Review of Current Understanding of Endocrinopathic Laminitis
Robert Judd DVM, Dipl. ABVP (Eq)
Endocrinopathic laminitis is defined as laminitis developing from hormonal influences rather than in association with pro-inflammatory and intestinal conditions. Conditions associated with endocrinopathic laminitis fall into 2 basic categories that can sometimes overlap including pituitary pars intermedia dysfunction (PPID) and insulin dysregulation including hyperinsulinemia and insulin resistance (IR) that are components of equine metabolic syndrome (EMS).
Insulin dysregulation can occur in conjunction with PPID. PPID is also called Equine Cushing’s Disease and usually occurs in horses more than 15 years of age and has a prevalence rate of 21% in this age of horses. The disease in horses is caused by hyperplasia or neoplasia of the pars intermedia whereas pituitary dependant hyperadrenocorticism in the dog usually develops in the pars distalis.
Corticotrophs of the pars distalis and melanotrophs of the pars intermedia secrete hormones derived from the hormone pro-opiomelanocortin (POMC). While adrenocorticotropin hormone (ACTH), beta endorphin and beta lipotropin are the primary products of POMC processing in the pars distalis, melanotrophs of the pars intermedia further process ACTH and release alpha melanocyte stimulating hormone (α MSH) and corticotrophin-like intermediate peptide (CLIP). Mammalian pars intermedia melanotrophs are under toxic inhibition of dopaminergic periventricular neurons and loss of dopaminergic inhibition results in pars intermedia hyperplasia.
Abnormal pars intermedia tissue in horses contains markedly reduced amount of dopamine, about 10% that of normal pars intermedia tissue, consistent with a specific loss of hypothalamic dopinergic innervations. Recent evidence suggests that this loss of dopinergic innervation is due to oxidant induced injury to hypothalamic tissue. Typical clinical signs in PPID may include delayed shedding of the winter haircoat, hypertrichosis (commonly referred to as hirsutism), skeletal muscle atrophy, poyluria and polydipsia, immunosuppression, regional fat distribution, abnormal sweating, recurrent infections, abnormal reproductive cycles and infertility, neurological deficits and night blindness, rounded abdomen, as well as laminitis. EMS is both an endocrine and metabolic disorder that can lead to laminitis.
Although the reports describing a phenotype that we now recognize as EMS were published as far back as the 1970’s, the term EMS was not introduced to the equine medicine vernacular until the early part of the last decade. A number of different names have been use to describe this condition including obesity-associated laminitis, peripheral Cushing’s syndrome, pre-laminitis metabolic syndrome, endocrinopathic laminitis, and pasture-associated laminitis.
The American College of Veterinary Internal Medicine (ACVIM) had defined the phenotype of EMS by the following criteria:
1. Generalized obesity and/or increased adiposity in specific locations (regional adiposity): An increase in the amount of fat surrounding the nuchal ligament (“cresty neck”) is a common example of regional adiposity in affected animals but abnormal fat deposits also may be evident close to the tail head, behind the shoulder or in the prepuce or the mammary gland region.
2. Insulin resistance (IR) characterized by hyperinsulinemia and/or abnormal glycemic and insulinemic response to oral or intravenous (IV) glucose or insulin challenges.
3. A predisposition toward laminitis that develops in the absence of other regional causes, such as grain overload, retained placenta, colitis, colic, or pleuropneumonia.
The syndrome is more common in ponies, Morgan horses, Arabians and Warmbloods and is likely to be heritable in these breeds that are predisposed to laminitis as these horses commonly develop the phenotype after overfeeding, especially feeding of excess grain or grazing on large pastures. Hyperinsulinemia accompanies IR in most animals and is used as a diagnostic marker as IR is defined as a failure of tissues to respond appropriately to the effects of insulin. It is also believed that ponies and horses with EMS are predisposed to PPID because low grade inflammation and oxidative stress associated with obesity contributes to neuronal degeneration and loss of dopaminergic inhibition. Horses with EMS should closely be monitored for PPID as they enter middle age as horses with EMS also affected with PPID are at a higher risk of developing laminitis.
