Equine metabolic syndrome (Proceedings)

Equine metabolic syndrome (EMS) is a term used to describe horses that manifest a cluster of problems, including obesity, regional adiposity, insulin resistance, and susceptibility to laminitis.  Other names originally proposed for this syndrome included peripheral Cushing's syndrome, insulin resistance syndrome, syndrome X, omental Cushing's syndrome and central obesity.

There is a similar cluster of endocrine-related signs in humans (obesity, insulin resistance, hypertension, sub-fertility in women, and accumulation of abdominal fat).  It remains to be seen whether this syndrome in horses is pathophysiologically similar to the syndrome described in humans.  Horses with EMS are described as "easy keepers", with thick, cresty necks and fat accumulation over their rumps and, if they are geldings, in their sheaths.  They tend to suffer from chronic, low-grade, recurrent laminitis. 

A specific etiology for this syndrome is currently unknown.  There is likely to be a genetic predisposition, since the syndrome is seen more commonly in certain breeds, including Morgans, Paso Finos, Mustangs, American Saddlebreds, Arabians, Tennessee Walking horses, and possibly Quarter horses.  It has been proposed that breeds that evolved in geographic areas where there were periods of decreased food supply developed an increased ability to store fat (which improved their ability to survive) but this also has led to an increased susceptibility to becoming insulin resistant.  At this time it is unclear whether any horse, no matter what breed, could potentially become insulin resistant and develop this syndrome if it is allowed to become obese.

Insulin resistance in horses with EMS appears to be similar to type 2 diabetes in humans. Most horses with EMS continue to demonstrate compensated insulin resistance, with very few of them progressing to diabetes mellitus. Thus, most horses with EMS have an increased acute pancreatic response of insulin secretion to a glucose load, as well as a more prolonged elevation of insulin that returns blood glucose to normal concentrations.  Insulin resistance can be caused by abnormalities in insulin receptors, abnormalities in insulin signaling pathways, or abnormalities in glucose transporter 4 (GLUT4) synthesis, translocation, or function.

Recently, impairment of GLUT4 translocation to cell membranes was demonstrated as a mechanism of peripheral insulin resistance in these horses.  Decreased insulin clearance may also play a role in increased serum concentrations of insulin in obese horses. As adipose tissue becomes filled with fat, fat begins to be deposited in additional tissues, including liver and muscle. Fatty infiltration of the liver interferes with the liver's ability to clear insulin from the blood.

Metabolic syndrome in humans is associated with abdominal or omental fat, as opposed to subcutaneous fat. Possible mechanisms for this include direct release of fatty acids from omental fat into the portal circulation, resulting in decreased hepatic clearance of insulin, and increased secretion of adipokines and inflammatory cytokines from omental fat. Two adipokines that have been studied in EMS horses include leptin and adiponectin.  Leptin down regulates orexigenic nerves resulting in decreased appetite. Insulin resistant horses have been shown to have increased blood concentrations of leptin, suggesting that they may be leptin resistant.

In one study, horses with serum leptin concentration >12 ng/ml were insulin resistant compared to horses with leptin concentrations <5 ng/ml, despite the two groups of horses having similar body condition scores. In another study, ponies with serum leptin concentrations > 7.3 ng/ml were more likely to develop laminitis.  Interestingly, leptin concentrations increase in late summer and leptin has been shown to increase pro-opiomelanocortin (POMC) synthesis. This may suggest a link between EMS and PPID in the horse.  Adiponectin increases insulin sensitivity. 

Humans with obesity, diabetes, and heart disease have low adiponectin concentrations.  Moderate weight loss leads to increased circulating adiponectin concentrations, with the increase in adiponectin correlating with improvements in insulin sensitivity and reduction of adipose tissue mass. In one study, lower adiponectin concentrations were measured in obese horses, as well as horses with systemic inflammation.  Increased TNF-α concentrations have been shown to reduce adiponectin expression in adipocytes. 

