"Equine metabolic syndrome (EMS) and associated insulin dysregulation (ID) have been identified as the most common causes of laminitis. Certain breeds seem susceptible to EMS, and we have identified breed differences in metabolic phenotypes. Muscle and adipose tissue have important roles in glucose and insulin regulation, but little is known about how their biology affects breed-related insulin sensitivity and other metabolic traits. In chapter 2, breed specific differences in insulin and glucose dynamics during three dynamic challenge tests for diagnosing EMS/ID were evaluated. An arginine stimulation test (AST), an oral sugar test (OST) and a frequently sampled insulin modified intravenous tolerance test (FSIGTT) were performed in 27, 82, and 90 individuals representing five different breeds (Quarter Horses [QH], Arabians, Morgans, Welsh Ponies [WP], and Thoroughbreds [TB]). The AST (70 mg/kg bwt intravenous dose of arginine hydrochloride) elicited a significant increase in insulin concentrations in adult horses, which lasted at least 15 minutes and was repeatable. During the OST, insulin but not glucose was useful for diagnosing ID, and insulin thresholds to diagnose ID, which are lower than previous recommendations were established. Longitudinal analysis of insulin and glucose trajectories demonstrated that breed, age, triglycerides, and high molecular weight adiponectin were all associated with differences in the shape of the insulin and/or glucose curve. Minimal model analysis of the FSIGTT was performed and compared between breeds, with QHs having some of the highest insulin sensitivities (SI). In Chapter 3, tail head adipose tissue (TAT) and gluteal muscle biopsies were performed in a cohort of horses and ponies for to identify differences in histologic traits and to evaluate these traits with respect to SI. Overall, measures of adiposity, adipocyte size, and muscle fiber type did not have strong correlations to tissue level SI and the acute insulin response to glucose providing further evidence that horses can demonstrate both a metabolically healthy obese, as well as metabolically unhealthy thin phenotypes. Breed differences existed in adipocyte area, with QH having a significantly smaller mean adipocyte area than both Arabians and WP but not TBs or Morgans. Muscle fiber type total percent area and proportion did not correlate to SI. QH did have a greater area of type 2B to 2A muscle fibers than type 1 fibers. Fiber type area and proportions of fiber types did not significantly differ between breeds. In Chapter 4, middle gluteal muscle and TAT biopsies obtained from 28 geldings from four breeds were examined for differential gene expression and functional analysis using RNASeq and Ingenuity Pathway Analysis. Each breed uniquely differentially expressed genes in each tissue (7- 1347 in adipose, 94-691 in muscle). In TAT, top networks in Arabians and WP were Carbohydrate Metabolism and Developmental Disorders/Lipid Metabolism respectively. Arabians had upregulation, and WP down regulation of peroxisome proliferator activated receptor, co-activation receptor 1. Novel genes and pathways were determined and breed specific patterns of differentially expressed genes may contribute to ID. Unifying themes of Chapters 2-4 were the effect of breed on EMS defining traits, and the need to evaluate the larger picture (systemic, histologic, and transcriptomic) to better understand the true phenotype of a horse or pony that is susceptible to EMS/ID."--Pages ii-iii.
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