Chronic renin inhibition with aliskiren improves glucose tolerance, insulin sensitivity, and skeletal muscle glucose transport activity in obese Zucker rats

Abstract

We have demonstrated previously that overactivity of the renin-angiotensin system (RAS) is associated with whole body and skeletal muscle insulin resistance in obese Zucker (fa/fa) rats. Moreover, this obesity-associated insulin resistance is reduced by treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor (type 1) blockers. However, it is currently unknown whether specific inhibition of renin itself, the rate-limiting step in RAS functionality, improves insulin action in obesity-associated insulin resistance. Therefore, the present study assessed the effect of chronic, selective renin inhibition using aliskiren on glucose tolerance, whole body insulin sensitivity, and insulin action on the glucose transport system in skeletal muscle of obese Zucker rats. Obese Zucker rats were treated for 21 days with either vehicle or aliskiren (50 mg/kg body wt ip). Renin inhibition was associated with a significant lowering (10%, P < 0.05) of resting systolic blood pressure and induced reductions in fasting plasma glucose (11%) and free fatty acids (46%) and homeostatic model assessment for insulin resistance (13%). Glucose tolerance (glucose area under the curve) and whole body insulin sensitivity (inverse of the glucose-insulin index) during an oral glucose tolerance test were improved by 15% and 16%, respectively, following chronic renin inhibition. Moreover, insulin-stimulated glucose transport activity in isolated soleus muscle of renin inhibitor-treated animals was increased by 36% and was associated with a 2.2-fold greater Akt Ser(473) phosphorylation. These data provide evidence that chronic selective inhibition of renin activity leads to improvements in glucose tolerance and whole body insulin sensitivity in the insulin-resistant obese Zucker rat. Importantly, chronic renin inhibition is associated with upregulation of insulin action on skeletal muscle glucose transport, and it may involve improved Akt signaling. These data support the strategy of targeting the RAS to improve both blood pressure regulation and insulin action in conditions of insulin resistance.

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

“…The present results in Ang II-treated rats are in agreement with previous studies indicating that specific increases in Ang II exposure are associated with decreased whole-body and skeletal muscle glucose disposal [9]. In addition, the results of the present study using the novel ARB AZIL-M are consistent with previous rodent model investigations from our research groups showing that interventions which suppress the RAAS, whether involving direct renin inhibition [11,12], ACE inhibition [13], ARB treatment [14,15,16], or mineralocorticoid receptor blockade [17], induce increases in skeletal muscle glucose transport activity due to enhanced Akt-dependent insulin signaling.…”

“…Blood pressure reduction is associated with decreased insulin resistance, making it difficult to make conclusions about the metabolic actions of AZIL-M independently of its blood pressure-lowering effects. However, we and others have demonstrated that RAAS blockade with renin inhibitors, ACE inhibitors, ARBs, and spironolactone exerts a positive effect on insulin sensitivity in skeletal muscle independently of changes in blood pressure in both rodents and humans [11,12,13,17]. Moreover, as glucose transport activity in skeletal muscle was assessed in vitro, this approach would not allow for the assessment of any potential effects of the Ang II and the ARB interventions on flow-dependent properties in the skeletal muscle tissues secondary to alterations in blood pressure.…”

“…Direct treatment of rat skeletal muscle with Ang II leads to impaired Akt signaling and impaired insulin-mediated glucose transport [10]. Moreover, blockade of the RAAS at any of several stages leads to amelioration of insulin-resistant states in rodents characterized by RAAS overactivation, including direct renin inhibition [11,12], angiotensin converting enzyme inhibition [reviewed in [4], [13]], Ang II type 1 receptor (AT1R) blockers (ARBs) [14,15,16], and mineralocorticoid receptor blockade [17]. In the clinical setting, ARBs may have a beneficial impact on insulin resistance and glucose dysregulation [13,18,19].…”

Chronic erythropoietin treatment improves diet-induced glucose intolerance in rats

“…After 2 weeks of EPO treatment, and 48 h after the sixth EPO injection, an intraperitoneal glucose tolerance test (IPGTT, 2 g/kg glucose) was performed under fasting conditions and blood was collected from the tail vein for glucose and insulin analysis. The glucose-insulin index was calculated as previously reported (Marchionne et al 2012). The animals were returned to their cage and received the final EPO injection.…”

The Renin-Angiotensin System in the Pathophysiology of Type 2 Diabetes

“…The effects of direct renin inhibition, or inhibition of aldosterone effects using mineralocorticoid receptor blockade, on glucose metabolism and the onset of type 2 diabetes may be different from treatment with ACEi and/or ARBs. Direct renin inhibition and mineralocorticoid receptor blockade has been shown to improve insulin sensitivity and skeletal muscle glucose uptake in obese Zucker rats [73], transgenic (mRen2)27 rats [74,75], and diabetic mice [76,77]. At the moment, however, no clinical data is available yet regarding the effect of these drugs on glucose metabolism in humans.…”