2. POTENTIAL PATHOPHYSIOLOGY OF ENDOCRINOPATHIC LAMINITIS
At this time, the pathophysiology of PPID and laminitis is based on theory and not scientific evidence so the mechanisms discussed are assumptions and possibilities only. When PPID develops, melanotrophs of the pars intermedia secrete more POMC derived hormones including ACTH and higher ACTH stimulates cortisol secretion from the adrenal glands and hyperadrenocorticism occurs. Histologically, cortisol causes lengthening and attenuation of primary and secondary dermal lamellae in horses with glucocorticoid excess and it has been suggested that this represents pulling apart of lamellae as structures weaken. Vascular changes such as reduced vasodilation occur with hyperadrenocorticism in humans and it is possible decreased blood supply can make these horses more susceptible and less able to heal after laminitis has occurred.
Glucocorticoids have also been shown to increase vasoconstriction as vasoconstrictor response to 5-HT within the equine digits is potentiated by corticosteroids. Glucocorticoids also increase apoptosis or programmed cell death in epithelial cells and may occur in equine lamellar epithelial cells but it is unknown if this is related to causing laminitis. Glucocorticoids also have catabolic effects of the epidermis as synthesis of collagen may be reduced. Production of keratin is important for conferring mechanical strength to the hoof wall and laminar interface and cortisol has been shown to decrease keratin in bovine hoof explants. In other species, corticosteroids have also been shown to decrease integrity of the intestinal mucosa and impair its barrier function which, if this occurs in horses, could lead to increased permeability of the large intestine, increased toxin production, and laminitis. Glucocorticoids also inhibit the action of insulin by disrupting receptor signaling pathways and dexamethasone has been shown to induce IR in horses.
Hyperinsulinemia is detected in some IR horses but not all horses with PPID have IR and this is an important determination to make when treating these horses. Some believe IR occurs with PPID only in horses that are predisposed to the condition. It is also possible that some horses have higher ACTH stimulated cortisol secretion and these are the horses with IR. It has been shown that horses with PPID had higher insulin concentrations over a 12 month period compared to normal horses and insulin concentrations above 188.6 µu/ml have a poor prognosis for 1-2 year survival in horses with PPID.
Obesity, IR, hyperinsulinemia and laminitis are associated in horses but some obese animals exhibit normal insulin sensitivity and there is a theory linking obesity with IR due to the release of inflammatory cytokines from adipose tissue that can be related to laminitis. Tumor necrosis factor alpha is secreted from adipose tissue in obese horses and this lowers insulin sensitivity. Adipokines such as leptin and adiponectin are affected in obese horses as leptin is increased and adiponectin is decreased and this can contribute to IR. However, it is important to realize than not all IR horses are obese and some may only have regional abnormal far deposits but still be IR. Also, obese horses have to carry excess weight on the hooves which also increases forces on the dermal-epidermal attachments.
It is known that large doses of insulin over a 2-3 day period can lead to laminitis and potential mechanisms include endothelial cell dysfunction within blood vessels of the foot, digital vasoconstriction, impaired glucose uptake by epidermal laminar cells, altered epidermal cell function of mitosis and matrix metalloproteinase activation by glucose deprivation or reactive oxygen species. Vasodilation normally occurs in response to insulin through the increased synthesis of nitric oxide by endothelial cells but may also promote vasoconstriction by stimulating synthesis of endothelin 1 and activating the sympathetic nervous system depending on the pathway involved. Therefore, vasoconstriction may be promoted in IR animals as nitric oxide production decreases as this pathway is blocked in IR animals and the endothelin 1 pathway remains fully functional which might impair the ability of vessels to respond to vascular changes.
