Endocrine disorders and laminitis

Two common endocrine disorders, pituitary pars intermedia dysfunction and equine metabolic syndrome, predispose horses and ponies to laminitis and may even induce the condition. The exact mechanisms involved in endocrinopathic laminitis have not been elucidated but hyperinsulinaemia and insulin resistance are currently being investigated. Obesity and regional adiposity may also contribute to laminitis susceptibility through the release of inflammatory cytokines and adipokines. In the case of pituitary pars intermedia dysfunction, glucocorticoid excess is likely to weaken hoof structures, alter vascular dynamics within the foot and induce or exacerbate insulin resistance. This review will summarise current theories regarding the pathophysiology of endocrinopathic laminitis and provide recommendations for the diagnosis and management of these common equine endocrine disorders.     

Neutrophil and cytokine dysregulation in hyperinsulinemic obese horses

Equine metabolic syndrome is characterized by obesity and regional adiposity coupled with evidence of recurrent laminitis. Although inflammation has been well characterized in several experimental models of acute laminitis, the inflammatory events associated with endocrinopathic laminitis are not well documented. The aim of this study was to characterize selected markers of inflammation in horses with clinical evidence of equine metabolic syndrome (EMS). Neutrophil phagocytosis and oxidative burst, as well as endogenous and stimulated cytokine expression were evaluated. A marked increase in neutrophil reactive oxygen species production upon phagocytosis was observed in horses with EMS that was strongly correlated to the blood insulin concentration. Increased oxidative burst activity of neutrophils in hyperinsulinemic horses may predispose horses with metabolic syndrome to laminitis. In contrast, peripheral blood cells of obese hyperinsulinemic horses showed decreased endogenous proinflammatory cytokine gene expression (IL-1 and IL-6) and similar cytokine response following immune stimulation compared to that of control horses. This may suggest that, unlike in people, cytokine-mediated inflammation does not increase in direct response to obesity or insulin resistance in horses. This species-specific disparity may explain the difference in clinical outcomes observed in obese horses compared to obese people.     

The equine metabolic syndrome peripheral Cushing's syndrome.

Certain management practices tend to promote the development of obesity (metabolic syndrome) in mature horses as they enter their teenage years. These management practices include the provision of starch-rich (high glycemic index) and fat-supplemented rations to healthy horses that are relatively inactive. Some horse breeds and ponies appear to be genetically predisposed to metabolic syndrome. The accretion of intra-abdominal adiposity by equids is associated with the development of insulin insensitivity (hyperinsulinemia), glucose intolerance, dyslipidemia, hypertension, and insidious-onset laminitis. Omental adipocytes are metabolically active, secreting free fatty acids and hormonally active mediators including cortisol, leptin, and resistin that might contribute to persistence and worsening of insulin refractoriness and the obese phenotype. We have hypothesized that obesity-associated laminitis arises as a consequence of vascular changes and a hypercoagulable state, similar to the development of atherosclerosis in human type 2 diabetes. Several molecular mechanisms that might serve to explain the development of insulin insensitivity as a result of excessive adiposity have been incriminated. Little investigation into the relationship between obesity, insulin insensitivity, and laminitis in horses has been reported to date. Insulin sensitivity and glucose tolerance can be improved by dietary restriction and exercise aimed at reversing omental obesity. Management practices that promote the development of obesity are likely initiated during the first 10 years of the horse's life. Veterinarians and horse owners must recognize that mature-onset obesity in adult horses is associated with a risk for development of laminitis. Obesity and insulin insensitivity might be prevented if horse owners can be educated to feed rations with a relatively lower glycemic index to inactive horses. Investigative research pertaining to the development of antiobesity drugs for human patients is continuing. Greater than 30 new pharmaceuticals are in various stages of research. However, it will likely take many years before any of these drugs are shown to be useful and safe in horses. Lifestyle changes in the form of diet and exercise patterns are still the crux of therapy for both human and equine patients.     

