Selective angiotensin II receptor antagonism reduces insulin resistance in obese Zucker rats
ABSTRACT Effects of oral administration of the angiotensin II receptor antagonist (selective AT(1)-subtype) irbesartan on glucose tolerance and insulin action on skeletal-muscle glucose transport were assessed in the insulin-resistant obese Zucker rat. In the acute study, obese rats received either vehicle (water) or irbesartan 1 hour before the experiment. Although irbesartan had no effect on glucose transport (2-deoxyglucose uptake) in the epitrochlearis muscle, which consists mainly of type IIb fibers, acute angiotensin II receptor antagonism led to a dose-dependent increase in insulin action in the predominantly type I soleus muscle. Irbesartan at 25 and 50 mg/kg induced significant increases (41% and 50%, respectively; P<0.05) in insulin-mediated glucose transport. Moreover, these acute irbesartan-induced improvements in soleus-muscle glucose transport were associated with enhancements in whole-body insulin sensitivity (r=-0.732; P<0.05), as assessed during an oral glucose tolerance test. After chronic administration of irbesartan (21 days at 50 mg. kg(-1). d(-1)), glucose tolerance was enhanced further, and insulin-mediated glucose transport was significantly elevated in both epitrochlearis (32%) and soleus (73%) muscle. Chronic angiotensin II receptor antagonism was associated with significant increases in glucose transporter-4 (GLUT-4) protein expression in soleus (22%) and plantaris (20%) muscle and myocardium (15%). Chronic irbesartan-induced increases in whole-body insulin sensitivity were associated with increased insulin-mediated glucose transport in both epitrochlearis (r=-0.677; P<0.05) and soleus (r=-0.892; P<0.05) muscle. In summary, angiotensin II receptor (AT(1)-subtype) antagonism, either acutely or chronically, improves glucose tolerance, at least in part because of an enhancement in skeletal-muscle glucose transport, and the effect of chronic angiotensin II receptor antagonism on type I skeletal-muscle glucose uptake is associated with an increase in GLUT-4 protein expression.
SourceAvailable from: Claudio Cabello-Verrugio[Show abstract] [Hide abstract]
ABSTRACT: Skeletal muscle is a tissue that shows the most plasticity in the body; it can change in response to physiological and pathological stimuli. Among the diseases that affect skeletal muscle are myopathy-associated fibrosis, insulin resistance, and muscle atrophy. A common factor in these pathologies is the participation of the renin-angiotensin system (RAS). This system can be functionally separated into the classical and nonclassical RAS axis. The main components of the classical RAS pathway are angiotensin-converting enzyme (ACE), angiotensin II (Ang-II), and Ang-II receptors (AT receptors), whereas the nonclassical axis is composed of ACE2, angiotensin 1-7 [Ang (1-7)], and the Mas receptor. Hyperactivity of the classical axis in skeletal muscle has been associated with insulin resistance, atrophy, and fibrosis. In contrast, current evidence supports the action of the nonclassical RAS as a counter-regulator axis of the classical RAS pathway in skeletal muscle. In this review, we describe the mechanisms involved in the pathological effects of the classical RAS, advances in the use of pharmacological molecules to inhibit this axis, and the beneficial effects of stimulation of the nonclassical RAS pathway on insulin resistance, atrophy, and fibrosis in skeletal muscle. © 2015 Wiley Periodicals, Inc.Medicinal Research Reviews 03/2015; DOI:10.1002/med.21343 · 8.13 Impact Factor
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ABSTRACT: Background: Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Cross-link between the rennin-angiotensin system (RAS) and insulin signaling has been demonstrated, the rennin angiotensin system (RAS) may regulate pancreatic islet blood flow, oxygen tension, and islet (pro) insulin biosynthesis. Objective: This study was designed to evaluate the effect of captopril and losartan in uncontrolled type 2 DM patients treated with oral hypoglycemic agents alone. Methods: The study was conducted on 60 uncontrolled type 2 diabetic patients for 4 months in National Diabetes Center; the diabetic patients were randomized into three groups: Group A (10) patients treated with placebo formula containing lactose only for 4 months, Group B (25) patients treated with 12.5 mg captopril, given once daily at bed time, for 4 months; Group C(25) patients treated with 25 mg losartan .Given as a single dose daily at bed time for 4 months, with their current hypoglycemic drug (glibenclamide). After 12 hours fasting, blood samples were collected from all subjects to measure; fasting plasma glucose (FPG),glycated hemoglobin (HbA1c),triglyceride (TG), Total cholesterol (TC),low density lipoprotein (LDL),high density lipoprotein (HDL),blood urea (Bu), blood creatinin, C-peptide, Erythrocyte sedimentation rate (ESR), ,Creactive protein ,alanin transaminase ,aspartat transaminase ,alkaline phosphates (ALP) and gamma glutamines transferees(GGT), urine sample for microalbuminurea (MAU), Body mass index (BMI), before starting drug treatment (as zero time sample) and then after 4 months of treatment to follow the changes in the studied parameters. Results: Significant reduction in FBS was reported in patients treated with captopril or losartan in addition to the currently used oral hypoglycemic agent compared to those treated with the oral hypoglycemic agents alone, and a significant reduction in HbA1c levels after 4 months of treatment. Both captopril and losartan improve the capacity of β-cells to secrete insulin, The present study revealed also a significantly greater improvement in the lipid profile of diabetic patients treated with captopril and losartan compared to those treated with the oral hypoglycemic agents alone. In addition a significant improves renal function. And a slight elevation in the serum levels of liver enzymes activity was seen. Conclusion: Inhibition of RAS by ACEIs or AT1 antagonists (ARBs) has been to both increase insulin sensitivity and improve endothelial function, where treatment of type 2 DM patients with captopril resulted in more suppressed hepatic glucose production and greater glucose utilization due to improved insulin sensitivity both in hepatic and extra-hepatic tissues.09/2008, Degree: PhD, Supervisor: Saad A. Hussain
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ABSTRACT: Experimental and epidemiological studies indicate that the correlation between metabolic disorders, oxidative stress and coronary artery disease (CAD) is continuous and graded. The greater the amount of oxidative stress and metabolic disorder in the form of type 2 diabetes or metabolic syndrome, the higher the risk of CAD. The extent of oxidative stress may be determined by endogenous antioxidants; superoxide dismutase and catalase, dietary antioxidants; vitamins, minerals and polyphenolics. Pharmacological antioxidants such as angiotensin II receptor blockers, ACE-inhibitors, statins, and flavidon are potent free radical inhibitors which have been used for the treatment of CAD. The imprint of metabolic disorder on consequences of coronary revascularization outcomes can vary depending upon the extent of the risk and antioxidant administration. Coronary angiography is associated with an enormous amount of oxidative stress and inflammation, which appears to be determined by the antioxidant index in the body. There is consistent association between metabolic disorder and oxidative stress, which are mediators of cardiovascular diseases (CVDs). However, the obvious lack of encouraging effects of antioxidants on cardiovascular consequences in an enormous number of clinical trials involving oxidative stress has tended to be of lesser importance. However, last but not least,reference is made for the application of antioxidantpharmacological agents, namely, angiotensin II converting enzyme (ACE) inhibitors,angiotensin II type I receptor blockers (ARBs) and metformin, forthe management of CVDs and metabolic risk.World Heart Journal 01/2015; 6(4):283-302.