A unification theory

Seven of your clients' horses are being fed the same grain diet, being pastured on the same grass field and being exercised the same way. Yet only one of them experiences an episode of laminitis. Why?

Chronic or recurrent laminitis is believed by some researchers to have a basis in insulin resistance, which causes decreased blood glucose to the foot's tissues. These histologic changes closely mimic those seen in peripheral neuropathies in human diabetics. If additional research confirms these theories, then new and potentially powerful methods of treating equine laminitis by way of addressing glucose homeostasis may be forthcoming.

You have treated the last 10 cases of laminitis presented to your clinic with good aggressive management and cutting-edge treatment and while most have responded and done well, a few have been slow to respond. Perhaps one or two, despite doing everything you could do, did not improve and were ultimately lost. Why?

There are some horses in your practice that are such easy keepers that they seem to get fat on air. They have thick, cresty necks and fat deposits over their backs and hips, though the owners have them on minimal rations. Your clients report that these horses have tremendous appetites though they are obviously fat. Dietary management is less than rewarding and exercise does not work well, as these horses seem to be slow and lethargic with poor muscle development. Why?

There is an 8-year-old horse in your practice exhibiting clinical signs that you have seen before. He is overweight and may have excess fatty deposits through his back or crest. He has a long, coarse haircoat that may not shed well and he may have problems sweating normally. This horse may have recurrent laminitic problems or may be prone to dermatitis or other infections. You think that this horse has Cushing's disease but he is too young and the blood work does not support that familiar diagnosis. Why?

Common cause

The answer to these questions may lie in a relatively common disease of humans but one that has been rare, at best, in horses. Typically diabetes has been thought to be uncommon in horses.

A literature review of the last 50 years shows a small number of cases of equine diabetes that were caused by either pancreatitis or by tumors of the pituitary gland.

Recently, however, researchers have speculated that horses may be much more inclined to develop a resistance to insulin that can lead, as in humans, to adult-onset or type-2 diabetes. These horses may mimic Cushinoid horses without the appropriate blood test results and they may exhibit a variety of clinical signs and disease patterns that have been confusing veterinarians for some time. Perhaps it is because horses are living longer and we are now seeing more and more of these cases. Perhaps these cases were always there but were going undiagnosed.

Increased care and attention are more commonly being paid to equine senior citizens and problems that might have been overlooked as simply "complications due to aging" are now being closely investigated. Any number of factors may have made diabetes more of a potentially recognizable disease in horses but the impact of this diagnosis is important.

Because this theory of insulin resistance and eventual diabetes answers a number of existing questions and because it fills in the holes in our understanding of a number of disease processes, it is being referred to as the "unification theory." If additional research confirms these speculations, this theory may point to some exciting new treatments for some old, frustrating problems.

No response

Insulin resistance is a condition that develops when the body's cells do not correctly respond to insulin.

Insulin secretion from the pancreas is triggered by a rise in blood glucose after eating a meal containing sugars or starches. Insulin stimulates cells to take up this circulating glucose and once in the cell it is used for energy or converted to glycogen or fat for storage. In conditions of insulin resistance, the cells do not respond to normal levels of insulin.

At first the body simply produces more insulin and these higher levels regulate blood glucose. Gradually though, the body fails to respond to higher and higher levels of insulin and eventual exhaustion and failure of the insulin producing cells of the pancreas occurs. At this point, type 2 diabetes is said to exist.

The exact dividing line is not specific. In fact, in humans there is a level of damage prior to diabetes that is called impaired glucose tolerance (IGT). These levels or conditions are partially academic and the bottom line is that insulin resistance should be looked at as a precursor to more serious disease and treated accordingly.

The "unification theory" would encourage veterinarians to look more closely at individual cases and not to put all older, hairy, overweight horses into the "Cushing's disease" category. Some of these horses may be insulin resistant and may respond to different treatment protocols.

Resistance

Typically, insulin resistance is associated with obesity because of the metabolic changes the body goes through as the blood glucose levels rise.

