Insulin Resistance and Cushing’s syndrome in horses
Adapted from a paper originally written in 2001, AHVMA conference

Introduction
Cushing’s syndrome in horses is currently being frequently diagnosed. However, The symptoms seen in horses labeled with Cushing’s syndrome range from mild to severe and can begin as early as seven years of age. Horses in their late teens and over twenty years old can exhibit many of the “classic” signs of Cushing’s disease including hursutism, polyuria/polydypsia, muscle wasting and refractory laminitis (2, 3). However, many of the younger horses show poor or slow shedding, obesity with lumpy fat pads, poor immune systems, chronic infections and, in some cases, laminitis.
The potential reasons for the apparent increase in the insulin resistance and Insulin resistance-type condition in horses are not totally clear, however there are a number of risk factors that need to be examined. Some of these factors include stress, high sugar content feeds, overuse of drugs and vaccines, genetics, and potentially the feeding of soy products, the frequent use of pyrethroid-based fly sprays and possibly the feeding of large amounts of glucosamine.

Physiology and pathophysiology
Glucose metabolism
Glucose, being water soluble, needs help being transported across the lipid membrane of the cell. The primary way for glucose to be transported into muscle and adipose cells is facilitated diffusion using the transmembrane protein GLUT 4. GLUTs 1, 2, 3 and 5 are transmembrane proteins used in other aspects of glucose transport. GLUT 4 remains inside the cell until it is activated by a stimulus such as insulin, exercise or a compound such as vanadium, all of which move the GLUT 4 into the cell membrane to transport glucose (4). One of the main reasons for insulin resistance is defects in the intra-cellular action of GLUT 4 preventing a normal response to insulin.

Insulin resistance
Many “Cushing’s horses” have elevated insulin levels in their blood (5 Garcia) without concurrently raised or lowered glucose levels (6, 7, 8 Beech, Loeb, Reed). Insulin resistance is a group of symptoms related to hyperinsulinemia (1). The cells show an inability to transport glucose into them.  Insulin resistance occurs in as much as 25% of the non-diabetic population (9). Cushing’s syndrome in horses has some of the same characteristics as Insulin resistance (5, 9) has in people. Some of the specific symptoms are obviously different, however, the general seriousness of the metabolic derangements are very similar, including glucose metabolism and circulatory problems.
People who are susceptible to insulin resistance are frequently from a genetic type considered “thrifty” or in horse terms, “easy keepers” (10, 11). In this type of individual, horse or human, the body is very efficient at storing fat for times of need, and in fact, if fed less, they often become more efficient at storing fat. In humans much of the fat stored from impaired glucose metabolism is distributed centrally, especially around the abdomen. Many horses store their fat in specific places; fat pads on their body, fat above the eyes and cresty necks. The fat on their body frequently becomes lumpy instead of smooth and often this is the first sign that the horse’s metabolism is changing. In fact, if this author sees a horse that has changed from smooth fat to lumpy fat, no matter what the age of the horse is, that horse will be a candidate for treatment as all conditions are easier to treat at the earliest sign of the disease.
The cardiac involvement that occurs in humans may not be directly related to the syndrome in horses, however, no research has been done in this area. Insulin affects the growth of smooth muscle cells in the arteries as well as lipogenesis in arterial vessels. Whether that has direct bearing on the laminitic horse remains to be seen. Dihydroepiandrosterone (DHEA) levels are not monitored in horses, however, in humans increases in insulin levels in some studies are shown to cause a decrease in DHEA. The decrease in DHEA is considered a cardiac disease risk factor.
In horses, it is not uncommon to see elevated insulin levels with normal blood glucose levels. In ambulatory equine practice, where it is often several hours or more until the blood samples are processed, it may also be necessary to collect a special glucose tube to get an accurate measure of blood glucose. The insulin is elevated because it is not able to get into the cells. Normally when a sugar or carbohydrate is eaten, the blood sugar levels increase, insulin is secreted by the pancreas, glucose is carried into the cells by the insulin and the blood sugar goes back to normal. In insulin resistance, the cell wall insulin receptors cannot transport glucose correctly (12, 13). About 25% of the hyperinsulinemic people become NIDDM, however, in horses, the actual occurrence of diabetes is quite low, indicating a difference in physiologic response between the two species. 
Hyperinsulinemia may contribute to hypertension through altering sodium and potassium metabolism. Hypertension does not occur in the equine, though it is unknown whether some of the electrolyte imbalances occur and what effect this may have.
The treatment of people with Insulin resistance using natural medicine incorporates many of the ingredients used when successfully treating the “Cushing’s” horses. The permeability of the cell walls to insulin is enhanced and nutrients are provided to help insulin and glucose pathways function better. The details are discussed below in the treatment section.  
            Many dogs fit the clinical picture of insulin resistance and diabetes, however this author has not collected any data at this time. Many dogs are extremely resistant to losing weight, gain weight on air, yet are not truly hypothyroid. Dogs do have more true hypothyroid problems than horses do. The therapy for Insulin resistance may prove to be very helpful in treating the obese dogs as well.