Correlation of Plasma Insulin Concentration with Laminitis Score in a Field Study of Equine Cushing's Disease and Equine Metabolic Syndrome

This study aimed to investigate endocrinologic test values and the response to treatment of two commonly encountered causes of endocrinopathic laminitis, equine Cushing's disease (ECD) and equine metabolic syndrome (EMS), in a veterinary practice setting. In particular, the study aimed to determine whether insulin concentration correlated to the severity of clinical laminitis in horses with EMS or ECD. Twenty-five horses were included in the study and assigned to one of three groups: ECD (n = 6), EMS (n = 10), and controls (n = 9). Blood samples were collected at an initial visit and then at regular intervals for the next 12 months. Plasma concentrations of adrenocorticotropin (ACTH), cortisol, and insulin and serum concentrations of glucose and total thyroxine (T4) were obtained. Horses with ECD had significantly higher plasma ACTH concentrations than EMS horses or controls. Horses with EMS and ECD both had significantly higher plasma insulin concentrations than control horses, which was correlated with the Obel grade of laminitis (r = 0.63). After treatment, there was a trend for a reduction in plasma ACTH concentration in horses with ECD. A program of diet and exercise for horses with EMS resulted in reductions in both plasma insulin concentrations and bodyweight, which was variable, depending on the individual. There was a significant correlation between the change in plasma insulin concentration and Obel grade of laminitis (r = 0.69). This study has highlighted the importance of baseline plasma insulin concentration as a potential indicator of the susceptibility of horses to laminitis and the response to a program of diet and exercise.     

Hypertension and insulin resistance in a mixed-breed population of ponies predisposed to laminitis

OBJECTIVE: To determine the metabolic phenotype of a group of laminitis-prone ponies when at pasture in summer, compared with when at pasture in winter. ANIMALS: 40 ponies of various breeds predisposed to recurrent pasture-associated laminitis and 40 unaffected control ponies. PROCEDURES: Body condition score and size of the crest of the neck were assessed, blood samples obtained, and blood pressure measured by use of an indirect oscillometric technique, while ponies were kept on winter pasture (last week of November or beginning of December) and again on summer pasture (June). Serum insulin concentration and plasma glucose, triglyceride, uric acid, and ACTH concentrations were measured. Insulin sensitivity was calculated with proxies derived from basal serum insulin and plasma glucose concentrations. RESULTS: No significant differences were apparent between ponies predisposed to laminitis and control ponies during winter. However, in June, laminitis-prone ponies had increased serum insulin concentration and plasma triglyceride and uric acid concentrations, compared with control ponies. Also, laminitis-prone ponies were relatively insulin resistant, compared with control ponies. Mean blood pressure was significantly higher during summer in laminitis-prone ponies (median [interquartile range], 89.6 mm Hg [78.3 to 96.9 mm Hg]), compared with control ponies (76.8 mm Hg [69.4 to 85.2 mm Hg]). CONCLUSIONS AND CLINICAL RELEVANCE: Summer pastures appear to induce metabolic responses in some ponies, leading to expression of the prelaminitic phenotype, which includes hypertension as well as insulin resistance. Signs of this metabolic syndrome may not be apparent in affected ponies during periods of grazing winter pasture. Understanding this syndrome may enable improved countermeasures to be devised to prevent laminitis.     

Evaluation of genetic and metabolic predispositions and nutritional risk factors for pasture-associated laminitis in ponies

OBJECTIVE: To evaluate genetic and metabolic predispositions and nutritional risk factors for development of pasture-associated laminitis in ponies. DESIGN: Observational cohort study. ANIMALS: 160 ponies. PROCEDURES: A previous diagnosis of laminitis was used to differentiate 54 ponies (PL group) from 106 nonlaminitic ponies (NL group). Pedigree analysis was used to determine a mode of inheritance for ponies with a previous diagnosis of laminitis. In early March, ponies were weighed and scored for body condition and basal venous blood samples were obtained. Plasma was analyzed for glucose, insulin, triglycerides, nonesterified fatty acids, and cortisol concentrations. Basal proxies for insulin sensitivity (reciprocal of the square root of insulin [RISQI]) and insulin secretory response (modified insulin-to-glucose ratio [MIRG]) were calculated. Observations were repeated in May, when some ponies had signs of clinical laminitis. RESULTS: A previous diagnosis of laminitis was consistent with the expected inheritance of a dominant major gene or genes with reduced penetrance. A prelaminitic metabolic profile was defined on the basis of body condition, plasma triglyceride concentration, RISQI, and MIRG. Meeting > or = 3 of these criteria differentiated PL- from NL-group ponies with a total predictive power of 78%. Determination of prelaminitic metabolic syndrome in March predicted 11 of 13 cases of clinical laminitis observed in May when pasture starch concentration was high. CONCLUSIONS AND CLINICAL RELEVANCE: Prelaminitic metabolic syndrome in apparently healthy ponies is comparable to metabolic syndromes in humans and is the first such set of risk factors to be supported by data in equids. Prelaminitic metabolic syndrome identifies ponies requiring special management, such as avoiding high starch intake that exacerbates insulin resistance.     