Temporary insulin resistance has been noted to occur in conditions of inflammation, infection, injury and other conditions involving hormonal variations such as puberty and pregnancy. It is not exactly known how insulin resistance relates to these disease states but human studies have shown that sustained elevated blood glucose leads to changes in the microvasculature of many tissues and the production of various cellular cytokines. These particles, in turn, cause reduced nerve perfusion and eventual hypoxia and tissue death.

It is well established that humans suffering from diabetes are at risk of developing severe infections, kidney and liver damage and peripheral nerve and vessel damage often leading to loss of digits or toes. Foot disease is, in fact, the most common complication of diabetes leading to hospitalization.

Of greatest benefit

It is here, in the discussion of foot disease, that the unification theory may benefit horses the most.

Recent research by Dr. C.C. Pollitt of the School of Veterinary Science at the University of Queensland in Australia suggests an underlying cause of all laminitis cases may be altered glucose metabolism. Lack of glucose in peripheral tissue of humans (as seen with diabetes) leads to peripheral neuropathy and to ischemic damage.

In Pollitt's studies, impaired glucose in hoof extract tissue led to damage of the basement membrane and separation of the dermal laminae from the epidermal laminae. This explains why one specific horse (that may be insulin-resistant to some degree) would founder when others in a similar environment do not or why one horse may not respond to laminitis treatment while other affected horses do respond.

Insulin resistance could be secondary to elevated cortisol levels resulting from primary Cushing's disease or from exogenous corticosteroid use. Generally "safe" or therapeutic doses of dexamethazone and other similar drugs may potentiate elevated glucose levels in already insulin-resistant horses. This might explain why certain horses founder after receiving doses of these drugs that cause no problems in most equines.

Increased cortisol levels can also be found in severely stressed or systemically ill horses. Many veterinarians have dealt with "stress founders" and with founder following uterine or other infections. Pollitt suggests that all these cases of laminitis share a cause relating to insulin resistance rather than to strict endotoxemia. Other researchers are also postulating that in cases of grain overload founder, elevated glucose levels cause a "toxicity" that causes temporary insulin resistance (so much glucose floods the system in such a short time that the body cannot produce enough insulin to compensate). This insulin resistance is intensified by elevated cortisol levels induced by endotoxemia seen in these cases. If this part of the theory is proven correct then the best method of treating or preventing laminitis is by treating or preventing conditions that lead to insulin resistance. There are many current projects looking at methods of doing that.

Insulin inhibits the breakdown of triglycerides (fat) into free fatty acids (FFA) and glycerol. In the absence of insulin this process of lipolysis can occur and FFA are released.

FFA are transported to the liver, packaged as very low density lipoproteins (VLDL) and stored in adipose tissue for potential later use. The cresty necked horses or overly fat ponies seen in veterinary practices may well be insulin-resistant animals and their body condition may be the first clue to their underlying condition. The unification theory would suggest that it is not difficult to now explain why these animals are at risk for laminitis in conditions that other horses seem to tolerate well.

Just as in humans, there appears to be a genetic component to type 2 diabetes and ponies, Morgans, other gaited breeds and some Arabian bloodlines may be affected; though this research is just beginning.

Promising

The practical advice available to veterinarians and their clients from these new theories is the most promising aspect of this research.

First an accurate diagnosis must be made. Appropriate testing for Cushing's disease and hypothyroidism should be done as these conditions may give a similar clinical appearance. Excellent treatment is available in the form of Pergolide or thyroid replacement hormone for these horses.

Blood glucose, insulin levels and a glucose tolerance test may be needed to accurately diagnose a horse as being insulin intolerant or diabetic. As in humans with type 2 diabetes, the first step in treatment is management of the diet and an increase in exercise. Many diabetics can be controlled for long periods of time with these simple steps (see box). Additional drugs to control glucose levels are being investigated and new treatment protocols will soon be suggested.

The most important point is to realize that these horses are different and that their failure to respond to normal treatments indicates the presence of a more important underlying condition-insulin resistance. Success in treating any of the clinical signs-laminitis, obesity, lethargy-will only come from addressing this problem as well.

Dr. Marcella, a 1983 graduate of Cornell University's veterinary college, was a professor of comparative medicine at the University of Virginia. His interests include muscle problems in sport horses, rehabilitation and other performance issues.