Date of Award

4-2016

Document Type

Thesis

Degree Name

Master of Science in Medical Sciences (MSMS)

Department

Microbiology, Molecular Biology and Biochemistry

First Advisor

Haider Raza

Second Advisor

Ernest Adeghate

Third Advisor

M. Emdadul Haque

Abstract

Background: Increased oxidative stress, inflammatory responses and mitochondrial dysfunction have been implicated in diabetes, obesity (diabesity) and cardiovascular diseases. Type 2 diabetes is the most common metabolic disorder, characterized by insulin resistance and pancreatic islet β-cell failure. The most common complications associated with type 2 diabetes are hyperinsulinemia, hyperglycemia, hyperlipidemia/dyslipidemia, increased inflammatory and reduced insulin response. Aspirin (ASA) and other non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with the prevention of diabetes, obesity and related cardiovascular disorders. Aspirin has been used in many clinical and experimental trials for the prevention of diabetes and associated complications.

Aims and hypothesis: Since inflammation, oxidative stress and mitochondrial dysfunction are hallmarks of many degenerative diseases, including diabetes, and aspirin and other NSAIDs have been used in clinical trials for the prevention of diabetes and related complications, we hypothesize that ASA might be involved in altering the molecular and metabolic targets affected in type 2 diabetes. Thus our main aim was to elucidate the mechanism of aspirin action in the pathophysiology and progression of disease using an experimental rat model for type 2 diabetes.

Methods: In this study, five month old Goto-Kakizaki (GK) rats, which showed signs of hyperglycemia were used. Two subgroups of GK and Wistar control rats were injected intraperitoneally with 100 mg aspirin/kg/body weight/day for 5 weeks. Animals were sacrificed and blood and tissues were collected after performing glucose tolerance (2 h post 2g IP glucose ingestion) tests in experimental and control groups. Results: Aspirin caused a decrease in hyperglycemia which was accompanied by a significant improvement in glucose tolerance after ASA treatment in GK rats compared to the nondiabetic Wistar rats. Also, the ASA treated GK rats exhibited a significant decrease in insulinemia. ASA treatment caused a marked reduction in the pro-inflammatory prostaglandin, PGE2, which was significantly higher in GK rats. Aspirin treatment also improved energy metabolism in peripheral tissues. On the other hand, no significant organ toxicity was observed after ASA treatment at this dose and time period. However, the total cholesterol and lipoprotein levels were significantly increased in GK rats, which decreased after ASA treatment. Immunofluorescence staining for insulin/glucagon secreting pancreatic cells showed improved β-cell structural and functional integrity in ASA-treated rats which was also confirmed by SDS-PAGE and Western blot analysis.

Conclusion: The improved glucose tolerance in ASA-treated GK rats may be associated with increased insulin responses due to the anti-inflammatory properties of ASA and improvements in ROS/RNS – dependent (oxidative stress related) alterations in mitochondrial functions which facilitated insulin signaling and energy utilization in target tissues. These results may have implications in determining the therapeutic use of ASA in insulin-resistant type 2 diabetes.

Significance: Since the UAE is one of the fastest growing countries where type 2 diabetes is prevalent, our study could help in identifying the metabolic targets affected in diabetes and after treatment with aspirin. The study might be significant in designing therapeutic strategies and in the management of this chronic disease.

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