Glutathione Increases in Response to a Glucose Challenge in Diabetic Rat Hearts

Abstract

Diabetic hearts are in great risk of increased oxidant production from sustained elevations of glucose through activation of several pathways. One of the major sources of oxidant production within the cell are mitochondria through substrate metabolism. Oxidation of mitochondrial enzymes may impair their function resulting in accumulation of intermediates and reverse electron transfer which contributes to mitochondrial dysfunction. Glutathione (GSH) is the most abundant antioxidant in the body which with the aid of peroxidases is able to reduce cellular oxidants through electron donation. Transcription factor nuclear factor erythriod‐2‐related factor 2 (Nrf2) induces expression of antioxidant genes including those responsible for GSH synthesis. Nrf2 translocation serves as a defensive mechanism when oxidant production increases in the cytosol. We hypothesized that an elevation in plasma glucose facilitates Nrf2 nuclear translocation and subsequent expression of Nrf2‐associated genes. To address this hypothesis, an oral glucose tolerance test (oGTT) was performed in four groups (n = 6–8/group) of rats: 1) LETO (lean strain‐control), 2) vehicle‐treated, IR obese OLETF, 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d), and 4) OLETF + angiotensin receptor blocker (ARB‐r). ARB normalized systolic blood pressure to control levels, while ARB‐r matched OLETF at 155±2.36 mmHg. Baseline GSH levels were maintained over 360 min post‐glucose administration in LETO, but GSH levels increased 125% in OLETF. While ARB had no detectable effect on GSH levels, GSH levels increased 52% in ARB‐r compared to LETO. Removal of ARB treatment may be more beneficial than long term ARB treatment. However, our data suggest that acute increases in glucose can increase GSH levels in the early phases of diabetic cardiomyopathy liking to protect against the potential for increased oxidant production.