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.

Introdução: Ratos com diabetes induzido por estreptozotocina (STZ) apresentam alterações nos proteoglicanos Sindecan-4 e Glipican-1 no tecido cardíaco concomitantes à instalação da disfunção diastólica, evento precoce que culmina na cardiomiopatia diabética. O uso de resveratrol (RSV) em modelos animais foi capaz de melhorar a função cardíaca e o controle autonômico. Espera-se que o tratamento com esse flavonoide atue nos níveis alterados dos proteoglicanos em animais diabéticos. Objetivo: Avaliar o efeito do RSV nos parâmetros cardiovasculares e na expressão dos proteoglicanos no músculo cardíaco. Materiais e Métodos: Foram avaliados ratos Wistar machos, com doze semanas de vida, divididos em 4 grupos: controle (C, N=8); controle + RSV (CR, N=8); diabetes STZ + nicotinamida (D, N=8) e diabetes STZ + nicotinamida + RSV (DR, N=8). Foram dosados os níveis séricos de glicose, de triglicérides e foi feito o teste de resistência à insulina. Registros diretos das curvas de pressão arterial foram realizados para a análise da variabilidade da frequência cardíaca (VFC) e variabilidade da pressão arterial sistólica (VPAS) no domínio do tempo e da frequência. A sensibilidade barorreflexa foi avaliada por meio de drogas vasoativas e a função cardíaca foi avaliada por ecocardiografia de alta resolução. A localização das proteínas no tecido cardíaco foi feita por imunohistoquímica. Análise estatística utilizada: ANOVA post test Student Newman-Keuls. p < 0,05. Resultados: O peso corporal dos grupos C e CR aumentou significativamente do inicio ao final do protocolo, enquanto os grupos D e DR mantiveram seu peso inicial. A concentração de glicose sérica e dos triglicerídeos, os grupos C e CR não demonstraram diferença ao longo do protocolo, enquanto os grupos D e DR demonstraram significante aumento ao final do protocolo. Os valores de concentração de insulina, do teste de tolerância à insulina e do índice de Lee foram menores nos grupos D e DR quando comparados aos grupos C e CR. A pressão arterial sistólica foi menor nos grupos diabéticos quando comparado aos grupos controles (C e CR) o mesmo acontecendo para os valores da frequência cardíaca. A pressão arterial diastólica apresentou valores semelhantes entre os grupos C e CR e o grupo DR, somente o grupo D apresentou queda quando comparado aos outros três grupos, a pressão arterial media apresentou esse mesmo comportamento. Não foram observadas diferenças para a sensibilidade barorreflexa tanto para a resposta bradicárdica como para a resposta taquicárdica entre os grupos. Nas avaliações da VFC foi observado o aumento do Intervalo de Pulso (IP) nos grupos D e DR quando comparados aos grupos C e CR, mas foram semelhantes entre os grupos controles e diabéticos (C vs. CR e D vs. DR, respectivamente). Na VPAS os grupos D e DR apresentaram diminuição tanto no desvio padrão (DP PAS) quanto na variância (VAR PAS) quando comparados aos grupos C e CR, não houve diferença entre os grupos controles e diabéticos (C vs. CR e D vs. DR, respectivamente). A disfunção diastólica foi detectada no grupo D. A expressão das proteínas Glypican-1 e Syndecan- 4, foram significantemente maiores no grupo D quando comparada aos demais grupos e menos expressas no grupo DR quando comparada aos demais grupos. Conclusões: A administração de RSV reverteu tanto alterações morfológias como a função cardíaca global que voltou a apresentar valores muito próximos aos valores de normalidade, sem alterar as condições hemodinâmicas e autonômicas / Introduction: Streptozotocin-induced rats model show changes in proteoglycans sindecan-4 and glipican-1 in cardiac tissue concomitantly with installation of diastolic dysfunction, which is an early event that culminates in diabetic cardiomyopathy. The use of resveratrol (RSV) in animal models showed the improvement of cardiac function and autonomic control. It is expected that the treatment with this flavonoid act on altered levels of proteoglycans in diabetic rats. Objective: To evaluate the effects of resveratrol in cardiovascular parameters and the expression of proteoglycans in cardiac muscle. Material and Methods: Male Wistar rats (12 weeks old) were allocated into 4 groups: control (C, N=8), controle+RSV (CR, N=8), Diabetes STZ + nicotinamide (D, N=8) and diabetes STZ+ nicotinamide + RSV (DR, N=8). Serum levels of glucose, insulin resistance test and triglycerides were measured in order to evaluate diabetes. Arterial blood pressure records were measured in order to analyze the heart rate variability (HRV) and systolic blood pressure variabilities in frequency and time domain. The baroreflex sensivity was evaluated by vasoactive drugs infusion and the evaluation of cardiac function by high resolution echocardiography. The location of the proteins in the heart tissue was performed by immunohistochemistry. Statistics and performed analysis used: ANOVA post test Student Newman-Keuls. p < 0,05. Results: Our results showed that the body weight of groups C and CR increased significantly from the beginning to the end of the protocol, while the groups D and DR continued to have the initial weight. Regarding serum glucose concentration and triglycerides, there were no statistically significant differences between group C and CR while the group D and DR increased significantly at the end of the protocol. The values of insulin concentration, insulin tolerance test and the Lee index were lower in groups D and DR when compared to groups C and CR. The hemodynamic parameters demonstrated that systolic blood pressure was lower in diabetic groups when compared to control groups (C and CR) as well as the heart rate values. Interestingly, diastolic blood pressure showed similar values between groups C, CR and group DR. The group D decreased its diastolic blood pressure when compared to the other groups, as well as the blood pressure mean. There were no significant differences either to baroreflex sensivity, bradicardiac response and tachycardia between both groups. The evaluation of heart rate variability (HRV) showed an increase of pulse interval (PI) in groups D and DR when compared to groups C and CR. The evaluation of systolic blood pressure variability of the groups D an DR showed a decrease in both the standard deviation (SD PAS) and variance when compared to groups C and CR and there were no differences between the diabete groups and the control (C vs CR and D vs DR respectively). The diastolic disfunction was detected in group D. The Glypican-1 and Syndecan-4 protein expression were significantly higher in group D when compared to the other groups and less expressed in group DR when compared to the other groups. Conclusion: The administration of RSV reversed both morphological changes and the global cardiac function, which showed very close values to the normal range values, without changing the hemodynamic and autonomic conditions

