Inhibition of Myeloperoxidase and MPO Reverses Microvascular Insulin Resistance in High-Fat Diet (HFD)-Fed Rats

Abstract

Chronic, low-level inflammation underlies much of the vascular and metabolic insulin resistance associated with HFD. Release of MPO by leukocytes may be an early contributor to the inflammatory process and endothelial dysfunction that accompanies HFD feeding. Plasma MPO concentrations are increased in both human obesity and diabetes and HFD-fed rats. However, the impact of MPO on microangiopathy and its relation to insulin resistance is unclear. We tested whether AZD5904 (a potent, irreversible inhibitor of MPO, AstraZeneca) improves endothelial function and vascular insulin responses in insulin resistant, adult male SD rats fed a HFD (60% calories from fat) for 2 weeks. HFD fed rats received vehicle (n=8) or AZD5904 (75 µmol/kg/day, n=10) via an Alzet Mini pump for 2 weeks. A 3rd group of rats (n=8, vehicle alone) were fed a chow diet for 2 weeks. After 2 weeks of HFD or control diet, rats were fasted overnight and received a 2-hour euglycemic insulin clamp (3 mU/kg/minutes). Hindleg muscle microvascular perfusion was assessed using contrast-enhanced ultrasound and insulin-stimulated steady-state whole body glucose disposal was determined. Insulin infusion increased muscle microvascular perfusion by 2-3 fold in chow fed rats (p<0.05). HFD feeding abolished insulin-induced microvascular recruitment in muscle, and decreased insulin-mediated glucose disposal by ∼45% (p<0.01). Simultaneous treatment with AZD5904 fully restored insulin-mediated muscle microvascular perfusion (p<0.05) in HFD rats, but did not improve insulin-stimulated glucose disposal in HFD-fed rats. We conclude that inhibition of MPO with AZD5904specifically reverses muscle microvascular insulin resistance in HFD rats. This implicates MPO as a significant contributor to HFD-induced endothelial inflammation and suggests a role for MPO inhibition to improve microvascular complications in patients with vascular insulin resistance. Disclosure E. Barrett: None. K.W. Aylor: None. W. Chai: None. L. Gan: Employee; Self; AstraZeneca.