3. CLINCIAL SIGNS OF PPID AND IR
Early clinical signs of PPID include decreased athletic performance, changes in attitude/lethargy, delayed hair coat shedding, regional hypertrichosis, changes in body conformation, regional adiposity and laminitis. In addition to these early signs, horses with advanced disease may be lethargic, have generalized hypertrichosis, loss of seasonal hair coat shedding, skeletal muscle atrophy, rounded abdomen, anhidrosis or hyperhidrosis, poyluria and polydipsia, recurrent infections, hyperglycemia and abnormal reproductive cycles and neurological deficits and blindness.
Clinical signs of EMS include regional adiposity, obesity, bilateral lameness due to lamnintis or evidence of previous laminitis due to divergent growth rings on the hooves. A cresty neck score has been developed to assess the expansion of adipose tissue within the neck region and a score greater than 3 on a 0-5 score is often detected in horses with EMS. A score of 3 is described as “the crest is enlarged and thickened so fat is deposited more heavily in the middle of the neck than toward the poll and withers giving a mounded appearance. The crest fills the cupped hand and begins losing side to side flexibility. Neck circumference can also be measured at the midpoint of the neck and the neck circumference to height at the withers ratio of greater than 0.71 was typical of EMS.
Although both diseases have some common clinical signs, EMS is usually recognized in younger horses whereas PPID usually occurs in older horses. However, both diseases can occur at the same time. Horses with PPID generally have signs not found in EMS horses including hypertrichosis, delayed shedding of winter hair, excessive or decreased sweating, poyluria and polydipsia, and skeletal muscle atrophy. Also, horses with EMS usually develop laminitis around May or June due to increased consumption of non-structural carbohydrates (NSC) in pasture forage. During periods of high sunshine, when sugars are produced in excess of the energy requirement of the horse for growth and development, they are converted into storage or reserve carbohydrates such as fructans and starches. Also, it has been shown a decrease in insulin sensitivity occurs in the summer due to pasture carbohydrate composition.
Although there is no seasonal pattern to laminitis related to PPID in the literature, it has been shown that there is a seasonal increase in ACTH levels in horses from August to October in North America5 and it has been shown plasma ACTH was significantly increased in Texas compared with 8 other months. This seasonal increase in ACTH may be the reason some horses with PPID seem to develop laminitis or have recurrence of laminitis in the fall compared to the rest of the year.
4. DIAGNOSIS OF PPID AND IR
Resting endogenous ACTH concentration is probably the most common test used as a screening or first tier test to diagnose PPID and requires a single EDTA plasma sample centrifuged within 8 hours of collection. The sample must be shipped cold overnight in plastic and because ACTH levels are not constant throughout the day, some clinicians will collect 2 samples 15 minutes apart and pool the plasma5 while others will collect samples morning, noon and night and pool the plasma.
Because there is a seasonal variation in ACTH levels, reference ranges for negative and positive results must be correlated with the lab at the time of year of sampling. The Equine PPID working group indicated that an ACTH concentration <29 pg/ml or <35 pg/ml (chemiluminescent assay) was negative for PPID November to July while an ACTH concentration of < 47 pg/ml was negative for PPID when tested August to October and results above these concentrations were considered positive. If an RIA test is used, the normal range used should be determined by the individual lab. The August to October period has been avoided in the past due to the seasonal variation but is now recommended as an appropriate time for testing. Recently it was recommended that an ACTH concentration >100 pg/ml from August to October strongly indicates the horse has PPID while concentrations 50 to 100 pg/ml is a weak indicator of disease and is more likely positive if clinical signs are present. It is also recommended that screening older horses for PPID or testing horses suspected of having early PPID be performed august to October as the normal increase in ACTH will act as a natural stimulation test as higher concentrations are detected at this time of year in normal horses but even higher levels are found in horses with PPID.
Another screening test for PPID is the Overnight Dexamethasone Suppression test (ODST) and involves a single cortisol measurement after administration of 0.04 mg/kg dexamethasone intramuscular at 5 PM and 19 hours later at noon the next day blood is collected without anticoagulant for cortisol concentration. Blood is allowed to clot and serum is sent to the lab overnight. From November to July, cortisol concentration <1.0 µg/dl is considered negative while levels above this concentration are considered positive for PPID. Testing for PPID with this test is not recommended in August through October because although a negative result can be confirmed with a cortisol level <1.0 µg/dl, concentrations above 1.0 may be positive or false positive and cannot be interpreted.
