Selective Angiotensin II Receptor Antagonism Reduces Insulin Resistance in Obese Zucker Rats

Bristol-Myers Squibb, New York, New York, United States
Hypertension (Impact Factor: 7.63). 10/2001; 38(4):884-90. DOI: 10.1161/hy1101.092970
Source: PubMed

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.

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    • "In addition, other ACEi (temocapril) were demonstrated to improve insulin resistance and glucose intolerance through increasing glucose uptake, especially in skeletal muscle, at least in part through enhancement of the bradykinin-nitric oxide (NO) system and consequently glucose transporter-4 (GLUT-4) translocation [104]. Moreover, oral administration of irbesartan, 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 [46]. "
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    ABSTRACT: Angiotensin-(1-7) is one of the most important active peptides of the Renin-Angiotensin System (RAS) with recognized cardiovascular relevance; however recently several studies have shown the potential therapeutic role of Ang-(1-7) on treating and preventing metabolic disorders as well. This peptide achieves a special importance considering that in the last few decades obesity and metabolic syndrome (MS) have become a growing worldwide health problem. Angiotensin (Ang) II is the most studied component of RAS and is increased during obesity, diabetes and dyslipidemia (MS); some experimental evidence has shown that Ang II modulates appetite and metabolism as well as mechanisms that induce adipose tissue growth and metabolism in peripheral organs. Recent articles demonstrated that Ang-(1-7)/Mas axis modulates lipid and glucose metabolism and counterregulates the effects of Ang II. Based on these data, angiotensin-converting enzyme 2 (ACE2)/Ang-(1-7)/Mas pathway activation have been advocated as a new tool for treating metabolic diseases. This review summarizes the new evidence from animal and human experiments indicating the use of Ang-(1-7) in prevention and treatment of obesity and metabolic disorders.
    Peptides 07/2014; DOI:10.1016/j.peptides.2014.07.002 · 2.61 Impact Factor
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    • "resistance, hypertriglyceridemia, fatty liver, obesity, and myogenic and adipogenic differentiation in muscle tissue in rats receiving a high fructose diet rats [14] [28]. Moreover, chronic treatment either with ACE or AT1 inhibitors improves insulin sensitivity, decreases obesity and reduces the incidence of diabetes [17] [18]. Captopril, an ACE inhibitor, decreased body weight gain partly through Ang1-7/Mas receptor/PI3K pathway [36]. "
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    ABSTRACT: Renin Angiotensin System (RAS) plays an important role in the development of Metabolic Syndrome (MS) and in aging. Angiotensin 1-7 (Ang 1-7) has opposite effects to Ang II. All of the components of RAS are expressed locally in adipose tissue and there is over-activation of adipose RAS in obesity and hypertension. We determined serum and abdominal adipose tissue Ang II and Ang 1-7 in control and MS rats during aging and the expression of AT1, AT2 and Mas in white adipose tissue. MS was induced by sucrose ingestion during 6, 12 and 18 months. During aging, an increase in body weight, abdominal fat and dyslipidemia were found but increases in aging MS rats were higher. Control and MS concentrations of serum Ang II from 6 month old rats were similar. Aging did not modify Ang II seric concentration in control rats but decreased it in MS rats. Ang II levels increased in WAT from both groups of rats. Serum and adipose tissue Ang 1-7 increased during aging in MS rats. Western blot analysis revealed that AT1 expression increased in the control group during aging while AT2 and Mas remained unchanged. In MS rats, AT1 and AT2 expression decreased significantly in aged rats. The high concentration of Ang 1-7 and adiponectin in old MS rats might be associated to an increased expression of PPAR-γ. PPAR-γ was increased in adipose tissue from MS rats. It decreased with aging in control rats and showed no changes during aging in MS rats. Ang 1-7/Mas axis was the predominant pathway in WAT from old MS animals and could represent a potential target for therapeutical strategies in the treatment of MS during aging.
    Peptides 07/2014; DOI:10.1016/j.peptides.2014.04.021 · 2.61 Impact Factor
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    • "However, insulin levels both before and during ivgtt were lower in the losartan-treated rats than in the rats not treated with losartan and subjected for 35 days to sham gas exchanges. This suggests that losartan improved insulin sensitivity, as it did in the obese Zucker rats (Henriksen et al., 2001). Importantly, angiotensin II antagonism can improve glucose disposal by modulating insulin receptor/insulin receptor substrate-1 signaling in skeletal muscles , with a convergent action on some of the same intracellular mechanisms that are also beneficially affected by exercise training (Henriksen, 2007). "
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    ABSTRACT: Background: Obstructive sleep apnea (OSA) is associated with glucose intolerance. Both chronic sleep disruption and recurrent blood oxygen desaturations (chronic-intermittent hypoxia, CIH) may cause, or exacerbate, metabolic derangements. Methods: To assess the impact of CIH alone, without accompanying upper airway obstructions, on the counter-regulatory response to glucose load and cardiorespiratory parameters, we exposed adult male Sprague-Dawley rats to CIH or sham room air exchanges for 10 h/day for 7, 21, or 35 days and then, 1 day after conclusion of CIH exposure, conducted intravenous glucose-tolerance tests (ivgtt) under urethane anesthesia. Additional rats underwent 35 days of CIH followed by 35 days of regular housing, or had 35 day-long CIH exposure combined with daily administration of the type 1 angiotensin II receptor antagonist, losartan (15 mg/kg, p.o.), and then were also subjected to ivgtt. Results: Compared with the corresponding control groups, CIH rats had progressively reduced glucose-stimulated insulin release and impaired glucose clearance, only mildly elevated heart rate and/or arterial blood pressure and slightly reduced respiratory rate. The differences in insulin release between the CIH and sham-treated rats disappeared in the rats normally housed for 35 days after 35 days of CIH/sham exposure. The losartan-treated rats had improved insulin sensitivity, with no evidence of suppressed insulin release in the CIH group. Conclusion: In adult rats, the glucose-stimulated insulin release is gradually suppressed with the duration of exposure to CIH, but the effect is reversible. Elimination of the detrimental effect of CIH on insulin release by losartan suggests that CIH disrupts glucoregulation through angiotensin/catecholaminergic pathways. Accordingly, treatment with continuous positive airway pressure may ameliorate pre-diabetic conditions in OSA patients, in part, by reducing sympathoexcitatory effects of recurrent nocturnal hypoxia.
    Frontiers in Neurology 04/2012; 3:51. DOI:10.3389/fneur.2012.00051
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