Clinical Techniques
Metabolic Predispositions to Laminitis in Horses and Ponies: Obesity, Insulin Resistance and Metabolic Syndromes

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Abstract

Equine veterinarians have long recognized an association between metabolic abnormalities, notably obesity and insulin resistance (IR), and increased risk for laminitis in horses and ponies. Recent observational studies have provided evidence that an insulin-resistant phenotype is strongly linked with a predisposition to laminitis. Although descriptions of this laminitis-predisposed phenotype have varied, in general there is a clustering of obesity (generalized or localized), IR, hyperinsulinemia, and hyperleptinemia. The observation that laminitis can be induced in healthy ponies by maintaining supraphysiologic circulating insulin (1,000–1,100 mU/L) concentrations for 2 to 3 days suggests that hyperinsulinemia may play a direct role in the pathogenesis of laminitis in susceptible animals. Therefore, laminitis may be triggered in a chronically insulin-resistant horse or pony under conditions that exacerbate IR or hyperinsulinemia, for example, the grazing of pasture with high nonstructural carbohydrate content (eg, during spring or when pastures are stressed by drought or frost), consumption of other feeds rich in starch and sugars (grains, sweet feeds), overfeeding that induces or worsens obesity, and the administration of corticosteroids. Identification of insulin-resistant horses and ponies at high risk for laminitis facilitates preemptive avoidance measures with a focus on strategies that (1) improve insulin sensitivity (eg, caloric restriction, increased exercise, judicious use of pharmacologic agents [levothyroxine sodium, metformin]) and (2) minimize exposure to environmental factors that increase risk of laminitis (elimination of grains and sweet feeds from the diet, restricted access to pasture during high-risk periods such as spring).

Introduction

Equine practitioners have long recognized that metabolic and endocrine abnormalities, notably obesity, insulin resistance (IR), and pituitary pars intermedia dysfunction (PPID), are associated with increased risk of laminitis in horses and ponies. These clinical observations have been supported by recent studies showing a strong association between a certain metabolic phenotype and predisposition to laminitis, particularly the pasture-associated form of this disease.1, 2, 3, 4, 5 The purpose of this review is to discuss current knowledge concerning metabolic predispositions to laminitis in horses and ponies, with emphasis on the role of obesity and IR. The implications for avoidance of laminitis in susceptible animals are also briefly discussed.

Obesity may be defined as the excessive accumulation of adipose tissue in the body. In human medicine, body mass index (BMI, kg/m2) is used to define people as normal weight (BMI 20–25), overweight (BMI 25–29.9), obese (BMI 30–34.9), or severely obese (BMI >35).6 A normal-weight obese syndrome also has been described in people. This syndrome is characterized by a normal body weight and BMI but a high fat mass (>30% of body weight), and evidence of a pro-inflammatory state that, like other forms of obesity, is a risk factor for diabetes and cardiovascular disease.7

There is no universally accepted definition of obesity in horses and ponies. According to the body condition scoring system (BCS) developed by Henneke et al,8 horses or ponies with a BCS of 8 (fat) or 9 (extremely fat) can be defined as obese, and animals with a BCS of 7 might be considered overweight if not obese. A body mass index (estimated weight/height2 = kg/m2) has been applied to horses and found to be moderately correlated (r = 0.60) with BCS.9 One limitation of BCS and BMI systems for assessment of obesity is the failure to detect differences in regional adiposity that may signify increased risk of disease. In humans, visceral (abdominal) adiposity is more closely linked to risk for diabetes and cardiovascular disease than generalized obesity, and measurement of waist circumference is a better indicator of abdominal fat accumulation than is BMI.10, 11 In horses and ponies, there may be a similar association between regional adiposity and disease risk. In our own studies of equids predisposed to pasture-associated laminitis, some affected animals are not obese on the basis of BCS (ie, BCS < 7) but have enlarged fat deposits on the neck (“cresty neck”), thoracic, or tailhead regions; these fat deposits are sometimes asymmetric in distribution.12

Few studies have examined the prevalence of obesity in horse and pony populations. The 1998 National Animal Health Monitoring System (NAHMS) study estimated that 4.5% of the horse population in the United States was overweight or obese.13 However, the accuracy of this estimate may be questioned because it was based on owner reporting, not the results of physical examination. In a recent prospective study of 300 randomly selected mature horses, 57 (19%) were classified as obese (BCS 7.5–9.0) (Craig Thatcher, Virginia Tech, unpublished observations 2007), a prevalence far higher than the NAHMS study estimate.

