Angiotensin II receptors modulate muscle microvascular and metabolic responses to insulin in vivo

Abstract

OBJECTIVE - Angiotensin (ANG) II interacts with insulin-signaling pathways to regulate insulin sensitivity. The type 1 (AT 1R) and type 2 (AT 2R) receptors reciprocally regulate basal perfusion of muscle microvasculature. Unopposed AT2R activity increases muscle microvascular blood volume (MBV) and glucose extraction, whereas unopposed AT 1R activity decreases both. The current study examined whether ANG II receptors modulate muscle insulin delivery and sensitivity. RESEARCH DESIGN AND METHODS - Overnight-fasted rats were studied. In protocol 1, rats received a 2-h infusion of saline, insulin (3 mU/kg/min), insulin plus PD123319 (AT 2R blocker), or insulin plus losartan (AT1R blocker, intravenously). Muscle MBV, microvascular flow velocity, and microvascular blood flow (MBF) were determined. In protocol 2, rats received 125I-insulin with or without PD123319, and muscle insulin uptake was determined. RESULTS - Insulin significantly increased muscle MBV and MBF. AT 2R blockade abolished insulin-mediated increases in muscle MBV and MBF and decreased insulin-stimulated glucose disposal by ∼30%. In contrast, losartan plus insulin increased muscle MBV by two- to threefold without further increasing insulin-stimulated glucose disposal. Plasma nitric oxide increased by >50% with insulin and insulin plus losartan but not with insulin plus PD123319. PD123319 markedly decreased muscle insulin uptake and insulin-stimulated Akt phosphorylation. CONCLUSIONS - We conclude that both AT 1Rs and AT 2Rs regulate insulin's microvascular and metabolic action in muscle. Although AT 1R activity restrains muscle metabolic responses to insulin via decreased microvascular recruitment and insulin delivery, AT 2R activity is required for normal microvascular responses to insulin. Thus, pharmacologic manipulation aimed at increasing the AT 2R-to-AT 1R activity ratio may afford the potential to improve muscle insulin sensitivity and glucose metabolism. © 2011 by the American Diabetes Association.