Review Article
Equine Metabolic Syndrome: A Complex Disease Influenced by Genetics and the Environment

https://doi.org/10.1016/j.jevs.2015.03.004Get rights and content

Abstract

Equine metabolic syndrome (EMS) refers to a cluster of clinical abnormalities including insulin resistance, generalized obesity, and/or increased adiposity in specific locations (regional adiposity) associated with an increased risk of laminitis. However, descriptions of the metabolic phenotype of laminitis-prone horses and ponies have varied among published studies. The metabolic phenotypes routinely measured (e.g., insulin, insulin responses, adipokines, adiposity, and so forth) are highly influenced by the environment and vary due to physiologic factors such as age, breed, and sex, even in normal individuals. Furthermore, not all components of the syndrome (e.g., obesity) may be present in individuals with underlying metabolic derangements. The complexity of the “EMS” phenotype has lead to an ongoing debate as to the canonical features that define the syndrome. Furthermore, little is understood about its pathophysiology. A better understanding of EMS requires a clearer phenotypic definition of EMS; a better grasp of the effects of both intrinsic and extrinsic factors that influence metabolic measures; and an appreciation of the complex interactions between the phenotypic components of the syndrome and the proposed risk factors. In this review, we will summarize the understanding of the EMS phenotype and propose a complex disease model that may help explain the variability in EMS.

Introduction

Equine metabolic syndrome (EMS) refers to a cluster of clinical abnormalities associated with an increased risk of laminitis [1], [2]. In 2002, Johnson [1] recognized that primary features of a laminitis-prone phenotype (i.e., obesity, insulin resistance) were analogous to those described for the metabolic syndrome (MetS) in humans which is a constellation of abnormalities, including obesity, dyslipidemia, glucose intolerance, and hypertension, associated with increased risk of cardiovascular disease and perhaps also type 2 diabetes mellitus [3], [4], [5]. Work by a number of authors has documented similarities between EMS and MetS (Table 1). In 2010, the American College of Veterinary Internal Medicine large animal consensus statement [2] listed several criteria for EMS based on available research data. The three main criteria included: documented or suspected insulin resistance (IR), that is hyperinsulinemia and/or abnormal glycemic and insulinemic responses to oral or IV glucose or insulin challenges; generalized obesity and/or increased adiposity in specific locations (regional adiposity) including the nuchal ligament (“cresty neck”), the tailhead, behind the shoulder, in the prepuce or mammary gland region; and predisposition toward laminitis that develops in the absence of other recognized causes, such as grain overload, retained placenta, colitis, colic or pleuropneumonia. Additional suggested components of the EMS phenotype included: hypertriglyceridemia, dyslipidemia, and increased low-density lipoprotein concentrations [6], [7], [8]; hyperleptinemia [9], arterial hypertension [10], [11], altered reproductive cycling in mares [12], [13], and increased systemic markers of inflammation in association with obesity [14].

Despite this consensus, our understanding of EMS pathophysiology and the risk factors associated with laminitis are still in their infancy. Furthermore, the features that define EMS are a subject of ongoing debate in the veterinary community. Descriptions of the metabolic phenotype of laminitis-prone horses and ponies have varied among published studies (Table 2) [6], [8], [10], [11]. This lack of consensus between reports may be a symptom of study design: for example, unmeasured explanatory variables, insufficient sample size to detect significant effects in the presence of confounding variables, and differences in experimental design including differences in test cohort, breed, or time of sample collection (time of day and/or season). However, this lack of consensus also likely reflects the complexity of the “EMS” phenotype. What has become increasingly clear is that the relationships between the primary phenotypic features and key diagnostic measurements used in clinical and research settings are complex. The metabolic phenotypes routinely measured (e.g., insulin, insulin responses, adipokines, adiposity, and so forth) are highly influenced by the environment and vary due to physiologic factors such as age, breed, and sex, even in normal individuals. Furthermore, not all components of the syndrome (e.g., obesity) may be present in individuals with underlying metabolic derangements. The variability in biochemical measurements and inconsistency in clinical signs between individuals at risk for laminitis makes it difficult to establish clear diagnostic criteria or a consensus phenotype.

A better understanding of EMS pathophysiology requires a more clear phenotypic definition of EMS; a better grasp of the effects of both intrinsic and extrinsic factors that influence metabolic phenotype and phenotypic measures; and an appreciation of the complex interactions between the phenotypic components of the syndrome and the proposed risk factors. In this review, we will summarize the understanding of the EMS phenotype and propose a complex disease model that may help explain the variability in this phenotype.

Section snippets

Insulin Resistance and Hyperinsulinemia

Although our understanding of the etiology and pathophysiology of EMS is far from complete, it seems likely that IR and/or associated hyperinsulinemia play an important role. Insulin resistance is usually defined in terms of the reduced ability of a given concentration of insulin to lower blood glucose levels. Although there has been much discussion about IR in the context of EMS, very few studies have reported quantitative data on insulin sensitivity (SI) and other aspects of glucose and

Proposed Model for EMS Susceptibility

Although environmental factors including excessive nutrition have been linked to EMS, obesity, insulin resistance, and laminitis, the high planes of nutrition and/or changes in the pasture do not result in metabolic derangements and laminitis in all horses. Recent studies indicate this individual variability may be due to an underlying genetic predisposition [6], [11], [74].

Conclusions

The genetics of metabolic trait variation and EMS or laminitis risk in horses is complex, with variability in risk alleles, allele penetrance, environmental risk factors, gene-by-environment, and gene-by-gene interaction all playing a role in an individual's risk. Furthermore, the variable phenotypes across breeds likely reflect the alleles segregating within each breed and their relative importance. Although we have made progress in identifying the breed differences in metabolic phenotypes and

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      Despite the current lack of a single “gold standard” test, insulin dysregulation is the most consistent and objectively measurable factor among the triad of EMS features (i.e., increased generalized or regional adiposity, IR, predisposition for laminitis). Interestingly, a lean phenotype of horses with insulin dysregulation and laminitis has also been observed, as well as obese horses that do not present insulin dysregulation [28]. In human medicine, this last phenotype is defined “metabolically healthy obese” [29–31].

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