Potential causes of altered glucose metabolism
            There are many potential reasons for altered glucose metabolism with the concurrent hormonal involvement. The direct cause and effect of the factors discussed in this section has not been established at the present time in equines. However, there are a number of management factors that can be controlled to reduce the incidence and severity of the disease. Some of the contributing factors are chronic stress, high sugar intake, overuse of drugs and vaccines, the potential of new homeopathic miasms being created, the feeding of soy products, pyrethroid fly sprays, genetics, overly rich feed, and possibly the frequent use of glucosamine, though this author has not observed a significant problem with the use of glucosamine.

Stress
            Many horses are living the same high-stress lives as their owners do. Competition horses are often on the road two to five days a week, with little turn-out time and constant work. These horses are often drugged with NSAIDs and exogenous steroids to mask pain and “improve” behavior. Influenza and herpes vaccines are often given every two months, with a large group of vaccines given twice a year as well. Since horses are naturally herd animals that thrive on running free and playing with their buddies, the show life is very unnatural and leads to stress as does confinement of other animals particularly chickens and wild animals (14). In fact, many horses have been identified as having stress-induced gastric ulcers, which can heal in two weeks time if the horses are turned out in a field with the stress of confinement removed and access to green grass increased (15). Stress is well known to raise endogenous glucocorticoid levels in humans (16), and to deplete the B vitamins as well as vitamin C. The immune system is also affected negatively by stress.
            Stress increases endogenous glucocorticoids through the activation of corticotrophin-releasing hormone (CRH). The action of glucocorticoids is to inhibit insulin sensitivity and glucose uptake by the muscle and increase insulin sensitivity in the adipose cells and to increase glycogen formation by the liver which increases blood glucose (16). Cortisol increases the rate of lypolysis and redistributes the fat into the liver and abdomen. During stress glucocorticoids inhibit pituitary gonadotropin secretion suppressing reproduction. Growth hormone and thyrotropin secretion are also inhibited (16).
           
Sugar intake
High sugar content feeds are commonly used in horses. In humans increased insulin levels can begin in childhood (17). Many horses completely change their behavior for the better and become more relaxed after removing the sweet feeds and replacing them with a plain grain or pelleted feed. The change can be dramatic. If the outward behavior of the horse changes so much, the internal stress must have been significant. Most of the prepared diets for foals and young growing horses are extremely high in sugar. The connection between feeding high sugar diets and Cushing’s or Insulin resistance has not been proven in horses, but there is a strong connection being made in humans with high sugar diets and insulin resistance (18).

Drug and vaccine use
The overuse of drugs and vaccines is rampant in many horses, especially horses used in competitions. Many competition horses receive multiple drugs during a show, and many live on a variety of non-steroidal anti-inflammatory (NSAIDs), antibiotics, steroids and bronco-dilators all the time. The level of internal stress created by the use of such a large quantity of drugs has a negative effect on the entire immune system, the health of the gastro-intestinal system and the ability of the horse to digest and absorb nutrients correctly.
The overuse of vaccines is understood to create problem with the immune system, though there is little human research to prove a connection between vaccines and insulin resistance. There are some reports of vaccines as part of the possible cause of insulin dependant diabetes (19 Ovetchkine), but very little proof. Clinically, however, many of the homeopathic remedies that fit the Insulin resistance and Cushing’s horses are the vaccinosis remedies. The vaccinosis remedies produce some excellent results, though some cases require other remedies not related to vaccinosis.

Miasms
As Insulin resistance cases are examined from a homeopathic perspective, one consideration for a disease with a consistent pattern has to be the possibility that a new miasm is being formed, or that the vaccines being used are creating this miasm. This author has not examined that hypothesis in detail, however there is a pattern the homeopathic prescribing that warrants more consideration.

Soy products
            Soybean meal has been a large part of horse feed for many years. The soy used is a byproduct of the vegetable oil industry that needs a place to dump its waste. Animal feeds are a great place to do that. Unfortunately, because the soy is a byproduct the meal is energy deficient because the natural oils in the soybeans which aid digestion and utilization are removed through a toxic solvent process. Feeding soybeans contributes to incomplete digestion, and all the problems that come with it. The only difference between soybean meal and urea is that urea breaks down instantly and soybean meal takes longer; both can be toxic to horses when fed in excess.
Research on the beneficial and adverse effects of soy are divided, some researchers showing positive and some negative effects of soy on glucose metabolism. The phytoestrogen isoflavones present in high quantities in soy fed to people and found in laboratory animal diets (made with the same ingredients as horse feed) have estrogen-like effects and have the potential to modulate genotypic and phenotypic expression, especially when fed to young developing animals (20). The isoflavones present in infant’s blood when fed soy formula was 13,000 to 22,000 times higher than infants fed breast milk (21). Horses are not generally fed a milk replacement unless they are orphaned, but the creep and young horse rations are very high in protein, and that protein is derived primarily from soy.
Soy can adversely affect the thyroid gland and is implicated in the formation of goiter (22, 23, 24). Reduced thyroid function has a profound and clear effect on insulin resistance and related symptoms (25 Iiataka). Thyroid hormones affect carbohydrate metabolism through increasing intestinal glucose absorption and facilitating the movement of glucose into fat and muscle cells (14 Cunningham). Thyroid hormones facilitate insulin-mediated glucose uptake by the cells.