Nutrition and Exercise in the Management of Horses and Ponies at High Risk for Laminitis

Obesity, insulin resistance (IR) and hyperinsulinemia are risk factors for laminitis in horses and ponies. Alterations in management, especially diet and physical activity, can be helpful in the management of these risk factors. Caloric restriction, ideally combined with increased physical activity, to promote weight loss and improve insulin sensitivity is indicated for the management of obese animals. Strict control of dietary NSC through the elimination of grains and sweet feeds and by restricted access to NSC-rich pastures is recommended for insulin-resistant animals, regardless of whether they are obese or not. Medical treatment with levothyroxine or metformin may be indicated in obese or insulin-resistant animals that do not respond to conservative management.     

Glucose transport in the equine hoof

Reasons for performing study: Several conditions associated with laminitis in horses are also associated with insulin resistance, which represents the failure of glucose uptake via the insulin‐responsive glucose transport proteins in certain tissues. Glucose starvation is a possible mechanism of laminitis, but glucose uptake mechanisms in the hoof are not well understood. Objectives: To determine whether glucose uptake in equine lamellae is dependent on insulin, to characterise the glucose transport mechanism in lamellae from healthy horses and ponies, and to compare this with ponies with laminitis. Methods: Study 1 investigated the effects of insulin (300 µU/ml; acute and 24 h) and various concentrations of glucose up to 24 mmol/l, on 2‐deoxy‐D‐[2,6‐³H]glucose uptake in hoof lamellar explants in vitro. Study 2 measured the mRNA expression of GLUT1 and GLUT4 transport proteins by PCR analysis in coronary band and lamellar tissue from healthy horses and ponies, ponies with insulin‐induced laminitis, and ponies suffering from chronic laminitis as a result of equine Cushing's syndrome. Results: Glucose uptake was not affected by insulin. Furthermore, the relationship between glucose concentration and glucose uptake was consistent with an insulin‐independent glucose transport system. GLUT1 mRNA expression was strong in brain, coronary band and lamellar tissue, but was weak in skeletal muscle. Expression of GLUT4 mRNA was strong in skeletal muscle, but was either absent or barely detectable in coronary band and lamellar tissue. Conclusions: The results do not support a glucose deprivation model for laminitis, in which glucose uptake in the hoof is impaired by reduced insulin sensitivity. Hoof lamellae rely on a GLUT1‐mediated glucose transport system, and it is unlikely that GLUT4 proteins play a substantial role in this tissue. Potential relevance: Laminitis associated with insulin resistance is unlikely to be due to impaired glucose uptake and subsequent glucose deprivation in lamellae.     

Seasonal Variation in Serum Concentrations of Selected Metabolic Hormones in Horses