The metabolic actions of insulin maintain whole body glucose homeostasis and promote efficient glucose utilization. Insulin stimulates glucose uptake into skeletal muscle and adipocytes and glycogen synthesis in muscle and liver, with simultaneous inhibition of gluconeogenesis in liver to assist with regulation of glucose homeostasis.14 Besides carbohydrate metabolism, insulin participates in a wide array of physiologic processes, including stimulation of fatty acid and triglyceride synthesis in liver and adipose tissue, inhibition of lipolysis, enhancement of protein anabolism, cell growth and survival, regulation of vascular endothelial function, and anti-inflammatory effects.15, 16 At the cellular level, insulin promotes its action by binding to its specific receptor, with activation of a cascade of intracellular signaling events. In skeletal muscle, these events result in recruitment of the glucose transport protein GLUT-4 to the cell surface, thereby facilitating glucose uptake.14 With regard to insulin action on glucose metabolism, the maximal effect of insulin defines “insulin responsiveness,” whereas the insulin concentration that elicits a half-maximal response defines “insulin sensitivity.”17 Insulin resistance is usually defined as decreased sensitivity or responsiveness to insulin-mediated glucose disposal or inhibition of hepatic glucose production.18 In humans, IR plays a central role in the pathophysiology of type 2 diabetes mellitus and is highly associated with other important health problems, including obesity, hypertension, and a cluster of metabolic and cardiovascular abnormalities termed the metabolic syndrome.19 The mechanisms of IR are not completely understood, but recent studies suggest that IR develops as a consequence of inflammation in adipose tissue and the liver and the accumulation of by-products of nutritional overload (eg, diacylglycerol, ceramides) in insulin-sensitive tissues such as skeletal muscle.20

The association between IR and laminitis risk in equids has heightened interest in the causes, consequences, diagnosis, and treatment of this condition. In horses and ponies, as in humans, obesity appears to be an important causative factor,21 although it is important to recognize that not all obese horses are insulin resistant and that IR can occur in nonobese animals.4, 5 Studies in humans and animal models have demonstrated that obesity induces a chronic inflammatory state, and this inflammation plays an important role in the pathogenesis of IR.16, 20 Similarly, Vick et al22 reported associations between obesity and blood mRNA expression of tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1β) in horses, suggesting that systemic inflammation may play a role in the IR of obesity. Some equids with PPID are insulin resistant, and this condition may predispose to laminitis, which is a common occurrence in PPID.23 In one report, hyperinsulinemia was associated with poor long-term survival in horses with suspected PPID.24 Diet is another factor that modifies insulin sensitivity. Studies in healthy horses have shown that chronic adaptation to sweet feeds rich in nonstructural carbohydrates (starch and sugars) results in decreased insulin sensitivity.25

In human medicine, metabolic syndrome is a set of diagnostic criteria that identifies individuals at high risk for morbidity associated with IR, primarily type 2 diabetes and cardiovascular disease.26, 27 Although the criteria for diagnosis of metabolic syndrome vary, the core components are obesity (especially visceral), IR, dyslipidemia, and hypertension. Several mechanisms likely contribute to the association between the metabolic syndrome cluster and increased risk of cardiovascular disease, but a common view is that IR plays a central role in the development of pathologic manifestations.19 Indeed, the term insulin resistance syndrome has also been used to describe the cluster of abnormalities that portend increased risk for cardiovascular disease.28

