Evaluation of the potential benefits of L-ergothioneine on selected complications associated with type-2 diabetes in a rat model.

Abstract

Several pathogenic factors promote type-2 diabetic complications in patients, including cardiomyopathy, nephropathy, and non-alcoholic fatty liver disease (NAFLD). Specific nutraceuticals from food may act as a medicinal adjuvant in managing diabetic complications. L-ergothioneine (L-egt), a bioactive compound obtained from medicinal mushrooms, beans and some meat products, has been shown to reduce lipid accumulation, provide cytoprotection in tissue injury and enhances therapeutic efficacy when used as adjuvant. This study investigated the effect of L-ergothioneine with or without metformin on pathogenic metabolic pathways and biomarkers associated with selected diabetic complications in a type-2 diabetic rat model. Ninety (90) adult male Sprague-Dawley (175±20)g rats were divided into three study groups [study 1 (36), study 2 (30) and study 3 (24)]. A 10% fructose solution was provided ad libitum to adult male Sprague- Dawley (175±20)g rats for 14 days followed by a single intraperitoneal injection of low dose streptozotocin (STZ 40mg/kg bwt, i.p) to induce type-2 diabetes after which the animals were randomly divided into six, five, and four groups (n=6) in studies 1 (liver), 2 (kidney), and 3 (heart), respectively. The control groups were administered 1ml/100g distilled water, while L-egt (35mg/kg bwt), metformin (500mg/kg bwt), and losartan (20mg/kg bwt) were administered in the other groups. At the end of each study, animals were euthanized via decapitation, blood samples were collected, while the heart, kidney, and liver tissue were excised and used for biochemical, RT-qPCR, ELISA, western blotting, and histopathological analysis. An in-silico study was done to evaluate the molecular antioxidant mechanism of L-egt. Administration of L-egt, with or without metformin, to diabetic animals positively altered selected biomarkers of hepatic, renal, and cardiac dysfunction and prevented structural damage in these tissues. This treatment regimen mitigated oxidative stress, inflammation, and fibrosis by downregulating (p<0.05) SREBP1c, FAS, NF-kB, fibronectin, TGFβ1, and Keap1 expression and upregulating (p<0.05) Nrf2, Sirt1, NQO1, and HO1 expression compared with the diabetic control animals. Interestingly, co-administration of L-egt and metformin improved glucose homeostasis and reduced HOMA-IR. The in-silico study showed that L-egt binds to the active site of Nrf2 and may serve as a ligand to activate this potent antioxidant molecule. The overall result from this study showed the potential benefits of L-ergothioneine in the management of selected complications associated with type-2 diabetes. This bioactive compound may be an effective adjuvant to attenuate hypertriglyceridemia, oxidative stress, and inflammation, thereby protecting vital organs associated with diabetic complications against injury and improving glycemic control when coadministered with metformin to delay the onset of diabetic complications.