There is no one test to definitively diagnose EMS.  Presumed diagnosis is based on presence of clinical signs (ie obesity, distribution of fat storage, tendency for laminitis) and demonstration of insulin resistance. While insulin resistance is a necessary component of EMS, it is not specific for the syndrome. Insulin resistance is associated with other disease conditions in addition to EMS, such as pituitary pars intermedia dysfunction (PPID) and hyperlipemia, as well as physiologic conditions such as stress, obesity, and pregnancy. Insulin sensitivity is also influenced by factors such as sex, diet, age, and exercise. To further complicate things, horses with EMS can develop PPID.

The “gold standard” test for measuring insulin sensitivity or resistance is the euglycemic hyperinsulinemic clamp technique. However, this test is primarily used in research settings.  A simple screening test to diagnose insulin resistance, easily performed on the farm, is to measure serum glucose and insulin after an overnight fast (horse allowed access to water and a flake of hay during this fast, but no grain or carbohydrate supplements).

Serum insulin concentration above the lab's reference range in the presence of normal or slightly increased glucose concentration is indicative of insulin resistance.  However, mildly affected horses may have normal fasting insulin concentrations. Various types of glucose tolerance tests have been described to diagnose insulin resistance in these horses. 

Several protocols for intravenous glucose tolerance tests have been described.  They all involve giving a bolus of 50% dextrose IV rapidly, followed by collection of multiple blood samples for measurement of serum glucose and insulin. Some protocols include an insulin bolus, in addition to the glucose, while others do not. While it is possible to perform these tests in the field, they are time consuming and are primarily offered at referral centers.  Two tests that can easily be performed in the field include the combined glucose insulin test (CGIT), and the oral sugar test.

The CGIT is performed as follows. The horse is fasted overnight (again, water and a flake of hay are allowed). A baseline blood sample is collected for measurement of glucose and insulin. Then an IV bolus of 50% dextrose, 150 mg/kg, is given rapidly, followed immediately by 0.1 U/kg regular insulin. Blood samples are then collected at 1, 5, 15, 25, 35, 45, 60, 75, 90, 105, 130, 135, and 150 minutes after injection. A hand held glucometer can be used to measure blood glucose concentration. Aliquots of the pre-injection and 45 minute blood samples are sent off for glucose and insulin measurement.

With this protocol, if blood glucose does not return to baseline concentration or if the insulin is > 100 uU/ml by 45 minutes after injection, the horse is determined to be insulin resistant. The additional blood glucose measurements simply help quantify the degree of resistance. Alternatively, the same protocol can be performed, but blood samples only collected prior to injection and again 45 minutes after injection.

For the oral sugar test, the horse is again fasted overnight as described previously. The owner then administers 15 ml/100kg light Karo syrup orally by catheter tip syringe (75ml for a 500 kg horse). The veterinarian then arrives at the farm to collect blood 60-90 minutes later. Insulin concentration > 60 uU/ml at this time is diagnostic for insulin resistance.

Treatment / management recommendations for equine metabolic syndrome primarily include weight reduction, which can be difficult in these horses.  Affected horses tend to maintain body weight on very little feed.  It has been suggested that these horses be fed a diet low in soluble carbohydrates (low glycemic index) and low in fat.  Although it makes sense to avoid feeding grain to these horses (many need nothing more than a good quality hay to maintain body weight), specific dietary studies have not been performed in these horses to substantiate these recommendations. 

Studies in ponies that tended to be insulin resistant showed that feeding a higher percentage fat diet actually resulted in lower serum triglycerides.  However, the higher fat diets did not reduce the insulin resistance.  Current dietary recommendations for severely affected EMS horses are to feed hay with < 10% non-structural carbohydrates at 1.5% of ideal body weight (dry matter basis) per day, along with a protein / vitamin / mineral supplement.  These horses should not be fed any grain, nor have any access to pasture. 