Pyrethroid-based fly sprays
Pyrethroid insecticides are used during the warm seasons on many horses. They are the most frequently-used insecticides world-wide and are generally considered safe by the EPA. The labels on the insecticides suggest spraying the horse every few days, or even just once a week. However the sprays generally are effective for a few minutes, sometimes as much as thirty minutes, so the owners spray their horses repeatedly, or saturate the skin in hopes that the flies will stay away. The effect is the dose to the horse is significantly higher than the manufacturer has the product labeled for, and the human dose is probably much higher than planned due to the handling of the horse.
Many equine barns have overhead spray systems that put out doses of the spray every few hours or more often. This spray goes onto the horse, into the water or feed bucket and onto the hay as well as into the respiratory system of the horse. Horses also reach around and bite at their sides when flies land on them, increasing oral exposure. The latest insecticide being sold to the horse owner is a super-concentrated pyrethroid to apply in a similar fashion to the dog tick product, Front LineTM.  Owners believe it is the same product due to the marketing the company does.
Some companies are selling their product as all-natural, when in fact, whether naturally derived or synthesized the pyrethrin compound is the same. Clients believe the companies when they are told the product is all natural, therefore safe. One study found pyrethroid residues as well as many other herbicide and pesticide residues in animal feed, adding to load already in the body (26). Overall horses are exposed to high levels of insecticides, both through oral, respiratory and topical routes. These sprays may be relatively safe at low concentrations, however, no one has studied the effects of the high doses on the animals and people in the barns. Clients who have converted to non-toxic repellants report that their health is better, and that they have fewer allergies and headaches.
Pyrethroid-based fly sprays (and flea sprays) can depress thyroid function (27, 28, 29) and the thyroid can play a role in insulin resistance as discussed above. Pyrethroids also have estrogenic activity as do many insecticides, but no progesterone activity in most studies (30, 31). Though it is less relevant to insulin resistance, pyrethroids also affect antibody production and macrophage function (32, 33).
Due to the high concentrations of pyrethrins in many horses’ environments and their ability to disrupt the hormonal system, it would be advisable to reduce the exposure as much as possible.

Glucosamine
Glucosamine is being fed to horses in large quantities, mostly for arthritis-related conditions. The effects of short-term glucosamine infusions in humans and laboratory animals are to increase insulin resistance in all species tested, however using different pathways in different species (34, 35). It is possible that the horse has an even different mechanism. Studies involving already hyperglycemic states showed the negative effects of glucosamine, while euglycemic participants showed no insulin resistance (35). Since most horses do not appear to be hyperglycemic, glucosamine may have no negative effect.
Glucosamine has been used orally for many years without insulin resistance being reported as a side effect and searching for studies using oral glucosamine for testing insulin resistance were not available. Glucosamine has been considered safe, and clinically this author has seen good responses to treatment for Insulin resistance and Cushing’s disease in horses that are concurrently on glucosamine. So, at present, it would seem prudent to observe responses to treatment and only remove glucosamine if the expected improvement is not occurring in an individual case. Some conventional doctors are using these studies to argue against the use of glucosamine, so it is important to understand the data they are referring to.

Genetics (thrifty phenotype)
Genetics plays a role in insulin resistance and sensitivity to rich foods. In humans the “thrifty genotype” has been described (10). The body of both humans and horses is well adapted to periods of famine and is capable of storing fat easily when plenty of glucose (food) is available. Most breeds of horses (especially Morgans, Arabs, pony breeds and donkeys) have been taken from natural environments where good food was scarce and placed on rich well-fertilized pastures where every bite of grass contains enough nutrients to fuel the horse for a long time. Then concentrated feeds and rich hay are added and horses become obese rapidly. In humans, however, not everyone with insulin resistance is obese, it occurs in the non-obese as well (36). Horses with Insulin resistance likewise are commonly overweight, however, not all are.
During an oral glucose tolerance test, human subjects who were already obese showed greater insulin resistance and increased blood glucose levels than those that had never been overweight suggesting a threshold effect of total body fat (37). Clinically, this author has observed horses and ponies to have a similar threshold in that they will develop symptoms, especially laminitis when they reach a certain level of obesity. The composition of the fat changes from smooth to harder and lumpier, with the characteristic crest. Until this certain point is reached, many of these horses seem to do well.

