Review ArticleFrom Table to Stable: A Comparative Review of Selected Aspects of Human and Equine Metabolic Syndrome
Introduction
In humans, the concept of metabolic syndrome (MetS) was first introduced in the 1970s, and described as a combination of obesity, abnormal glucose regulation, dyslipidemia, and hypertension [1]. The modern definition evolved over the years and presents slight variations based on statements from different medical associations (World Health Organization [2], European Group for the Study of Insulin Resistance [3], American College of Endocrinology [4], American Diabetes Association [5], International Diabetes Federation [6], etc.). Based on these definitions, MetS describes a cluster of risk factors that predispose patients to type II diabetes mellitus (T2DM) and cardiovascular disease (CVD): obesity, insulin resistance (IR), hypertension, and dyslipidemia. The prevalence of MetS is continuously increasing worldwide, affecting on average around 20%–25% of the population, with socioeconomic, ethnic, and age variations [7]. Obesity appears to be the earliest sign in most cases, and its prevalence is ever rising [8]. The World Health Organization reported that in 2016, among the adult worldwide population, 39% were overweight (i.e., body mass index [BMI] ≥ 25 kg/m2), with a third (13%) being obese (BMI ≥ 30 kg/m2) [1].
In parallel with the obesity epidemic in people, companion animals have been experiencing a similar escalation over the past few decades. A multicenter retrospective study published in 2006 showed that, based on data from 1995, 29% of dogs were overweight and 5.1% were obese in the United States [9]. From the same data set, 35% of adult cats were scored as overweight or obese [10], and recent reviews report a feline combined overweight and obesity prevalence of 25%–40% [11], [12]. More recent prevalence data for obesity in companion animals are lacking, but anecdotally the practitioners’ perception is that overweight and obesity are now well above those ranges and still increasing.
As horses have shifted from transportation and farm work to sport and leisure companions, their life span and tendency to become overweight have both increased. As displayed in Table 1, recent studies show an alarming prevalence of overweight horses when scored by experienced investigators in several areas of the world, ranging from 24% to 51%, with an obesity prevalence of 8.3%–23.1% [13], [14], [15], [16], [17], [18], [19], [20], [21]. In all reports in which owners were requested to assess the body condition of their horses, they tended to underestimate it compared with the researcher [13], [15], [20]. Ponies and cobs tended to be more overweight in several studies [17], [18], [20].
A certain proportion of over conditioned horses can present a cluster of symptoms, in which insulin dysregulation is preponderant and represents a strong risk factor for laminitis. This group of risk factors was compared with the human metabolic syndrome in 2002 by Johnson, who suggested that it should be called “equine metabolic syndrome” (EMS) [22]. In 2010, the consensus statement of the American College of Veterinary Internal Medicine (ACVIM) [23] defined the most common EMS phenotype as having increased generalized or regional adiposity, IR, and a predisposition for laminitis. Since then, equine endocrinopathies have become the most commonly diagnosed cause of laminitis [24], identifying EMS as a source of major welfare concerns. Consequently, scientists have been investigating the syndrome from many different viewpoints, culminating in the publication of a new consensus statement by the European College of Equine Internal Medicine (ECEIM) [25].
The objective of the present review was to summarize recent advances in the characterization of EMS, with particular focus on the inflammatory, oxidative, cardiovascular, and neuropathic mechanisms and to compare these findings with the current knowledge about MetS.
The literature search was performed between September 2017 and March 2019 on PubMed, Google Scholar, and the University of Saskatchewan library database.
Section snippets
Insulin Dysregulation in MetS and EMS
Insulin dysregulation and its diagnosis in the horse have been reviewed in recent publications [26], [27]. 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
Metaflammation
The term metaflammation defines a low-grade, chronic inflammatory state originated by an aberrant immune response to excessive availability of nutrients and propagated by the consequent reaction of tissues involved in metabolism, in particular the adipose tissue [42].