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Hyperglycemia and dyslipidemia are common comorbidities that often coincide and have a significant impact on the severity of diabetes. This current study investigates the pathology and mechanism behind skeletal muscle cachexia and cardiac dysfunction in diabetic dyslipidemia. Stem cells continue to be critical as a regenerative strategy to restore damaged tissue, however, several drawbacks have been observed with use of stem cells including thrombogenesis, low survival, and tumorigenicity. Therefore, we isolated exosomes from stem cells and assessed their ability to attenuate diabetes-induced sarcopenia and cardiomyopathy. Exosomes are nanosized particles released by cells, containing proteins and nucleic acids that allow it to exhibit similar properties to the cell type of origin. To model diabetic dyslipidemia, we utilized ApoE knockout mice (10±2 weeks) and divided them into 4 groups consisting of control (saline intraperitoneal (IP) injection), diabetic (STZ IP injection), treatment group administered intravenous (IV) exosomes derived from miR-1 ES-Exos (microRNA-1 enriched Embryonic Stem Cells) or MSC-Exos (Mesenchymal Stem Cells), and negative control treatment MEF-Exos (Mouse Embryonic Fibroblasts). Heart and soleus tissue samples were analyzed for inflammation, inflammatory cell death expression, and adverse tissue remodeling using histology, immunohistochemistry, western blotting, RT-PCR, cytokine, and luciferase-based arrays. In summary we found diabetic dyslipidemic mice acquire cardiac and skeletal muscle dysfunction. Administration of miR-1 ES-Exos and MSC-Exos significantly mitigated inflammation and cell death marker expression, resulting in improved cardiac and skeletal muscle function. In conclusion our data shows that miR-1 ES-Exos and MSC-Exos are effective therapeutic agents in attenuating diabetes-induced sarcopenia and cardiomyopathy.

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