The most commonly used second tier test for diagnosis of PPID is the Thyrotropin-releasing hormone (TRH) stimulation test and is believed to be the most sensitive diagnostic test for PPID at this time. However, many are now recommending this test as the initial test in diagnosing PPID as TRH is becoming available at many pharmacies. Testing is not recommended from August to October as season specific values have not been established. To perform the test, a baseline blood sample is collected and 1.0 mg TRH is administered intravenous as a bolus and a second blood sample is collected in 30 minutes. Plasma is handled as with the resting ACTH screening test and baseline concentration is interpreted as the previously described resting ACTH test. If the ACTH level is <35 pg/ml (chemiluminescent assay) after TRH injection, the horse is negative for PPID. If the concentration is >75 pg/ml after 30 minutes, it is a strong indication PPID is present and if concentration is between 35 and 75 pg/ml at 30 minutes, this is a weak indication for PPID. If clinical signs are present, treatment is recommended. If no clinical signs are present, it is recommended to retest in 3-6 months.
Another test for PPID that is not routinely used is measuring the diurnal cortisol rhythm by checking serum cortisol concentration in the morning and again at midnight. Normal horses will have midnight cortisol values less than 30% of morning values but other stressors and disease can also affect plasma cortisol and this test is not recommended. A combined dexamethasone suppression/thyrotropin stimulation test has been described as dexamethasone is used to suppress cortisol in both PPID and normal horses and then TRH is administered. Three hours after dexamethasone administration, cortisol concentration is checked, TRH is administered and cortisol concentration is checked again in 30 minutes, and then at 24 hours. A 50% increase in cortisol after TRH adminstration and lack of cortisol suppression at 24 hours is suggestive of PPID. Due to the cost of this test and difficulty for the ambulatory clinician due to numerous blood samples at various times, it is not widely used. A domperidone stimulation test has also been described which involves determining plasma ACTH concentrations prior to and 4 and 8 horses after administration of 3.3 mg/kg domperidone. As a dopamine receptor antagonist, domperidone should exacerbate the loss of dopaminergic inhibition in horses with PPID and increase the release of ACTH by pars intermedia melanotropes. In one study, plasma ACTH increase by less than 50% in normal horses while it doubled in horses with PPID although seasonal variation could have been involved with the results of the study. Also, another study revealed the TRH stimulation test was more accurate than the domperidone stimulation test.
Diagnostic testing for EMS currently focuses upon detection of IR and hyperinsulinemia and it is important to realize that there are multiple tests available and all could be potentially affected by pain and stress. Current screening tests for IR focus on measurement of glucose and insulin concentrations in single blood samples although hyperglycemia is rarely detected in horses with EMS because most animals maintain an effective compensatory insulin secretory response in the face of IR. If persistent hyperglycemia is detected, diabetes mellitus should be considered. Hyperinsulinemia in the absence of confounding factors such as stress, pain, and recent feeding provides evidence of IR in horses and a resting serum insulin of greater than 20 µU/ml after an overnight feeding of only 1 flake grass hay is a general guideline for documenting hyperinsulinemia.