Clinical signs related to Insulin resistance 
The clinical signs most commonly associated with Insulin resistance in horses are poor coat with slow shedding, obesity with lumpy fat pads, poor immune systems, chronic infections and in some cases, laminitis. Other symptoms may appear in certain individuals, with some horses exhibiting very few clinical signs, while others have many signs that have been attributed to Cushing’s disease (table 1). There are horses with no outward clinical signs, yet blood work shows an increase in insulin and possibly other parameters.
Many horses diagnosed with Insulin resistance are overweight and are very easy keepers, sometimes unable to eat more than a small amount of hay each day to try to control their weight. In some cases, horses that were previously easy keepers suddenly start requiring more food to maintain their body weight. The overweight horses generally have fat pads in specific places and cresty necks. The crest will become harder as the glucose metabolism becomes altered. The fat pads are generally behind the shoulder blades, on each side of the tail and along the lumbar area, In addition, the fat on their body is often visibly lumpy. Some of the horses begin to lose weight yet maintain their fat pads despite the obvious weight loss.

Diagnosis
The most important diagnostic tool for identifying Insulin resistance as the primary problem is the history and clinical signs. A thorough physical exam may reveal some of the less obvious signs such as poor teeth and reproductive problems.
The supporting lab work can be inconclusive, but can be helpful and should be performed if possible (39, 40). Part of the problem is that in equine practice single blood samples are taken whenever the practitioner is at the farm, so there is little standardization of the timing of the samples. Many parameters used have diurnal variations and may change due to stress or other factors including the amount of exercise a horse has had before the blood was drawn.
Elevated blood cortisol can indicate high levels of stress in the body. Is the high cortisol coming from the Cushing’s or has the Cushing’s come from chronic stress affecting the feedback system in the pituitary gland? Cortisol as a single sample appears to be an inaccurate test for Cushing’s disease (40, 6). However, in this author’s opinion, an increase in endogenous cortisol, even without other parameters being altered, indicates an endocrine imbalance.
Resting insulin levels (5), ACTH (40, 41) and glucose are sometimes used. Clinically, even a slightly high insulin confirms altered glucose metabolism in this author’s experience. In some cases the blood levels of glucose are altered or raised as well, confirming a diagnosis of Insulin resistance that could become diabetes. Certainly not all cases will have these parameters altered, but when they are, a confirmation can be made.
Several other diagnostic tests used include the ACTH stimulation test and the low-dose dexamethasone suppression test (LDDS). However, in holistic practice this author avoids using the LDDS and stressing the adrenals further. Another possible test is the oral glucose absorption test (42). If this test is performed, a concurrent insulin test should be performed. Little if any data has been gathered in the equine relating insulin and glucose levels during a glucose tolerance test.
A thyroid panel can be done, however the single sample test usually performed in equine practice is little more than a window into thyroid function and rarely proves valuable, except in motivating the clients to work hard to improve a low test (41).        
Some new laboratory profiles are being offered that combine certain tests taken at certain times of the day. These may be more accurate in positively diagnosing full-blown Cushing’s disease, but research needs to be performed before these tests can be considered more accurate than those that are already available. Most of these tests do not define the more subtle aspects of Insulin resistance.
While doing the other laboratory tests, a complete blood count (CBC) is advisable to help check the immune system status. Many horses seen in this author’s practice have low white blood cell (WBC) counts. The neutrophil and lymphocyte counts vary, with one or both contributing to the low WBC. A chemistry screen is also advisable since some of these horses have a variety of metabolic problems associated with their condition, including liver disease and chronic infections.

Treatment
            The treatment of Insulin resistance is multifaceted and is the best example of a truly holistic approach, as each horse is different, and each needs to be reevaluated regularly to see what is needed.

Nutrition
Nutritional support is critical in treating the Insulin resistance horse and includes the basics of feed, water and hay as well as specific nutrients. The nutrients discussed here are ones this author has found clinically useful.