In horses and ponies susceptible to recurrent laminitis, an insulin-resistant phenotype resembling the human metabolic syndrome has been described.1, 2, 3, 4, 5 Descriptions of this laminitis-predisposed phenotype have varied but have included a clustering of obesity (generalized or regional), IR, hyperinsulinemia, hyperleptinemia, mild hypertriglyceridemia, and current or historical (eg, founder lines) evidence of laminitis.1, 2, 3, 4, 5, 11 Johnson29 proposed use of the term equine metabolic syndrome (EMS) to describe horses and ponies with this phenotype, whereas Treiber et al1 coined pre-laminitic metabolic syndrome (PLMS) for identification of a set of risk factors in Welsh and Dartmoor ponies that predict increased risk of pasture-associated laminitis. The EMS phenotype has been described in several breeds, but it may be more common in Morgans, Paso Finos, Arabians, Saddlebreds, and Norwegian Fjords.29

As with the human metabolic syndrome, it is hypothesized that IR and associated hyperinsulinemia are pivotal in the pathologic manifestations of EMS (or PLMS), in particular susceptibility to laminitis. It has also been proposed that one or more genetic polymorphisms underlie EMS and PLMS. In the aforementioned Welsh and Dartmoor pony herd studied by Virginia Tech, pedigree analysis suggested a dominant mode of inheritance for the PLMS phenotype, supporting the possibility of a genetic basis for the IR and susceptibility to pasture-associated laminitis in this population.1 Further studies in more outbred populations are required to confirm these findings. Nonetheless, it is tempting to speculate that these susceptible ponies have a “thrifty genotype” in which, at least in part, the IR is an adaptive strategy for survival in nutritionally sparse environments. However, this strategy may fail when these animals are exposed to high-carbohydrate diets, with development of obesity, exacerbation of IR, and increased risk of laminitis.1, 2 A similar scenario may contribute to the suggested increased susceptibility of “easy keeper” horses (eg, Morgan, Arabians, Paso Fino, and Spanish Mustang breeds) to pasture-associated laminitis.

The idea that IR and hyperinsulinemia are involved in the pathogenesis of laminitis is not new. Studies in the 1980s reported lower insulin sensitivity in ponies that suffered recurrent laminitis compared with healthy controls, based on blood glucose responses during insulin30 or glucose31 tolerance tests. These observations have been supported by more recent studies that have sought to characterize the phenotype of ponies and horses apparently predisposed to recurrent laminitis.1, 2, 3, 4, 5, 32

Treiber et al1 evaluated a herd of pure and crossbred Welsh and Dartmoor ponies and statistically derived a set of risk factors for laminitis (termed the PLMS) based on physical and metabolic differences between ponies with a history of previous laminitis (PL) versus ponies with no such history (NL). The risk factors were (1) insulin resistance (RISQI < 0.32 [mU/L]-0.5), where RISQI is calculated as the inverse of the square root of plasma or serum insulin; (2) compensatory β-cell secretory response (MIRG >5.6 mU2/[10.L.mgglu]), where MIRG is a modified insulin-to-glucose ratio; (3) hypertriglyceridemia (plasma triglycerides >57.0 mg/dL); and (4) obesity (body condition ≥6 on a scale of 1–9, with localized fat deposits on the neck and tailhead). The PLMS criteria predicted 11 of 13 cases of clinical laminitis observed in May of the same year, with an odds ratio of 10.4. In other words, the previously laminitic ponies were at approximately 10 times higher risk for development of laminitis when grazing spring pasture compared with non–insulin-resistant ponies. Subsequent studies that applied minimal model analysis of a frequently sampled intravenous glucose tolerance test (FSIVGTT) confirmed profound IR with an exaggerated insulin response to glucose administration in a subset of the laminitis-prone ponies.32 Furthermore, episodes of laminitis in these ponies are preceded by exacerbation of hyperinsulinemia (Geor RJ, unpublished data), an interesting observation in light of the recent finding that prolonged periods (48–72 hours) of hyperinsulinemia result in laminitis in otherwise healthy ponies.33

