Inhibiting myeloperoxidase prevents onset and reverses established high-fat diet-induced microvascular insulin
Weidong Chai1, Kevin Aylor1, Zhenqi Liu1
1Division of Endocrinology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia.
Abstract:
A high-fat diet (HFD) can rapidly recruit neutrophils to insulin target tissues and within days induce microvascular insulin resistance (IR). Myeloperoxidase (MPO) is highly enriched in neutrophils, can inhibit nitric oxide-mediated vasorelaxation in vitro and is associated with increased cardiovascular disease risk. AZD5904 irreversibly inhibits MPO and in human clinical trials. MPO knockout, or chemical inhibition, blunts HFD-induced metabolic IR in mice. Whether MPO affects microvascular IR or muscle metabolic insulin sensitivity in vivo is unknown. We used contrast-enhanced ultrasound and the euglycemic insulin clamp to test whether inhibiting MPO could prevent the development or reverse established HFD-induced metabolic and/or microvascular IR in Sprague-Dawley rats. Two weeks of HFD feeding blocked insulin-mediated skeletal muscle capillary recruitment, inhibited glucose utilization, and insulin signaling to muscle. Continuous subcutaneous AZD5904 infusion during the 2 wk selectively blocked HFD's microvascular effect. Furthermore, AZD5904 infusion during the last 2 of 4 wk of HFD feeding restored microvascular insulin sensitivity but not metabolic IR. We conclude that inhibiting MPO selectively improves vascular IR. This selective microvascular effect may connote a therapeutic potential for MPO inhibition in the prevention of vascular disease/dysfunction seen in IR humans.
Insights
Inhibiting myeloperoxidase (MPO) selectively improves vascular insulin resistance caused by high-fat diets. This suggests MPO inhibitors may prevent vascular dysfunction in insulin-resistant individuals.
Area of Science:
- Biomedical Science
- Metabolic Disease Research
- Cardiovascular Physiology
Background:
- High-fat diets (HFD) rapidly induce insulin resistance (IR), affecting neutrophils and microvasculature.
- Myeloperoxidase (MPO), abundant in neutrophils, inhibits vasodilation and is linked to cardiovascular disease.
- Previous studies show MPO inhibition blunts metabolic IR in mice, but its effect on microvascular IR is unclear.
Purpose of the Study:
- To investigate if MPO inhibition prevents or reverses HFD-induced metabolic and microvascular IR in rats.
- To determine the specific effects of MPO inhibition on insulin sensitivity in muscle tissue.
Main Methods:
- Utilized contrast-enhanced ultrasound and euglycemic insulin clamp techniques in Sprague-Dawley rats.
- Administered continuous subcutaneous AZD5904 (an MPO inhibitor) during HFD feeding.
- Assessed insulin-mediated skeletal muscle capillary recruitment, glucose utilization, and insulin signaling.
Main Results:
- Two weeks of HFD impaired insulin-mediated capillary recruitment and glucose utilization in muscle.
- AZD5904 infusion during HFD selectively blocked the microvascular effects of the diet.
- AZD5904 administration in the later HFD period restored microvascular insulin sensitivity but not overall metabolic IR.
Conclusions:
- MPO inhibition demonstrates a selective therapeutic effect on vascular insulin resistance.
- Targeting MPO may offer a strategy to prevent vascular complications associated with insulin resistance.
- Further research could explore MPO inhibitors for managing vascular dysfunction in IR patients.
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