Feed
Once the digestive system is supported, high quality nutrients should be provided. The nutritional requirements for horses with Insulin resistance appear to be higher than normal horses. In this author’ experience, horses with Cushing’s-based laminitis require a high fiber, low carbohydrate diets. Grass or other lower protein hays can be given free choice. Some horses can tolerate an alfalfa/grass hay, especially if more protein is needed. Generally alfalfa should not be used alone and should not be fed to the very overweight horse.
The feed should be low in sugar if the horse has any signs of Insulin resistance with altered insulin levels or diabetes. Sweet feeds should be avoided.
When evaluating the feeding program, examine the treats being given. Many people feed treats high in sugar including large quantities of apples and carrots. Plain corn (about 25%), barley (about 35%) and oats (about 45%) make a simple, clean grain mixture without sugar. Some of these grains may not be available or useable in certain parts of the country depending on harvest situations. Some horses react poorly to eating oats; if that seems to be the case, barley and corn together are enough.
Higher levels of protein (up to 14%) and calories may be needed in the horses with weight loss problems, but should not be fed to normal or overweight horses (43, 44). Horses that are normal weight or underweight often do well on the senior diets, which are higher in protein and fat. Many chronic laminitis horses lose weight due to the stress of walking in pain and actually need increased amounts of feed. Practitioners often restrict feed in all laminitic horses, however, some horses need extra calories to maintain normal physiologic functions. Increased calories can be given as fats (vegetable oils or rice bran) and are well digested by most horses. Increasing total calories with oils may be preferable to using high-protein feeds and hays.

Antioxidants
Coenzyme Q10 is useful in reversing free-radical damage secondary to sepsis from an endotoxin overload (http://shop.harmanyequine.com/shop/product_info.php?cPath=4&products_id=86). This is thought to occur with the coenzyme Q10 acting as an oxygen free-radical scavenger, thus stabilizing mitochondrial membranes, and by inhibiting the arachidonic acid metabolic pathway and the formation of various prostaglandins (45 Lelli). Coenzyme Q 10 clinically seems to be one of the best antioxidants for use in laminitis cases. Horses become less painful rapidly when Co Q 10 is used without concurrent NSAIDs. The therapeutic dose is 300-600 mg per day for the first week or two, then the dose can be decreased slowly to a maintenance of about 100 mg per day.
Vitamin C is an excellent antioxidant that can regulate the phagocytic process in endotoxic shock, mainly by decreasing free radical production (http://shop.harmanyequine.com/shop/product_info.php?cPath=4&products_id=103). Vitamin C is also a nutrient for collagen manufacture as well as offering some immune system support. Doses range from 3 to 8 gms per day. Horses tolerate these doses well with few cases of diarrhea or stomach irritation.
Other antioxidant nutrients that may be useful are Vitamin E, superoxide dismutase (SOD), and dimethylglycine (DMG). These antioxidants are generally used by the author in the more refractory cases.

Minerals
One of the most important aspects of any nutritional program for horses is the use of free-choice minerals with the salt fed separately (http://shop.harmanyequine.com/shop/product_info.php?products_id=2&osCsid=b257fbb60e0a9303c933cf5ad4fe769f). Many Insulin resistance horses will eat large quantities of minerals for extended periods of time indicating their need for minerals.
A commercial salt-mineral block contains about 94% salt so horses that do not crave salt will not consume the amount of minerals they need. The author have observed horses consuming large quantities of minerals when provided mineral supplementation with salt fed separately.
There are several key minerals needed for glucose metabolism that help the Insulin resistance horses. Magnesium affects insulin secretion and its action in the cells. Magnesium also helps the cells be more flexible and permeable to insulin (46). Chromium helps make muscle more sensitive to insulin so glucose can be taken into the muscle cells more easily. Chromium is also related to elevated blood sugar and has been shown to be effective in reducing fasting blood sugar levels.(47, 48). Vanadium or vanadyl sulfate has actual insulin-like effects on glucose metabolism (French) which helps transport glucose into the cells (49). (http://shop.harmanyequine.com/shop/product_info.php?cPath=4&products_id=11)
MSM is a natural source of sulfur. Sulfur is important as it helps make the disulfide bonds in the laminae. The disulphide bonds are an important part of the tissue that connects the hoof wall to the healthy lamina (50 Grosenbaugh). Sulfur may be an important nutrient for these horses and can be fed free choice or in a supplement such as MSM.

Vitamins
It is important to supply high quality supplements to help these horses heal. Prepared foods cannot have all the vitamins needed by a sick animal. However, formulated supplements which contain low quality, synthetic vitamins, inorganic minerals, and fillers may actually cause the horse's system to become more out of balance. Food-source vitamin mineral supplements include: blue-green algae, kelp, apple cider vinegar, carrots, and oranges. Several companies manufacture additive-free supplements.

Essential fatty acids
Essential fatty acids (EFAs) are needed to help make the cell wall more sensitive to insulin (51, 52 McCarty, Gerbie). Omega 3 fatty acids are especially deficient in human diets and may be deficient in many equine diets. Some of the high-fat equine foods use animal fat that is high in saturated fats rather than vegetable oils, though more companies are using vegetable oils currently than in the past. Flax and hemp oil or stabilized flax meal provide Omega 3 fatty acids that are palatable to the equine, though fish oils may have an even better fatty acid profile (52 Gerbie) (http://shop.harmanyequine.com/shop/product_info.php?cPath=4&products_id=11).

