"Understanding the relationship between age, diet, and glucose and insulin dynamics in horses is important given their role in equine metabolic disorders such as insulin dysregulation, equine metabolic syndrome (EMS), and pituitary pars intermedia dysfunction (PPID). However, our understanding of the pathophysiology of metabolic disorders is limited, which hampers the development of new treatment and management strategies, and identification of reliable clinical diagnostic tests. In human medicine, the advent of technologies for comprehensive metabolic analysis ("metabolomics") has opened new avenues for understanding metabolic diseases. To date, there has been minimal application of metabolomics for the study of metabolic disorders of horses. Chapter 1 is a literature review that describes the interaction between diet and physiologic state on glucose and insulin dynamics in horses and explores the use of metabolomics to gain insight into the underlying physiology and pathophysiology of healthy and diseased individuals. Chapter 2 describes the effect of age and dietary carbohydrate profiles on glucose and insulin dynamics in healthy horses. Sixteen horses, a combination of Thoroughbred and Standardbred mares and geldings, were divided into two groups by age. Using a balanced Latin square design, horses were fed four isocaloric diets: CONTROL (restricted-starch-and-sugar, fortified pellets), STARCH (control plus kibbled corn), FIBER (control plus unmolassed sugar beet pulp/soybean hull pellets), and SUGAR (control plus dextrose powder). Following dietary adaptation, horses underwent an insulin-modified frequently sampled intravenous glucose tolerance test (FSIGTT), modified oral sugar test (OST), and a dietary meal challenge. Data were analyzed using a multivariable linear mixed regression model. Aged horses had higher insulin responses to both intravenous and oral glucose challenges. However, the effect of diet on glucose and insulin dynamics was variable depending on the method of assessment. Chapter 3 describes the effect of dietary carbohydrate profiles and time of year on adrenocorticotropic hormone (ACTH) and cortisol concentrations in adult and aged horses. Following dietary adaptation, thyrotropin releasing hormone (TRH) stimulation tests and overnight dexamethasone suppression tests were performed in March, May, August, and October. Aged horses had higher baseline ACTH and post-dexamethasone cortisol adapted to the starch-rich diet. After controlling for age and diet, baseline ACTH concentrations were significantly increased in October compared to March, May, and August while post-TRH ACTH was higher in August and October compared to March and May. Postdexamethasone cortisol was significantly higher in October compared to March, May, and August. Diet, age, and time of year are potential confounders on endocrine parameters. Chapter 4 describes the use of untargeted metabolomics for insight into metabolic adaptations associated with age and dietary carbohydrate profiles. The metabolomic analysis was performed on plasma samples before (day 0) and after dietary adaptation (day 42) as well as during a modified oral sugar test (0 minutes and 75 minutes). The metabolomic profile revealed a large number of metabolite ion peaks (> 2000) were significantly different between age groups and diet groups demonstrating changes in cellular metabolism. On-going analysis and improved metabolite identification are needed to fully interpret this dataset. Chapter 5 describes the use of metabolomic approaches for insight into metabolic perturbations in Welsh Ponies with insulin dysregulation, obesity, and history of laminitis. The metabolomic analysis was performed on serum samples obtained at 0 minutes (baseline) and 75 minutes during an oral sugar test (OST). Significant metabolite differences, primarily in the lipid and amino acid pathways, were detected between groups which provides new knowledge regarding the pathophysiology of metabolic perturbations. Chapter 6 focuses on conclusions and future directions based on this research. The effect of age and dietary carbohydrate profiles on glucose and insulin dynamics, ACTH concentrations, and cortisol concentrations are important factors to consider when evaluating hormonal and biochemical parameters. In addition, metabolomics is a powerful tool for defining metabolic changes in different physiologic (age) and pathophysiologic states (insulin dysregulation) and in response to changes in diet."--Pages ii-iii.
Read