Further evidence of the association between IR and predisposition to laminitis has come from studies of nonobese, mixed-breed ponies in the United Kingdom.4, 5 Consistent with the observations of Treiber et al,1 minimal model analysis of an FSIVGTT showed that laminitis-prone ponies were insulin resistant with an exaggerated insulin response to intravenous glucose administration when compared with age- and body condition–matched ponies with no history of the laminitis.4 Although basal insulin concentration was similar between the two groups when fed a hay diet, the laminitis-prone ponies had substantially higher serum insulin concentrations compared with control ponies when grazing high-carbohydrate pasture and demonstrated exaggerated increases in serum insulin in response to the feeding of fructan carbohydrate.4 Thus, diet composition—especially the type and amount of carbohydrate—is important in the clinical expression of hyperinsulinemia in insulin-resistant, laminitis-prone ponies.

This hypothesis is supported by the findings of a second study by Bailey et al5 in which the phenotypes of 40 laminitis-prone ponies and 40 control ponies were compared when ponies were grazing winter (December) and summer (June) pasture. In summer, but not winter, the laminitis-prone ponies had higher blood pressure and serum concentrations of insulin, triglycerides, and uric acid, suggesting that consumption of summer pasture (higher in nonstructural carbohydrates including fructans) may induce expression of a prelaminitic phenotype that includes hyperinsulinemia and hypertension.5

There are minimal published data on the possible association between IR and laminitis in horses, although clinical observations have associated hyperinsulinemia and glucose intolerance with increased risk of laminitis in horses of various breeds.3, 29, 34 It is worth mentioning that insulin sensitivity is markedly lower in ponies when compared with horse breeds,2 potentially explaining the apparent higher susceptibility of pony breeds to pasture laminitis reported in some epidemiologic studies.

There is some evidence that obesity or regional adiposity are predisposing factors for laminitis in horses and ponies. In a prospective case-control study of 258 cases of laminitis seen at six veterinary teaching hospitals, a cresty neck was found in significantly more cases than controls.35 Additionally, obesity has been a feature in some1, 3, 11 but not all4, 5 studies describing the phenotype of laminitis-prone horses and ponies. However, it has not been established whether obesity per se raises the risk of laminitis (eg, via mechanical overload of the hooves secondary to increased body mass) or if the increased risk is attributable to other factors such as IR and inflammation, which are consequences of obesity.21, 22

The mechanisms linking IR and laminitis have not been elucidated. One theory is that IR impairs glucose uptake by lamellar epithelial cells. In vitro studies have suggested that hoof tissues have a high requirement for glucose, evidenced by pronounced dermal–epidermal separation when explants of hoof tissue are deprived of glucose.36, 37 Furthermore, Mobasheri et al38 determined that GLUT-4 proteins are present in equine keratinocytes, suggesting that insulin-stimulated glucose uptake may occur in the hoof. However, in a recent report, GLUT-4 was not detected in laminar tissue, and glucose uptake in lamellar explants was independent of insulin.39 Thus, it is likely that other mechanisms underlie the link between IR and laminitis.

An alternate explanation is that IR predisposes equids to laminitis via disturbances in vascular function that render the laminae more susceptible to injury when exposed to other factors promoting the development of laminitis (eg, carbohydrate overload). Studies in humans and other species have shown that the vascular endothelium is responsive to insulin, with insulin stimulating both vasodilatory and vasoconstrictive pathways.40 Insulin stimulates production of the vasodilator nitric oxide (NO) via the phosphatidylinositol 3-kinase (PI-3K) pathway, but also activates release of endothelin-1 (ET-1), a potent vasoconstrictor, through the mitogen-activated protein kinase (MAPK) pathway.40 In insulin-resistant states, there is impairment to PI-3K activation (contributing to disrupted glucose disposal), whereas the MAPK pathway is unaffected and may even be over stimulated in the face of hyperinsulinemia. Thus, there is potential for vasoconstriction caused by an imbalance between the production of NO and ET-140; similar events in the vasculature of the hoof could contribute to vasospasm and lamellar ischemia. Vascular endothelial dysfunction associated with IR is thought to underlie the hypertension observed in humans with metabolic syndrome.16, 40 The recent report by Bailey et al5 in which hypertension was observed in insulin-resistant, laminitis-prone ponies at summer pasture suggests that vascular endothelial dysfunction also is a component of the metabolic syndrome phenotype in equids.

