The Novel Angiotensin II Receptor Blocker Azilsartan Medoxomil Ameliorates Insulin Resistance Induced by Chronic Angiotensin II Treatment in Rat Skeletal Muscle

Cardiorenal Medicine

Fernando R. Santos¹  Guido Lastra¹  Annayya R. Aroor¹  Paria Hooshmand¹  Erik J. Henriksen¹  Irina Mugerfeld¹  Vincent G. DeMarco¹  James R. Sowers¹  Payam Hooshmand¹ 

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关键词: Angiotensin II;    Glucose transport;    Red skeletal muscle;    Akt;    AS160;    AMPK;    p70 S6K1;   

DOI  :  10.1159/000353155

来源: S Karger AG

【 摘 要 】

Angiotensin receptor (type 1) blockers (ARBs) can reduce both hypertension and insulin resistance induced by local and systemic activation of the renin-angiotensin-aldosterone system. The effectiveness of azilsartan medoxomil (AZIL-M), a novel imidazole-based ARB, to facilitate metabolic improvements in conditions of angiotensin II (Ang II)-associated insulin resistance is currently unknown. The aim of this study was to determine the impact of chronic AZIL-M treatment on glucose transport activity and key insulin signaling elements in red skeletal muscle of Ang II-treated rats. Male Sprague-Dawley rats were treated for 8 weeks with or without Ang II (200 ng/kg/min) combined with either vehicle or AZIL-M (1 mg/kg/day). Ang II induced significant (p < 0.05) increases in blood pressure, which were completely prevented by AZIL-M. Furthermore, Ang II reduced insulin-mediated glucose transport activity in incubated soleus muscle, and AZIL-M co-treatment increased this parameter. Moreover, AZIL-M treatment of Ang II-infused animals increased the absolute phosphorylation of insulin signaling molecules, including Akt [both Ser⁴⁷³ (81%) and Thr³⁰⁸ (23%)] and AS160 Thr⁶⁴² (42%), in red gastrocnemius muscle frozen in situ. Absolute AMPKα (Thr¹⁷²) phosphorylation increased (98%) by AZIL-M treatment, and relative Thr³⁸⁹ phosphorylation of p70 S6K1, a negative regulator of insulin signaling, decreased (51%) with AZIL-M treatment. These results indicate that ARB AZIL-M improves the in vitro insulin action on glucose transport in red soleus muscle and the functionality of the Akt/AS160 axis in red gastrocnemius muscle in situ in Ang II-induced insulin-resistant rats, with the latter modification possibly associated with enhanced AMPKα and suppressed p70 S6K1 activation.

【 授权许可】

Unknown