Background: Determination of adrenocorticotropic hormone (ACTH) concentration is a commonly used test in the evaluation of endocrine causes of equine laminitis, but the concentration in healthy horses can be high at certain times of year, which alters the specificity of the ACTH test. Objective: To determine if circulating concentrations of ACTH, cortisol, glucose, insulin, and thyroxine vary month to month in healthy horses and in horses with equine metabolic syndrome (EMS). Animals: Nine healthy adult horses were studied on their farm/stable over the course of 1 year. After the diagnosis of EMS, 10 laminitic horses residing at the same farm/stable were also studied. Methods: Prospective study of healthy and laminitic horses. Plasma/serum samples were analyzed for concentrations of hormones and glucose. Results: ACTH was the only analyte to show a discrete seasonal pattern, with concentrations in healthy and EMS horses frequently outside of the reference range (9–35 pg/mL) in August through October. Insulin was elevated (>40 μIU/mL) in EMS horses during most months and median serum glucose was generally higher in EMS horses (100 mg/dL, range, 76–163 mg/ dL) than in controls (94 mg/dL, range, 56–110 mg/dL), but no seasonal patterns for insulin or glucose were found. Conclusions and Clinical Importance: An increased ACTH concentration in horses in late summer or autumn should be interpreted with caution. In contrast, insulin concentration is maintained within the reference range throughout the year in healthy horses, thus an increased insulin concentration at any time of year should raise suspicions of EMS, ECD, or both.     

Insulin dysregulation

Abnormalities of insulin metabolism include hyperinsulinaemia and insulin resistance, and these problems are collectively referred to as insulin dysregulation in this review. Insulin dysregulation is a key component of equine metabolic syndrome: a collection of endocrine and metabolic abnormalities associated with the development of laminitis in horses, ponies and donkeys. Insulin dysregulation can also accompany prematurity and systemic illness in foals. Causes of insulin resistance are discussed, including pathological conditions of obesity, systemic inflammation and pituitary pars intermedia dysfunction, as well as the physiological responses to stress and pregnancy. Most of the discussion of insulin dysregulation to date has focused on insulin resistance, but there is increasing interest in hyperinsulinaemia itself and insulin responses to feeding. An oral sugar test or in‐feed oral glucose tolerance test can be performed to assess insulin responses to dietary carbohydrates, and these tests are now recommended for use in clinical practice. Incretin hormones are likely to play an important role in postprandial hyperinsulinaemia and are the subject of current research. Insulin resistance exacerbates hyperinsulinaemia, and insulin sensitivity can be measured by performing a combined glucose‐insulin test or i.v. insulin tolerance test. In both of these tests, exogenous insulin is administered and the rate of glucose uptake into tissues measured. Diagnosis and management of hyperinsulinaemia is recommended to reduce the risk of laminitis. The term insulin dysregulation is introduced here to refer collectively to excessive insulin responses to sugars, fasting hyperinsulinaemia and insulin resistance, which are all components of equine metabolic syndrome.     

Animal welfare in prevention and therapy of laminitis

Laminitis is a systemic disease which is manifested as a non infectious condition in the foot. The management of feeding and housing conditions is necessary to treat the endocrinological and metabolic disturbances of laminitic horses. The Equine Metabolic Syndrome (EMS) is predisposing for developing laminitis, and it is characterised by obesity, insulin resistance, hypertension and dyslipidaemia. A genetical predisposition is supposed and EMS is accompanied by a lack of exercise and inadequate energy intake. Laboratory examinations are of great importance for diagnosis. Analyses of insulin, glucose and ACTH are of interest. Several approaches to treat laminitis are available, including pharmacological and orthopaedic strategies as well as the management of the feeding and housing conditions. However, the prophylaxis to prevent laminitis has to be emphasised. Predisposed horses should be detected and adequately treated; especially weight reduction in obese horses is in the focus of interest. Horses in the acute stage of laminitis have to be stabled. Furthermore redistributing weight from the most stressed wall is necessary to prevent pain and to minimise laminar damage and displacement of the distal phalanx. In cases of displacement of the distal phalanx a close communication between the veterinarian and the authorised farrier is necessary, in these cases treatment should be supported by x-ray diagnosis. Horses have to be treated with NSAISs to ensure a proper therapy to consider animal welfare. Horses have to be fed with hay and supplemented with minerals and vitamins. Feeding exclusively straw and feed restriction has to be avoided.     