In cases that have clinical signs consistent with EMS and resting insulin is normal, dynamic testing is recommended because tissue insensitivity to insulin may only be revealed when glycemic control is challenged by inducing hyperglycemia. The combined glucose-insulin test (CGIT) is one of the dynamic tests and the horse is fasted for 6 hours to perform this test. A baseline glucose and insulin concentration is determined and 150 mg/kg body weight 50% dextrose solution is injected IV immediately followed by 0.10 U/kg body weight regular insulin IV. This is equivalent to 150 ml of 50% dextrose and 0.5 ml of 100 U/ml regular insulin for a 500 kg horse. After injection, blood glucose is measured at 1, 5, 15, 25, 35, 45, 60, 75, 90, 105, 120, 135, and 150 minutes after injection. In healthy animals, blood glucose returns below baseline by 45 minutes and the test can be concluded. Blood collected at baseline and 45 minutes is submitted for insulin concentration and horses with insulin greater than 100 µU/ml are considered to be IR. Hypoglycemia is a rare complication of this test and if symptoms develop including sweating, weakness, and muscle fasciculations, or if blood glucose falls below 40mg/dl, administer 60 ml 50% dextrose IV as needed.7 An oral sugar test is also used as a dynamic test for IR and involves administering corn syrup after a fast from midnight onwards. In the morning, clear corn syrup is administered at 0.15 ml/kg body weight by a dose syringe. After administration of the syrup, blood samples are collected at 60 and 90 minutes and a glucose and insulin concentration is determined. If insulin concentration is less than 45 µU/ml at 60 and 90 minutes, results are normal.2 An insulin concentration greater than 60 µU/ml at either point is considered evidence of hyperinsulinemia. Results are considered equivocal if the insulin concentration is 45-60 µU/ml and an excessive glucose response is determined by a glucose concentration greater than 125 mg/dl at 60 or 90 minutes.
5. CLINICAL MANAGEMENT OF PPID AND IR
The most common medication used for clinical management of PPID is pergolide mesylate (Prascend®) that is an ergot alkaloid dopamine receptor agonist that is used to restore dopaminergic inhibition of melanotrophs.3 Interaction of the drug with D2 receptors inhibits propriomelanocortin hormone synthesis and secretion and may also slow the progression of disease.2,3 Pergolide is prescribed at a starting dose of 0.002 mg/kg (1 mg for a 500 kg horse) and the dosage range extends up to 0.01 mg/kg (5 mg for a 500 kg horse). Anorexia and temporary dullness are common side effects reported in about 30% of the horses on initial treatment but both usually resolve after giving half of the dose for a few days.
Cyproheptadine can be administered to horses as both pergolide and cyproheptadine both lower plasma ACTH levels but pergolide is more effective. Cyproheptadine can be used along with pergolide in advanced cases of PPID at a dosage of 0.25 mg/kg PO q 12 hours. Cyproheptadine antagonizes serotonin which is thought to be a stimulatory neurotransmitter for pars intermedia melanotrophs and some horses may exhibit sedation when treatment is initiated.
Trilostane is a 3-beta hydroxysteroid dehydrogenase inhibitor and acts by inhibiting corticosteroid synthesis within the adrenal cortex. Trilostane is commonly used in dogs for the management of pituitary-dependant hyperadrenocorticism when increased ACTH secretion from the pars distalis induces adrenal hyperplasia. However, the reported incidence of adrenal hyperplasia is low (20%) in horses with PPID so this may limit the usefulness of trilostane in the horse. However, it was reported that trilostane at a mean dosage of 0.5 mg/kg body weight did improve clinical signs in 20 horses with PPID including decreased lethargy, decreased polydipsia/polyuria, and improvement in recurrent or chronic laminitis. The recommended dosage for trilostane has been subsequently increased to 1.0 mg/kg bwt once daily given in the evening for horses with PPID.
Best practices for managing PPID include measurement of plasma ACTH concentrations 30 days after pergolide treatment is initiated. It is also recommended to measure ACTH levels biannually in the fall and spring, adjusting dosages accordingly keeping in mind the normal values for the different times of the year. Ideally, pergolide would return plasma ACTH values to normal range. However, in horses with very high plasma ACTH concentrations, sometimes in excess of 1000 pg/ml, a significant decrease in plasma ACTH is an initial goal of therapy. The dose of pergolide can be increased until ACTH levels are normal and can be administered up to 5 mg for a 500 kg horse per day without adverse effects. Although this is ideal, the cost of pergolide may prohibit some clients from using a larger dose and a significant decrease in ACTH over the initial value may be more practical. Also, monitoring of pergolide treatment should consist of monitoring improvement in clinical signs including increased alertness, decrease in polydipsia/polyuria, lower incidence of laminitis, improved immune function and fewer bacterial infections, mitigation of hyperglycemia and hyperinsulinemia, increased muscle mass, improvements in hair coat quality and shedding. The rate of clinical improvement may be higher than the normalization of endocrine test results.
