Arginine deprivation/citrulline augmentation with ADI-PEG20 as novel therapy for complications in type 2 diabetes.

Objective: Chronic inflammation and oxidative stress mediate the pathological progression of diabetic complications, like diabetic retinopathy (DR), peripheral neuropathy (DPN) and impaired wound healing. Studies have shown that treatment with a stable form of arginase 1 that reduces l-arginine levels and increases ornithine and urea limits retinal injury and improves visual function in DR. We tested the therapeutic efficacy of PEGylated arginine deiminase (ADI-PEG20) that depletes l-arginine and elevates l-citrulline on diabetic complications in the db/db mouse model of type 2 diabetes (T2D).

Systemic Administration of Pegylated Arginase-1 Attenuates the Progression of Diabetic Retinopathy.

Diabetic retinopathy (DR) is a serious complication of diabetes that results from sustained hyperglycemia, hyperlipidemia, and oxidative stress. Under these conditions, inducible nitric oxide synthase (iNOS) expression is upregulated in the macrophages (MΦ) and microglia, resulting in increased production of reactive oxygen species (ROS) and inflammatory cytokines, which contribute to disease progression. Arginase 1 (Arg1) is a ureohydrolase that competes with iNOS for their common substrate, L-arginine.