Induction of laminitis by prolonged hyperinsulinaemia in clinically normal ponies

The purpose of this study was to determine the effects of prolonged administration of insulin, whilst maintaining normal glucose concentrations, on hoof lamellar integrity in vivo on healthy ponies with no known history of laminitis or insulin resistance. Nine clinically healthy, unrelated ponies were randomly allocated to either a treatment group (n =5; 5.9+/-1.7 years) or control group (n =4; 7.0+/-2.8 years). The treatment group received insulin via a euglycaemic hyperinsulinaemic clamp technique modified and prolonged for up to 72 h. Control ponies were infused with an equivalent volume of 0.9% saline. Ponies were euthanized at the Obel grade 2 stage of clinical laminitis and hoof lamellar tissues were harvested and examined for histopathological evidence of laminitis. Basal serum insulin and blood glucose concentrations were 15.7+/-1.8 microU/mL and 5.2+/-0.1 mmol/L, respectively (mean+/-SE) and were not significantly different between groups. Mean serum insulin concentration in treatment ponies was 1036+/-55 microU/mL vs. 14.6 microU/mL in controls. All ponies in the treatment group developed clinical and histological laminitis (Obel grade 2) in all four feet within 72 h (55.4+/-5.5h), whereas none of the control ponies developed laminitis. There was no clinical evidence of gastrointestinal involvement and the ponies showed no signs of systemic illness throughout the experiment. The data show that laminitis can be induced in healthy young ponies, with no prior history of laminitis, by maintaining prolonged hyperinsulinaemia with euglycaemia. This suggests a role for insulin in the pathogenesis of laminitis, independent of hyperglycaemia, or alterations in hind-gut fermentation. For the clinician, early detection and control of hyperinsulinaemia may facilitate management of endocrinopathic laminitis.     

Equine laminitis: Induced by 48 h hyperinsulinaemia in Standardbred horses

Reasons for performing study: Hyperinsulinaemia is known to induce laminitis experimentally in healthy ponies with no history of the condition. Horses are more insulin sensitive than ponies and whether prolonged hyperinsulinaemia and euglycaemia would have a similar laminitogenic effect requires study. Objectives: To determine if laminitis results when the prolonged euglycaemic hyperinsulinaemic clamp technique (p‐EHC) is applied to clinically normal Standardbred horses, and to monitor hoof wall temperature seeking an association between vascular activity and laminitis development. Methods: Eight young, clinically normal Standardbred horses were assigned into 4 pairs and within each pair, one was assigned randomly to either treatment (n = 4) or control (n = 4) groups. Treated horses received continuous infusions of insulin and glucose until clinical signs of laminitis developed, at which point the horses were subjected to euthanasia. Control horses received an equivalent volume of a balanced electrolyte infusion for the same period. Hoof wall surface temperature (HWST) was monitored continuously throughout the experimental period. Results: All horses in the treatment group were calculated to have normal insulin sensitivity. All treated horses, and none in the control group, developed laminitis (P = 0.01). Pronounced digital pulses were a feature of the treatment group, while insignificant digital pulses occurred in control horses. HWST was higher and less variable in treated horses once hyperinsulinaemia was established. Conclusions: Healthy Standardbred horses subjected to prolonged hyperinsulinaemia develop laminitis within 48 h, demonstrating that laminitis in horses can be triggered by insulin. Potential relevance: Insulin resistance and the associated hyperinsulinaemia place horses and ponies at risk of developing laminitis. This study demonstrates a need for prompt management of the persistent hyperinsulinaemia seen in some endocrinopathies.     

Current concepts of hyperlipaemia in horses and ponies

Hyperlipaemia is an important condition in ponies, not just because of the seriousness of the clinical signs and biochemical changes involved, but because of the distress it causes owners and breeders that have had animals suffer from it. Hyperlipaemia occurs most commonly in fat ponies in late pregnancy and is rarely seen in larger horses. The syndrome has similarities with conditions in other species but the definitive aetiologies are not yet known. The condition in ponies is undoubtedly related to stress. The biochemical mechanisms involved in equine hyperlipaemia are considered and an hypothesis of possible pathogenesis is put forward. This hypothesis is tested by presenting the results of a preliminary study to evaluate glucose and lipid metabolism in horses and ponies. It appears that the pony is markedly insensitive to insulin compared to larger horses which means that triglycerides are more readily mobilised and the animal is therefore susceptible to hyperlipaemia in a situation of negative energy balance. The effect of stress is to increase cortisol levels which only exacerbates the insulin insensitivity and so creates a vicious circle. The importance of an innate insulin insensitivity may also be important in the pathogenesis of such conditions as laminitis.     