If PPID horses are insulin sensitive, they may be fed normal rations such as senior feeds, sweet feed, or oats fed with hay or pasture and additional calories can be provided as needed. However, PPID horses that also have IR will need to be managed as those horses with IR that will be discussed below. Also, anecdotal reports suggest that horses with IR are predisposed to PPID and pituitary dysfunction may develop earlier in IR animals. Consequently, it is important for nutritional reasons to determine if PPID horses also have IR and probably wise to be cautious in allowing PPID horses to graze high carbohydrate pasture or be fed sweet feed or oats that contain high levels of carbohydrates.
Management of horses with IR involves weight loss in obese horses as the initial goal of therapy and to improve insulin sensitivity through dietary management and exercise. Obese horses should be placed on a weight reduction diet consisting of hay only diet plus a protein, vitamin and mineral supplement3 or fed a hay diet plus a pelleted feed containing less than 10% non-structural carbohydrates (NSC). Hay is initially fed at 1.5% of ideal body weight per day (7.5 kg for a 500 kg horse) but if weight loss is not occurring after 1 month, the amount of hay should be lowered to 1% body weight until weight loss occurs. Grain and all pelleted rations higher than 10% NSC should be removed from the diet and no access to pasture should be allowed until insulin sensitivity has improved because carbohydrates consumed on pasture can lead to laminitis in susceptible horses.
Ideally, hay should be tested and hay should be fed that is less than 10% NSC. However, this can be difficult for many owners because most hay is purchased in small quantities and frequent testing of hay would be required as the hay available at the feed store may be from different sources. An option is to soak the hay in cold water for up to 1 hour as soaking reduces NSC content of the hay. However, soaking may or may not decrease the NSC percentage below the recommended 10% depending on the original NSC content of the hay and the length of soaking time used so soaking may not be an effective option in feeding these IR horses. Early maturity hay with a high leaf-to-stem ratio should be replaced by later-maturity hay that typically has lower energy content. However, since mature grass hays generally contain lower amounts of Vitamin E, copper, zinc and other minerals, a vitamin-mineral supplement or ration balancer is usually recommended.
Many of the low starch pelleted feeds designed for IR horses also have increased levels of these nutrients to aid in balancing the ration.
Ideally, horses with IR should be housed in a small paddock that allows sufficient room for exercise as exercise is likely to reduce appetite, improve insulin sensitivity and induce weight loss. Once insulin sensitivity has improved and weight loss has occurred, mildly affected horses can sometimes be returned to pasture but this must be done cautiously when the grass is going through dynamic phases such as rapid growth in the spring and preparation for cold weather in the fall. Also, grazing in the morning is likely to be safer for horses with IR and grazing periods of less than 1 hour in a small pen or hand grazing can be used. Grazing over 1 hour should not be allowed without a grazing muzzle because it has been shown that ponies will consume up to 1% of their body weight as dry matter within only 3 hours of pasture turnout so if grazing is allowed without a grazing muzzle, it must be a very short period. The use of a grazing muzzle has been shown to decrease dry matter intake by up to 80%. Certainly all ration changes should be made slowly and abrupt starvation should be avoided especially in ponies, donkeys and miniature horses to prevent hyperlipidemia. Also, severe dietary restriction may increase the risk of gastric ulceration and stereotypical behaviors.
