Diabetic cardiomyopathy: phenotypes, mechanisms, and therapeutic targets

Thesis (Ph.D.), College of Pharmacy, Washington State UniversityDiabetic cardiomyopathy (DCM) is a syndrome of cardiac dysfunction, fibrosis, and hypertrophy that is often associated with type 2 diabetes mellitus (T2DM) independent of classical risk factors for cardiovascular disease. Identifying specific therapies for DCM has been elusive because the etiology and natural history of this condition are poorly understood. Therefore, the purpose of this dissertation was to investigate the hypothesis that DCM has a unique etiology from other types of hypertrophic disorders, to study the phenotypes and mechanisms of this disease in preclinical animal models of DCM, and investigate new therapeutic targets for the treatment of DCM. Studies in type 2 diabetic (db/db) mice reveal that post-translational protein glycosylation and the activity of histone deacetylase (HDAC) enzymes may be contributing factors to the development of DCM. Several methodological advances are also identified that can be used to improve preclinical DCM research, including a standard protocol for exercise training diabetic mice with a “human" exercise prescription. Finally, systematic analysis of the phenotype of DCM in preclinical animal models highlights confounding effects of species, diabetogenic agents, and laboratory methods that need to be standardized to improve the accuracy and precision of research in this field. Cumulatively, this dissertation provides insight into the preclinical presentation of DCM and potential underlying mechanisms that can be used to inform future research into the etiology and management of this condition.College of Pharmacy, Washington State Universit