Development of a chronic, pro-inflammatory state is another possible mechanism underlying increased susceptibility to laminitis in equids with an insulin-resistant phenotype. Studies in humans and animal models have shown that inflammation plays an important role in the pathogenesis of IR, evidenced by improvement in insulin sensitivity after high-dose aspirin (salicylates) treatment.41, 42 Furthermore, there now is strong evidence that obesity-associated IR is attributable to a pro-inflammatory state that originates in adipose tissue.20, 41, 42 Adipocytes produce a large array of adipokines (hormones and cytokines, eg, leptin, TNF-α, and IL-1β, IL-6, and IL-8), many of which are pro-inflammatory.43 In obesity, there is a progressive dysregulation of adipose function with increased adipokine production, increased recruitment of monocytes to adipose tissue, and amplification of the inflammatory response.41, 43 Systemic release of these inflammatory molecules leads to disruption of insulin signaling in multiple tissues (eg, skeletal muscle, vascular endothelium) and development or exacerbation of IR and other effects such as vascular endothelial dysfunction.20 As mentioned, preliminary studies in horses and ponies have provided evidence that inflammation may be a factor in obesity-associated IR. Blood TNF-α and IL-1β mRNA expression was higher in obese horses and identified as an independent risk for IR,22 whereas increased serum TNF-α concentrations have been observed in a well-characterized population of insulin-resistant, laminitis-prone ponies.44 Further research is required to determine whether and how IR-associated (or obesity-associated) inflammation contributes to laminitis susceptibility.

Another piece of the laminitis puzzle yet to be unraveled is the mechanism(s) that triggers episodes of laminitis in horses and ponies with an insulin-resistant phenotype. The recent finding that laminitis can be induced in healthy ponies by maintaining supraphysiologic circulating insulin concentrations (serum insulin approximately 1,000–1,100 mU/mL) for 2 to 3 days suggests that hyperinsulinemia could play a direct role in the pathogenesis of laminitis.33 Thus, it is reasonable to hypothesize that laminitis may be triggered in a chronically insulin-resistant horse or pony under conditions that exacerbate IR or hyperinsulinemia—such conditions would include grazing pasture with high nonstructural carbohydrate content (eg, during spring or when pastures are stressed by drought or frost),1, 2 consumption of other feeds rich in starch and sugars (eg, sweet feeds),25 overfeeding that induces or worsens obesity,21, 22 the administration of corticosteroids,45 or episodes of endotoxemia.46 In support of this, we have observed a marked increase in the serum insulin concentrations of laminitis-prone ponies during the transition from winter to spring in association with an increase in forage water-soluble carbohydrates (which include simple sugars and fructans), with the most profound increases observed in ponies that subsequently developed laminitis.47 Similarly, Bailey et al4 reported exacerbation of hyperinsulinemia in laminitis-prone ponies, but not control ponies, in response to an increase in dietary fructan (both the controlled feeding of inulin, a type of fructan, and a switch from a low-fructan hay diet to pasture grazing).