Pituitary support          
This author has been using a pituitary glandular support along with general glandular support because the pituitary gland is central to the function of the entire hormonal system. Glandulars can be useful in equine nutrition and should be considered instead of synthetic organ replacement, as in thyroid therapy or as support for other organs such as the pituitary gland (http://shop.harmanyequine.com/shop/product_info.php?cPath=4&products_id=124). Cushing's and Insulin resistance horses are about the only time this author will use glandulars because of the vegetarian nature of the horse. Additional thyroid supplementation natural or homeopathic, may be necessary in some cases.

Homeopathy
Constitutional homeopathic medicines selected according to the symptoms the individual is exhibiting are a key to correcting these horses for the long term. If homeopathy is used, it is advisable to work with an experienced homeopath. Constitutional homeopathy needs be prescribed based on the history, clinical signs and personality. It is not possible to cover the details or remedies here, however, the principles of classical homeopathy are followed by this author.
             
Chinese medicine
Chinese medicine, both with acupuncture and herbs can be used to help these horses. It is best to work with a veterinarian experienced in either herbs or acupuncture. Acupuncture treatment should be directed towards the acupuncture points that relate to imbalances diagnosed in each individual animal according to the principles of Chinese medicine. Chinese herbal formulas have been very successful in some cases.

Western Herbs
Aloe vera is a nutritional herb, which will support healthy bacterial growth and help heal the damaged intestinal lining (http://shop.harmanyequine.com/shop/product_info.php?cPath=16&products_id=133). Be sure to use good quality aloe since it takes special processes to save the active ingredients, and feed at a rate of 1-4 ounces (depending on the product) each feeding for 2-4 weeks.
Slippery elm bark is another nutritional herb, which protects and aids in healing the intestinal wall. It is especially useful with aloe vera to heal the intestinal irritation secondary to the use of non-steroidal anti-inflammatory drugs such as phenylbutazone.
Chasteberry or vitex can be a useful supportive herb for some cases, though is probably not curative for most horses in the long run. Proprietary formulas are being promoted heavily, however, any good quality form of the herb should be helpful.
There are some formulas designed to improve circulation in the feet that may be very useful. Some of the “Cushing’s” formulas may be helpful, but probably are not as effective as many of the other therapies listed in this paper.

Vaccinations
This author would recommend not vaccinating or decreasing the vaccination program to the absolute minimum. Vaccine titers are available for most diseases, and most horses tested seem to be maintaining good titers from previous vaccinations. Insulin resistance is a condition of mature horses, most of whom have been vaccinated heavily or have been exposed to many diseases and have natural immunity.

Environment
Many horses are kept in high-stress situations that contribute to adrenal stimulation and cortisol release. Competition horses are often traveling to shows two to four days of the week, living in trailers and stalls with little if any turnout time, and with heavy use of NSAIDs (such as Bute) during the competitions. If it is possible to decrease environmental stress, the horse will benefit greatly. Many of these horses may be past their high-stress years, and the current owner may not be showing heavily or keeping the horse in the high stress environment, yet Cushing's disease is still a factor. These horses are experiencing the previous lifetime of stress, excessive drug use and poor nutrition. Insulin resistance is the result of many years and many factors.
Pasture turn-out time is very important; however many horses cannot be on rich pasture without exacerbating their symptoms. Clients should be encouraged not to fertilize their fields or mow and manage them too carefully. Natural fertilization with trace minerals is a good practice, though if grass becomes too rich from good organic practices an overweight horse will result. A few weeds (herbs) are a good thing. For many horses a “fat pen” will need to be built, just a small area outside with minimal grass so they can be out in the sunshine and near their friends, but not have too much grass.
           
Conclusion
Treat each horse as an individual and seek quality practitioners to help you. Try to recognize the signs as early as possible, if you see horses starting to exhibit any of the clinical signs, so that treatment can be more successful. Enjoy the challenge.

