Ellagic Acid Ameliorates Insulin Sensitivity and Hepatic Oxidative Stress in Diabetic Female Rats: A Potential Anti‐Oxidant Agent for Type II Diabetic Complications.
Authors: Burke Cameron Michael , França Lucas Martins , Kramer Benjamin , Carrillo‐Sepulveda Maria Alicia 
Published: June 2021

Hyperglycemia and insulin resistance are found in Type 2 Diabetes Mellitus (T2D) and together contribute to the early onset of non‐alcoholic fatty liver disease (NAFLD). Together they lead to overproduction of reactive oxygen species (ROS)‐ induced oxidative stress, which is considered to be a key mechanism in the development of NAFLD. However, current diabetic therapeutic strategies have failed to halt hepatic oxidative stress efficiently, indicating that anti‐oxidant therapeutic research is needed. Recent studies from our laboratory have demonstrated that Ellagic Acid (EA), a naturally occurring polyphenol found in berries and nuts, possesses an anti‐oxidant effect in the vasculature of diabetic rats. Based on these previous findings, we hypothesize that EA improves hepatic oxidative stress and insulin resistance in type 2 diabetic rats. To test our hypothesis, we utilized adult female Goto Kakizaki (GK) rats, a non‐obese, spontaneous model of T2D. GK rats were randomized into two groups: The experimental group received 50 mg/kg of EA via gavage daily for six weeks compared to the control group which was treated with a placebo vehicle. After euthanasia with isoflurane (via nasal 5% in 100% O2), blood and liver samples were collected. Strikingly, we found that while EA treatment decreased the fasting blood glucose of GK rats (109 ± 3.674 vs. 139.3 ± 10.35 in control, p<0.05), there was no significant difference in the fasting triglyceride levels (33.7 ± 4.27 vs. 38.52 ± 5.785 in control). Using dihydroethidium (DHE) staining, we found that treatment with EA reduced levels of oxidative stress in the liver of diabetic rats (Figure 1), confirming that the anti‐oxidant effect of EA is also implicated in the liver. Moreover, EA treatment had a 21.8% reduction in the HOMA‐IR value, indicating decreased insulin resistance (Figure 2). Next, we evaluated the effect of EA in the activation of Akt, a key molecule in the insulin signaling pathway. Levels of phosphorylated Akt (Serine 473), an active Akt form, were increased in hepatic tissues after treatment with EA (2.4 fold increase vs. control, p<0.05). We also found that NF‐E2‐related factor‐2 (Nrf‐2), a crucial transcriptional factor that regulates antioxidant mechanisms, was upregulated in the livers of diabetic rats treated with EA (1.8 fold increase vs. control, p<0.05). Collectively, our findings indicate that EA ameliorates insulin sensitivity and hepatic oxidative stress via Akt/Nrf‐2 signaling pathway activation. In conclusion, these results support EA as a potential adjunctive treatment in T2D, given the ability to halt oxidative damage and potentially inhibit the development of NAFLD.Support or Funding InformationIn‐house grant: New York Institute of Technology College of Osteopathic MedicineThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.