Alternatively, disturbances to hindgut fermentation and bacterial flora, as occurs in the starch or fructan overload models of laminitis,48, 49, 50 may be primary in the triggering of disease in animals with an insulin-resistant phenotype. However, as first proposed by Dr. Nicholas Frank,34 the threshold for induction of laminitis may be lower in insulin-resistant horses and ponies when compared to animals with normal insulin sensitivity. With carbohydrate overload, there are major alterations within the hindgut, including proliferation and lysis of streptococcal species, a decrease in pH, and an increase in intestinal permeability.50 The latter promotes entry of endotoxins, other bacterial components, and vasoactive amines into circulation50 with initiation of a systemic and lamellar inflammatory response that triggers laminitis.51 It is possible that these inflammatory responses are heightened in insulin-resistant animals with an existing pro-inflammatory state—or, viewed another way, the quantity of starch or fructan required to trigger lamellar inflammation that results in clinical laminitis may be lower in these susceptible animals.

From the preceding discussion, it is clear that IR, hyperinsulinemia, and obesity are associated with increased risk for development of laminitis. Recognition of these predisposing factors justifies (1) clinical evaluation of insulin resistance in horses or ponies with a history of recurrent laminitis or clinical signs suggestive of metabolic (eg, obesity, a cresty neck) and endocrine (ie, PPID) abnormalities associated with heightened incidence of laminitis; and (2) instigation of counter-measures to IR and obesity such that future episodes of laminitis may be avoided.

Insulin sensitivity/resistance can be assessed by dynamic evaluation of glucose and insulin responses or by simple analysis of steady-state (ie, resting) blood glucose and insulin concentrations. Gold standard, dynamic tests such as Minimal Model analysis of an intravenous glucose tolerance test, and the euglycemic-hyperinsulinemic provide a direct measure of insulin sensitivity but are impractical in clinical settings. Conversely, single-sample measurements of basal (resting) blood glucose and insulin concentrations are useful for screening evaluation because IR in horses and ponies is often characterized by hyperinsulinemia and normoglycemia, indicative of compensated IR.1, 2, 3, 4 Although more work is needed to determine appropriate cutoffs, a serum insulin concentration greater than 30 mU/L (where 1 mU/L = 1 μU/mL) has been used to diagnose IR.34 Standardization of sampling and analytical procedures is critical for reliable interpretation of results because a large number of animal and environmental factors can affect basal insulin and glucose concentrations. Stress associated with a change in housing, feed withholding, or sampling procedures may result in hyperglycemia and hyperinsulinemia. Additionally, diet composition, particularly the nonstructural carbohydrate (starch and sugars) content of feeds and forages, can markedly impact insulin concentration.33, 47 A suggested sampling protocol is as follows: Grain and commercial concentrates and sweet feeds should not be fed during the 12-hour period before sampling. However, grass hay should be provided, for example, 1 to 2 flakes overnight, with blood drawn between 7:00 am and 10:00 am. For animals maintained at pasture, removal from pasture to a drylot or stall for a 10- to 12-hour period before sampling is recommended, especially during periods of active forage growth (eg, spring) when the high sugar content of pasture forage can affect resting blood glucose and insulin concentrations. Insulin assays vary between commercial laboratories, so use of a single laboratory, preferably one with appropriately developed equine reference ranges, is recommended for measurement of serum insulin concentration. In laminitic animals, testing should be delayed until after resolution of the acute laminitic episode because the associated pain and stress will exacerbate IR and hyperinsulinemia.

A detailed discussion on this topic is beyond the remit of this review, and the reader is referred elsewhere for further information.34, 52, 53 In brief, lowering the risk of laminitis involves instigation of interventions that (1) improve insulin sensitivity and alleviate hyperinsulinemia, and (2) prevent or minimize exposure to environmental conditions (eg, “lush” spring pasture) known to trigger laminitis in these susceptible animals. Such interventions include a reduction in dietary energy (caloric intake), decreased dietary nonstructural carbohydrates, restricted access to pasture during high-risk periods, increased physical activity, and, in refractory cases, the use of pharmacologic agents (eg, levothyroxine sodium, metformin) that increase insulin sensitivity or promote weight loss.

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    Presented at the 4th International Equine Conference on Laminitis and Diseases of the Foot, November 1–4, 2007, West Palm Beach, Florida.

    Refereed

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