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.

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.

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.

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.