A ration consisting of mostly grass hay may not meet the energy requirements of IR horses, especially those that are also affected with PPID. If these horses are in work and need additional calories without exacerbating the hyperinsulinemia response to feeding, feeding non-molassed sugar beet bulp at 0.5-1 kg/day can be effective. Beet pulp is rich in highly digestible fibers, provides more digestible energy that most hays, and does not elicit a marked glycemic or insulinemic response. Beet pulp must be soaked in water that is 3-4 times the amount of the volume of beet pulp to be fed. Another option to safely increase calories in the ration is the use of corn or soy oil that can be gradually added to the ration starting at ¼ cup of oil once daily and increasing to ½ to 1 cup of oil twice daily as needed. One standard cup of vegetable oil (approximately 225 ml) provides 1.7 Mcal of digestible energy. Another option for increased calories is feeding stabilized rice bran that is approximately 20% fat assuming the calcium:phosphorus ratio of the entire diet is considered.
Medical management of horses with IR involves the use of levothyroxine sodium as it has been shown to induce weight loss and increase insulin sensitivity. Levothyroxine sodium has been given to horses and larger ponies at a dosage of 48 mg/day in the feed in conjunction with dietary changes and increased exercise while ponies weighing less than 250 kg are administered 24 mg daily. Long term effects of 48 mg levothyroxine/day on body weight and insulin sensitivity were evaluated in healthy mares over a 48 week period and echocardiographic evaluations, complete blood count and plasma biochemical analysis were also performed in the same study. A greater than 2 fold increase in insulin sensitivity was detected and this mirrored a reduction in body weight and no adverse health results were detected.1 After recommended weight loss has occurred over a 3-6 month period, horses are routinely gradually weaned off levothyroxine.
However, in horses that have already developed laminitis and dietary restrictions are questionable or if the horse still has IR, some practitioners continue levothyroxine at a maintenance dosage of 12mg to 24 mg/day to aid in increasing insulin sensitivity. Also, some practitioners report anecdotal evidence of placing horses on unrestricted pasture without a grazing muzzle after laminitis is stable and weight loss has occurred by continuing a maintenance dosage of levothyroxine. However, this practice of allowing horses increased pasture while on levothyroxine is questionable because levothyroxine is likely to induce hyperphagia which may offset the effects of treatment.
After weight loss has occurred, an oral sugar test or resting insulin concentration test can be performed to determine the presence of IR and then possible need for continuation of levothyroxine. The risk of a possible episode of acute on chronic laminitis by allowing increased access to pasture without a grazing muzzle even if feeding levothyroxine should be discussed with the owner before recommending this practice. Benefits of treating horses with levothyroxine at lower dosages for longer periods has not been evaluated scientifically.
Another medication administered to IR horses is metformin hydrochloride that is a biguanide drug that enhances the action of insulin within tissues at the post receptor level and inhibits gluconeogenesis within the liver. Results of one study indicates that metformin acts locally at the intestinal level to lower post prandial glucose and insulin concentrations although the oral bioavailability has been shown to be low. Current recommendations are to administer 30mg/kg body weight every 8-12 hours with the drug administered 30-60 minutes before the horse is fed is possible. Some authors reserve the use of metformin for horses and ponies with markedly increased oral sugar tests insulin concentrations even after weight loss and dietary management.
A number of other medications are marketed with claims of improving insulin sensitivity and reducing the risk of laminitis but there is little evidence to support these claims. Chromium is thought to potentiate insulin action through activation of insulin receptor kinase and/or inhibition of insulin receptor tyrosine phosphatase. However, the feeding of a supplement containing 5 mg/day chromium, 8.8 g/day magnesium, and other unspecified nutraceuticals for 16 weeks did not alter morphometric measurements, resting serum glucose and insulin concentrations, or insulin sensitivity in obese horses with a history of laminitis.
Along with chromium and magnesium, cinnamon and chasteberry have also been recommended for management of EMS but there is insufficient scientific evidence to support the use of these supplements at this time. One study did reveal that normal non-obese unexercised horses did have a lower post-prandial blood glucose concentration when fed 90-270 grams psyllium per day for 60 days than did control horses and horses in the same study fed 270 grams psyllium for 60 days had lower insulin concentrations than did control horses. It is possible that feeding psyllium could be beneficial to obese IR horses but additional research will be needed.
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