Alterations in Energy Metabolism, Mitochondrial Function and Redox Homeostasis in GK Diabetic Rat Tissues Treated with Aspirin.

Annie John,Ernest Adeghate,Frank Christopher Howarth,Layla Amiri,Jasmin Shafarin,Haider Raza,Saeed Tariq

doi:10.3390/life12010104

Abstract

Our recent studies have demonstrated that aspirin treatment prevents inflammatory and oxidative stress-induced alterations in mitochondrial function, improves glucose tolerance and pancreatic endocrine function and preserves tissue-specific glutathione (GSH)-dependent redox homeostasis in Goto-Kakizaki (GK) diabetic rats. In the current study, we have investigated the mechanism of action of aspirin in maintaining mitochondrial bioenergetics and redox metabolism in the liver and kidneys of GK rats. Aspirin reduced the production of reactive oxygen species (ROS) and oxidative stress-induced changes in GSH metabolism. Aspirin treatment also improved mitochondrial respiratory function and energy metabolism, in addition to regulating the expression of cell signaling proteins that were altered in diabetic animals. Ultrastructural electron microscopy studies revealed decreased accumulation of glycogen in the liver of aspirin-treated diabetic rats. Hypertrophic podocytes with irregular fusion of foot processes in the renal glomerulus and detached microvilli, condensed nuclei and degenerated mitochondria observed in the proximal convoluted tubules of GK rats were partially restored by aspirin. These results provide additional evidence to support our previous observation of moderation of diabetic complications by aspirin treatment in GK rats and may have implications for cautious use of aspirin in the therapeutic management of diabetes.

Highlights

Introduction published maps and institutional affilDespite decades of extensive research and medical breakthroughs, there is still no therapeutic silver bullet to prevent the progression of diabetes and its complications, which are increasing alarmingly worldwide
Our study demonstrates that aspirin treatment exerted beneficial effects on GK diabetic rats via modulation of redox homeostasis, mitochondrial function and energy metabolism
Results are expressed as mean ± SD from three independent experiments and asterisks indicate significant difference, which was fixed as p < 0.05 (* indicates p < 0.05 compared with control and ∆ indicates p < 0.05 compared with GK rats)

Summary

Introduction

Despite decades of extensive research and medical breakthroughs, there is still no therapeutic silver bullet to prevent the progression of diabetes and its complications, which are increasing alarmingly worldwide. Type 2 diabetes mellitus (T2D) is the most common endocrine metabolic disorder, characterized by impaired insulin response and insulin resistance. The Goto-Kakizaki (GK) rat, a non-obese and spontaneous (genetic) model of T2D, exhibits alterations in β-cell response, impaired glucose-induced insulin secretion, glucose intolerance, peripheral insulin resistance and chronic inflammation [2–4]. These animals are widely used to study T2D and its complications [5,6]. Glucolipotoxicity in diabetes is associated with increased inflammation, oxidative stress and mitochondrial dysfunction, which iations

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