References

1. Zavaroni I, Bonini L, Fantuzzi M, et al. Hyperinsulinemia, obesity and syndrome X. J Int Med. 1994;235: 51-56.
2. Dybal, N. Pituitary pars intermedia dysfunction (equine Cushing's-like disease). In: Robinson NE, ed. Current Therapy in Equine Medicine. Philadelphia: WB Saunders; 1997:499-503. Pollitt, C. Equine laminitis: A revised pathophysiology. Proceedings Am Assoc Eq Pract, 1999:45: 188-192.
3. Boujon CE, Bestetti GE, Meier HP et al. Equine pituitary adenoma, a functional and morphological study. J Comp Path. 1993;109: 163-178.
4. Shepherd PR, Kahn BB. Glucose transporters and insulin action. Implications for insulin resistance and diabetes mellitus. N Engl J Med. 1999;341(4):248-257.
5. Garcia MC, and Beech J. Equine intravenous glucose tolerance test: glucose and insulin responses of health horses fed grain or hay and of horses with pituitary adenoma. Am J Vet Res. 1986;47: 570-572.
6. Beech J and Garcia M. Hormonal response to thyrotropin-releasing hormone in healthy horses and in horses with pituitary adenoma. Am J Vet Res. 1985;46: 1941-1943.
7. Loeb WF, Capen CC and Johnson LE. Adenomas of the pars intermedia associated with hyperglycemia and glycosuria in two horses. Cornell Vet. 1966;56: 623-626.
8. Reed, SM. Pituitary adenomas: equine Cushing’s disease. In: Reed SM and Bayly WM, eds. Equine Internal Medicine, Philadelphia: WB Saunders Company; 1998: 912-915.
9. Reaven, GM. Pathophysiology of insulin resistance in human disease. Phys Rev. 1995;75(3): 473-485.
10. Neel JV. The “thrifty genotype” in 1998. Nutr Rev. 1999;57(5): S2-S9.
11. Coffman JR, Colles CM. Insulin tolerance in laminitic ponies. Can J Comp Med. 1983;47:347-351.
12. Adamo M, LeRoith D, Simon J. Effect of altered nutritional states on insulin receptors. Ann Rev Nutr. 1988;149-166.
13. Cline GW, Peterson KF, Krssak M, et al. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. N Engl J Med. 1999;341: 240-246.
14. Cunningham JG. Endocrine glands and their function. In Textbook of Veterinary Physiology. 2nd ed. WB Saunders Co, Philadelphia, PA. 1997, p404-439.
15. Vatistas, NJ. Treatment of gastric ulceration. 36th Br Eq Vet Assoc Congress, Harrogate, Sept 1997, p54.
16. Chrousos GP. The role of stress and the hypothalamic-pituitary-adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S50-5.
17. Barnard R, Ugianskis E, Martin D, et al. Role of diet and exercise in the management of hyperinsulinemia and associated atherosclerotic risk factors. Am J Cardiol. 1992;69: 440-444.
18. Garg A, Bantle H, Henry R, et al. Effects of varying carbohydrate content of diet in patients with non-insulin-dependant diabetes mellitus, JAMA. 1994;271: 1421-1428.
19. Ovetchkine P. [Secondary effects of vaccinations]. Arch Pediatr. 2001 Mar;8(3):316-20.
20. Brown NM, Setchell KD. Animal models impacted by phytoestrogens in commercial chow: implications for pathways influenced by hormones. Lab Invest 2001 May;81(5):735-47.
21. Setchell KD, Zimmer-Nechemias L, Cai J, et al. Isoflavone content of infant formulas and the metabolic fate of the phytoestrogens in early life. Am J Clin Nuti 1998 Dec;68(6 Suppl):1453S-1461S.
22. Ishizuki Y, Hirooka Y, Murata Y et al. [The effects on the thyroid gland if soybeans administered experimentally in healthy subjects]. Nippon Naibunpi Gakkai Zasshi. 1991 May 20;67(5):622-9.
23. Divi RL, Chang HC, Doerge DR. Anti-thyroid iso-flavones from soybean: isolation, characterization, and mechanism of action. Biochem Pharmacol. 1997 Nov 15;54(10):1087-96.
24. Suwa J, Koyanagi T, Kimura S. Studies on soybean factors which produce goiters in rats. J Nutr Sci Vitaminol (Tokyo). 1979;25(4):309-15.
25. Iitaka M, Katayama S. [Insulin resistance in pituitary, thyroid, and adrenal diseases]. Nippon Rinsho. 2000 Feb;58(2):451-5.
26. Chamberlain SJ. Determination of multi-pesticide residues in cereals, cereal products and animal feed using gel-permeation chromatography. Analyst. 1990 Sep;115(9):1161-5.
27. Akhtar N, Kayani SA, Ahmad MM et al. Insecticide-induced changes in secretory activity of the thyroid gland in rats. J Appl Toxicol 1996 Sep-Oct;16(5):397-400.
28. Maiti PK, Kar A. Is triiodothyronine capable of ameliorating pyrethroid-induced thyroid dysfunction and lipid peroxidation? J Appl Toxicol. 1998 Mar-Apr;18(2):125-8.
29. Zaidi SS, Bhatnagar VK, Gandhi SJ, Shah MP, Kulkarni PK, Saiyed HN. Assessment of thyroid function in pesticide formulators. Hum Exp Toxicol. 2000 Sep;19(9):497-501.