If they have not lost weight after one month on this diet, a further reduction to 1% of initial body weight can be tried. Hay can be analyzed by Equi-Analytical Laboratories.  Alternatively, soaking hay in water for 30-60 minutes will leach some carbohydrate out of it. Some have proposed increasing magnesium or chromium in the diet to decrease insulin resistance, but currently there is no documented evidence to show such supplementation to be helpful, and in fact, specific dose recommendations are lacking. 

Exercise has been shown to be useful to decrease insulin resistance and to promote weight loss, but increasing the amount of exercise may be difficult or impossible in horses with active laminitis. If the horse is able to work, it is recommended it be lunged or ridden for at least 30 minutes at a trot or canter, 4-7 days per week. Horses that are less severely affected can be allowed some access to pasture, which will also provide some exercise. To limit the amount of grass that is ingested, it is recommended that horses be turned out in dirt paddocks with limited access to areas with grass, or that they wear grazing muzzles to decrease the amount of grass they are able to consume.

Drugs being developed in human medicine may one day prove to be useful in horses with equine metabolic syndrome, but at this time little research has been done with these drugs in the horse.  Drugs that increase the action of insulin in tissues include thiazolidinedione and metformin. Drugs that inhibit cortisol synthesis include metapyrone, aminoglutethamide, ketoconazole, miconazole,and trilostane.

Metformin is an oral biguanide drug that has been used in human medicine to increase insulin sensitivity.  There have been scattered reports of the use of metformin in horses with equivocal results. In one report, 15 mg/kg orally twice daily resulted in significant decreases in serum insulin, plasma glucose, and insulin:glucose ratio, without any changes in idiet or management, in a group of insulin resistant horses suffering from recurrent bouts of laminitis. No adverse reactions were reported.

Subjectively, owners reported improved clinical signs in 14 of 18 horses (78%) and similar or worse clinical signs in 4 of the horses (22%).  Subsequently, a pharmacokinetic study showed that bioavailability of metformin is very low in horses. Bioavailability was approximately 7% in unfed horses and 4% in fed horses. The maximal concentration of metformin following oral administration of 6gms (approximately 15mg/kg) in unfed horses occurred 1h after administration and was 0.4 μg/mL. It appears that a larger dose of metformin, given more frequently, would be required in order to achieve a therapeutic blood concentration.

Pioglitazone is a thiazolidinedione class of anti-diabetic agent that increases insulin sensitivity in humans with non-insulin dependent diabetes mellitus. A recent pharmacokinetic study showed that 1 mg/kg, mixed in unflavored gelatin and given orally once daily, resulted in plasma drug concentrations slightly below those considered therapeutic in people. Half life was 9-10h. No adverse effects were noted in any of the horses used in the study.  Therefore this drug may prove to be useful in treating insulin resistance in horses with equine metabolic syndrome or pituitary pars intermedia syndrome.  

In the past, horses with clinical signs of EMS were thought to be hypothyroid and treated with thyroid hormone supplementation.  While it is now clear that these horses have normal thyroid gland function, it is possible that thyroid hormone supplementation may help ameliorate clinical signs through a pharmacologic, rather than a physiologic, mechanism.  Thyroid hormones increase metabolic rate and potentiate the action of β-agonists at their receptor sites. 

Therefore, induction of mild hyperthyroidism could potentiate weight loss by increasing the metabolic rate and by altering fat metabolism.  In addition, β-agonists generally relax vascular smooth muscle, which could lead to increased blood flow to laminitic feet.  Recent studies have shown that administration of thyroid hormone at supraphysiologic doses (0.1 mg/kg) was associated with weight loss and increased insulin sensitivity in a small group of horses.

Thyroid hormone administration may be used short term (3-6 months) to facilitate weight loss in severely obese horses. When used in this manner, it is important that food consumption be limited as described above; otherwise horses may simply consume more food while on the drug and will not lose weight.