477-P: Inhibiting Myeloperoxidase (MPO) Prevents Onset and Reverses Established High-Fat Diet (HFD)-Induced Microvascular Insulin Resistance (IR)

HFD rapidly recruits neutrophils to insulin target tissues and induces microvascular IR. MPO is abundant in neutrophils, inhibits nitric oxide mediated vaso-relaxation, and associates with increased cardiovascular risk. AZD5904 (AstraZeneca) irreversibly inhibits MPO and is in clinical trials. MPO knockout, or chemical inhibition, improves glucose regulation in HFD-fed mice. Whether MPO affects muscle microvascular or metabolic IR in vivo is unknown. To test whether AZD5904 can prevent onset of HFD-induced vascular and metabolic IR, Sprague-Dawley rats were fed chow or a HFD (60% calories) for 2 weeks. HFD-fed rats received vehicle (n=8) or AZD5904 subcutaneously (n=10) via Alzet pump. Chow-fed rats (n=8) received vehicle alone. On day 15, we measured muscle microvascular perfusion in all rats by contrast-enhanced ultrasound, at 0, 60 and 120 minutes of a 2-hour euglycemic insulin clamp (3 mU/kg/minutes) and glucose disposal was determined. We next tested whether AZD5904 can reverse established vascular IR. Two groups of rats (n = 10, each) were fed the HFD for 2 weeks to induce vascular and metabolic IR, HFD was continued for 2 additional weeks while giving vehicle or AZD5904. Microvascular and metabolic insulin action was measured again using the insulin clamp. HFD for 2 weeks completely blocked insulin-mediated muscle capillary recruitment, decreased glucose utilization by 35%, and inhibited muscle Akt phosphorylation (P<0.05, for each measure). AZD5904 during HFD selectively and completely restored insulin-induced microvascular sensitivity (P<0.05). Furthermore, AZD5904 during the last 2 of 4 weeks of HFD feeding fully restored insulin-mediated microvascular perfusion (P<0.05) again without affecting glucose disposal. We conclude that inhibiting MPO selectively corrects vascular IR. This effect may connote a therapeutic potential for MPO inhibition in the prevention of vascular disease/dysfunction seen in IR humans.