Abstract:
Diabetes mellitus is estimated to affect approximately 7% of the populations living a
western lifestyle. Of the multiple etiologies associated with diabetes, heart failure is the
most common cause of death. A specific type of heart disease called diabetic
cardiomyopathy is thought to be partially responsible. At this time, no one specific
treatment is available for diabetic cardiomyopathy due to the wide variety of possible
complex molecular changes, including metabolic disturbances, myocardial fibrosis, LV
hypertrophy, and increased ROS production.
Abnormal copper metabolism in diabetes has been proposed to form part of the
pathway that leads to diabetic cardiomyopathy. Our group have shown that treatment with
the copper (CuII) chelator, triethylenetetramine, ameliorates the effects of diabetes on the
heart at both the functional and molecular level.
This thesis aimed to further these studies by increasing our understanding of the
mechanism of triethylenetetramine action on the diabetic heart. This was primarily
achieved through the use of microarray technology but included the use of a range of
molecular experimental techniques.
During this investigation it was determined that the most suitable microarray
platform for our studies was the Affymetrix GeneChip® system. Using this system we
identified more than 1600 gene changes associated with diabetes in the left ventricle wall.
A disproportionate number of significant messenger RNA transcript changes were
associated with the mitochondria and further investigation of these genes revealed
changes associated with perturbed lipid metabolism and increased oxidative stress.
A second study investigated the molecular mechanisms underpinning improved
cardiac function in the left ventricle of the heart from diabetic and sham animals treated
with triethylenetetramine. There was an observed decrease in diabetic cardiac tissue
triglyceride towards normal, possibly through improvement of the structure and stability of
the mitochondria. Only a small number of changes in gene expression were detected after
triethylenetetramine treatment using microarray technology, and none were detected
using real time-quantitative PCR.
The final aim of this thesis was to understand the absorption and excretion of
triethylenetetramine by both sham and diabetic animals. Our study found differences in
the ability of diabetic animals to absorb and metabolise triethylenetetramine compared to
sham animals. Also, the length of exposure was found to be an influencing factor in
triethylenetetramine metabolism.