Abstract 623: Angiotensin Receptor Activation Contributes to Glucose Intolerance and Increased Insulin Resistance Independent of Elevated Systolic Blood Pressure, Adiposity and Dyslipidemia in a Model of Metabolic Syndrome

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Activation of the renin-angiotensin system (RAS) leads to an increase in blood pressure and onset of insulin resistance (IR); however, the contributions of increased blood pressure and AT1 activation independently on the manifestation of IR are not well defined. The goal of this study was to determine the contribution of elevated blood pressure, independent of RAS, to the onset of IR in a model of metabolic syndrome. To address the hypothesis that AT1 activation, and not elevated blood pressure independently, is the principal contributor of obesity-associated IR, we measured changes in systolic blood pressure (SBP), adiposity, plasma triglycerides (TG), glucose tolerance, and insulin resistance index (IRI) in four groups of rats: 1) lean strain-control Long Evans Tokushima Otsuka (LETO; n=5), 2) obese Otsuka Long-Evans Tokushima Fatty (OLETF; n=7), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg; n=8), and 4) OLETF + calcium channel blocker (CCB; 5 mg amlodipine/kg; n=7). ARB treatment alleviated the obesity-related increase in mean SBP, while the decrease with CCB remained 10.2 mmHg greater than LETO. ARB (0.51 g/100g body mass) and CCB (0.64 g/100g body mass) reduced mean relative retroperitoneal fat mass and mean plasma triglycerides (28.4 and 27.4 mg/dL respectively) compared to OLETF, but both remained greater (1.7, 1.57 g/100g body mass and 28.94, 29.94 mg/dL respectively) than LETO. ARB improved glucose tolerance by 4605.94 of 34965.94 and mean calculated IRI by 5581429.5 of 17398363, but CCB had no detectable effect on either. Despite relatively similar reductions in SBP, adiposity and plasma TG (principal components of metabolic syndrome), CCB did not improve glucose tolerance and IRI (additional metrics of metabolic syndrome), while ARB did, demonstrating that AT1 activation is the primary factor contributing to the development of impaired glucose metabolism and regulation during metabolic syndrome, independent of the hypertension, adiposity and dyslipidemia. Thus, targeting RAS to improve the consequences of metabolic syndrome appears to be prudent and effective.

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