14] Huang F, Lezama MA, Ontiveros JA, Bravo G, Villafana et al. Effect of losartan on vascular function in fructose-fed rats: the role of perivascular adipose tissue. Clin Exp Hypertens 2010;32:98–104.

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Angiotensin 1-7 improves insulin sensitivity by increasing skeletal muscle glucose uptake in vivo.

The renin-angiotensin system (RAS) regulates skeletal muscle insulin sensitivity through different mechanisms. The overactivation of the ACE (angioten...
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