ECEIM consensus statement on equine metabolic syndrome

Equine metabolic syndrome (EMS) is a widely recognized collection of risk factors for endocrinopathic laminitis. The most important of these risk factors is insulin dysregulation (ID). Clinicians and horse owners must recognize the presence of these risk factors so that they can be targeted and controlled to reduce the risk of laminitis attacks. Diagnosis of EMS is based partly on the horse's history and clinical examination findings, and partly on laboratory testing. Several choices of test exist which examine different facets of ID and other related metabolic disturbances. EMS is controlled mainly by dietary strategies and exercise programs that aim to improve insulin regulation and decrease obesity where present. In some cases, pharmacologic aids might be useful. Management of an EMS case is a long‐term strategy requiring diligence and discipline by the horse's carer and support and guidance from their veterinarians.     

Investigation of the Effects of a Dietary Supplement on Insulin and Adipokine Concentrations in Equine Metabolic Syndrome/Insulin Dysregulation

High insulin concentrations are a common clinical feature of equine metabolic syndrome (EMS) and insulin dysregulation. Hyperinsulinemia can induce laminitis, so reduction of insulin concentrations in response to an oral challenge should decrease risk. In human studies, diets containing a polyphenol (resveratrol) led to improvements in insulin sensitivity. In rodents, the addition of leucine to a resveratrol supplement caused a decrease in the amount of resveratrol needed to achieve a clinical effect. We hypothesize a supplementation with a low dose of a synergistic polyphenol and amino acid blend including leucine (SPB+L) would improve metabolic health in EMS/insulin dysregulated horses. Fifteen EMS/ID horses received a high or low dose of SPB+ L daily for 6 weeks. Insulin during an oral sugar test (OST), body condition score, weight, baseline high-molecular-weight (HMW) adiponectin, triglycerides, nonesterified fatty acids, and tumor necrosis factor alpha were assessed before supplementation (PRE) and after supplementation (POST) via paired Student’s t-tests and a repeated-measures mixed-model analysis of variance (significant at P < .05). There were no differences between doses. Horses in the POST group weighed significantly less, had significantly higher baseline HMW adiponectin concentrations, and had significantly lower insulin concentrations at 60- and 75-minute time points (P < .05). Insulin concentrations of the horsesin the POST group, but not in the PRE group, were lower and similar to results from the study conducted three years before the present study (PRIOR) for 0- and 60-minute time points (P < .002). An increased HMW adiponectin level supports increasing insulin sensitivity after supplementation. These results suggest that SPB + L supplementation at either dose leads to improvements in the clinical manifestations of EMS/insulin dysregulation, potentially reducing laminitis risk.     

Assessment of Insulin and Glucose Dynamics by Using an Oral Sugar Test in Horses

Straightforward testing procedures are needed to facilitate the diagnosis of insulin dysregulation in horses because hyperinsulinemia and insulin resistance are associated with laminitis. Results of an oral sugar test (OST) were compared with those of the intravenous glucose tolerance test (IVGTT). We hypothesized that OST and IVGTT area under the curve values for glucose (AUCg) and insulin (AUCi) would be closely correlated, as defined by a correlation coefficient value ≥0.90. Both tests were performed in 10 horses meeting the criteria for equine metabolic syndrome (EMS) and 8 Quarter horse crossbred mares from a university teaching herd (control group). The OST was also performed in 21 Quarter horse crossbred mares from the same herd, and test repeatability was evaluated in 8 of these horses. All testing was performed under fasting conditions. Median AUCg and AUCi values were 1.3- and 9.0-fold higher, respectively, for the IVGTT and 1.3- and 6.8-fold higher, respectively, for the OST in the EMS group than those in the control group. AUCg (Spearman correlation coefficient [r_s] = 0.58; P = .012) and AUCi (r_s = 0.90; P < .001) values for the two tests were positively correlated. Mean ± SD coefficients of variation for repeated tests in 8 mares were 6.4% ± 3.1% and 45.1% ± 36.2% for AUCg and AUCi, respectively. We conclude that OST and IVGTT insulin results are closely correlated, so the OST warrants further consideration as a field test for insulin dysregulation in horses.