Abstract 308: Losartan Increases Muscle Insulin Delivery via Microvascular Recruitment and Rescues Insulin’s Metabolic Action during Lipid Infusion

Abstract

Rationale: Insulin delivery and transendothelial insulin transport are two discrete steps that limit muscle insulin action. Angiotensin II type 1 receptor (AT 1 R) blockade recruits microvasculature and increases glucose use in muscle. Increased muscle microvascular perfusion is associated with increased muscle delivery and action of insulin. Objective: To examine the effect of acute AT 1 R blockade on muscle insulin uptake and action in rats. Methods and Results: Rats were studied after an overnight fast to examine the effects of losartan on muscle insulin uptake (protocol 1), microvascular perfusion (protocol 2), and insulin’s microvascular and metabolic actions in the state of insulin resistance (protocol 3). Endothelial cell insulin uptake was assessed using 125 I-insulin as tracer. Systemic lipid infusion was used to induce insulin resistance. Losartan significantly increased muscle insulin uptake (∼60%, p<0.03), which was associated with 2-3-fold increase in muscle microvascular blood volume (MBV, p=0.002) and flow (MBF, p=0.002). Losartan ± angiotensin II had no effect on insulin internalization in cultured endothelial cells. Lipid infusion abolished insulin-mediated increases in muscle MBV and MBF, and lowered insulin-stimulated whole body glucose disposal (p=0.0001) which were reversed by losartan administration. Inhibition of nitric oxide synthase abolished losartan-induced muscle insulin uptake and reversal of lipid-induced metabolic insulin resistance. Conclusion: AT 1 R blockade increases muscle insulin uptake mainly via microvascular recruitment and rescues insulin’s metabolic action in the insulin resistant state. This may contribute to the clinical findings of decreased cardiovascular events and new onset of diabetes in patients receiving AT 1 R blockers.