Oxidative and Dicarbonyl Stress
Oxidative stress, defined as an imbalance between antioxidant mechanisms and production of reactive oxygen species, has been observed in conjunction with obesity and insulin dysregulation in humans [78]. Lower levels or inadequate intake of vitamins, such as vitamin A, C, and E [79] and microelements, such as magnesium [80] and selenium [81] have been associated with reduced efficacy of antioxidant systems in obesity and MetS in humans. The adipokine leptin, which increases in adipose tissue
Macrovascular and Microvascular Complications of Metabolic Syndrome
A person with MetS has a threefold risk of cardiovascular disease compared with a healthy person, and 5 times greater chance to develop T2DM [7], which frequently has long-term cardiovascular consequences. In human medicine, cardiovascular complications are further classified as macro- and microvascular, with possible common pathogenic mechanisms that involve AGEs, oxidative stress, and low-grade chronic inflammation [92].
Macrovascular disease in humans encompasses ischemic heart disease,
Neuropathy: Human Diabetic Foot and Equine Laminitis
Oxidative stress and microvascular injury are the underlying mechanisms of nerve damage involved in sensorimotor and autonomic neuropathies. These pathologies have a significant prevalence as complications of type I and type II diabetes mellitus, but are also frequently found in prediabetic patients, where the neuropathy can be the first sign of disease [110]. MetS and obesity have been strongly associated as risk factors to some of these neuropathies, such as the distal symmetric sensory
Conclusions
In light of the expanding trans-species obesity epidemic, a shift has occurred in what owners (and parents/caregivers) perceive as a “normal” body condition of their animals (and children) [118]. As in humans, this shift increasingly affects pets' and horses’ welfare and promotes future negative health outcomes. Without being an exhaustive review of the complex mechanisms involved in EMS, the aim of this article was to collect recent work that has been produced in human and equine medicine
Acknowledgments
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Authors' contributions: V.M.R. contributed to conceptualization, investigation, writing–original draft, review and editing. G.A.Z. contributed to conceptualization, resources, writing–review and editing, supervision. C.D.K. contributed to investigation, data curation, writing–review and editing, visualization. J.B.M. contributed to conceptualization, resources,
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Cited by (13)
Equine insulin dysregulation causes tissue specific alterations of proinflammatory cytokines and acute phase proteins in a NF-kB independent manner
2022, Veterinary Immunology and ImmunopathologyCitation Excerpt :Interestingly, an upregulation of mRNA level of the above mentioned acute phase proteins (i.e., HSP90, A2M, fibrinogen) was reported in lamellae following a prolonged insulin infusion (Campolo et al., 2020). However, the pathogenic role of pro-inflammatory cytokines remains under investigated in equids with naturally occurring insulin resistance (Waller et al., 2012; Waller et al., 2011). Therefore, the objective of this study is to understand novel inflammatory pathways underlying equine insulin resistance and identify specific biomarkers and therapeutic targets for the condition.
Continuous digital hypothermia reduces expression of keratin 17 and 1L-17A inflammatory pathway mediators in equine laminitis induced by hyperinsulinemia
2021, Veterinary Immunology and ImmunopathologyCitation Excerpt :Such an experimental system is available through the euglycemic/hyperinsulinemic clamp (EHC) model, which mimics naturally-occurring endocrinopathic laminitis driven by excess insulin (Asplin et al., 2007; De Laat et al., 2010). Laminitis develops rapidly in this model, demonstrating that hyperinsulinemia is sufficient to compromise the function of the lamellar tissue linking the inner hoof wall to the distal phalanx (van Eps and Burns, 2019; Ragno et al., 2019). Treatment with continuous digital hypothermia (CDH) during the experimental protocol prevents tissue failure (Stokes et al., 2019) and limits expression of some inflammatory mediators (Stokes et al., 2020).
Morphometric, metabolic, and inflammatory markers across a cohort of client-owned horses and ponies on the insulin dysregulation spectrum
2021, Journal of Equine Veterinary ScienceCitation Excerpt :As only few studies have explored local adipose tissue inflammation in the nuchal ligament [17,24] and other sites [24,48], this area of EMS research warrants further consideration. Owners have been repeatedly reported to underestimate horses’ body condition and adipose distribution [15,49]. This finding re-emphasizes the importance of client education in monitoring not only for generalized over conditioning but especially for localized adiposity, which can lead to early screening and timely management of ID.
Animal welfare/ethical statement: The authors declare that no animals or client data were used in the preparation of this review manuscript, therefore no ethical approval was needed.
Conflict of interest statement: The authors declare no conflicts of interest.