30. Sumida K, Saito K, Ooe N, Isobe N, Kaneko H, Nakatsuka I. Evaluation of in vitro methods for detecting the effects of various chemicals on the human progesterone receptor, with a focus on pyrethroid insecticides. Toxicol Lett. 2001 Jan 3;118(3):147-55.
31. Go V, Garey J, Wolff MS, Pogo BG. Estrogenic potential of certain pyrethroid compounds in the MCF-7 human breast carcinoma cell line. Environ Health Perspect. 1999 Mar;107(3):173-7.
32. Punareewattana K, Smith BJ, Blaylock BL, Longstreth J, Snodgrass HL, Gogal RM Jr, Prater RM, Holladay SD. Topical permethrin exposure inhibits antibody production and macrophage function in C57Bl/6N mice. Food Chem Toxicol. 2001 Feb;39(2):133-9.
33. Diel F, Horr B, Borck H, Savtchenko H, Mitsche T, Diel E. Pyrethroids and piperonyl-butoxide affect human T-lymphocytes in vitro. Toxicol Lett. 1999 Jun 30;107(1-3):65-74.
34. Monauni T, Zenti MG, Cretti A et al. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes 2000 Jun;49(6):926-35.
35. Miles PD, Higo K, Olefsky JM. Exercise-stimulated glucose turnover in the rat is impaired by glucosamine infusion. Diabetes 2001 Jan;50(1):139-42.
36. Prando R, Chell V, Melga P et al. Is type 2 diabetes a different disease in obese and nonobese patients? Diabetes care, 1998;21(10):1680-85.
37. Rosenbaum M, Hirsch J, Murphy E, Leibel RL. Effects of changes in body weight on carbohydrate metabolism, catecholamine excretion, and thyroid function. Am J Clin Nutr. 2000 Jun;71(6):1421-32.
38. Dybal NO, Hargreaves KH, Madigan JE et al. Diagnostic testing for pituitary pars intermedia dysfunction in horses. J Am Vet Med Assoc. 1999;204: 627-632.
39. van der Kolk H. Diseases of the pituitary gland, including hyperadrenocorticism. In: Watson TDG ed. Metabolic and Endocrine Problems of the Horse, Philadelphia: WB Saunders; 1998: 41-59.
40. Hillyer MH, Taylor FGR, Mair TS, et al. Diagnosis of hyperadrenocorticism in the horse. Equine Vet Edu. 1992;4: 131-134.
41. Sojka JE, Johndon MA and Bottoms GD. Serum tri-iodothyronine, total thyroxine, and free thyroxine concentrations in horses. Am J Vet Res. 1993;54: 52-55.
42. Field JR and Wolf C. Cushing’s syndrome in a horse. Eq Vet J. 1988;20: 301-304.
43. Glade MJ, et al. Dietary protein in excess of requirements inhibits renal calcium and phosphorus in young horses. Nut Res Intern. 1985;31: 649-660.
44. Miller-Graber PA, Lawrence LM, Foreman JH, et al. Dietary protein level and energy metabolism during treadmill exercise in horses. J Nutr 1991;121: 1462.
45. Lelli JL, Drongowski RA, Gastman B, et al.  Effects of coenzyme Q10 on the mediator cascade of sepsis. Circ Shock. 1993;39(3): 178-87.
46. Paolisso G, Sgambato S, Gambardella A, et al. Daily magnesium supplements improve glucose handling in elderly subjects. Am J Clin Nut. 1992;55: 1161-1167.
47. Linday LA. Trivalent chromium and the diabetes prevention program. Med Hyp. 1997;49:47-49.
48. Evans GW, Bowman TD. Chromium picolinate increases membrane fluidity and rate of insulin internalization. J Inorg Bio. 1992;46:243-250.
49. Schechter LI, Meyerovitch, et al. Insulin-like actions of vanadate are mediated in an insulin-receptor-independent manner via non-receptor protein tyrosine kinases and protein phosphotyrosine phosphates. Mol Cell Biochem. 1995;153(1-2): 39-47.
50. Grosenbaugh DA, Hood DM. Keratin and associated proteins of the equine hoof wall. Am J Vet Res. 1992;53(10): 1859-63.
51. McCarty MF. Complementary measures for promoting insulin sensitivity in skeletal muscle. Med Hyp. 1998;51:451-464.
52. Gerbie A, Maixent JM, Ansalki JL, et al. Fish oil supplementation prevents diabetes-induced nerve conduction velocity and neuroanatomical changes in rats. J Nutr. 1999;129: 207-213.

Table 1
Signs attributed to Cushing’s disease
hirsutism
not shed out in the summer
hyperhydrosis
refractory laminitis
winter laminitis
weight problems (over- or underweight).
sluggish thyroid glands
insulin resistance
thyroid dysfunction
muscle soreness
diabetes
polyuria/polydipsia (Pu/Pd)
collagen breakdown
poor hair coat.
frequent infections of the skin or other organs
colic
poor teeth
multiple dental abnormalities
lowered immunity to intestinal parasites
altered intestinal function laboratory tests
decreased intestinal wall integrity.
infertility
muscle wasting

 

This article cannot be reused or redistributed under the terms of the Harmany Equine fair use policy. If you are interested in reprinting this article contact us directly at info@harmanyequine.com