Insulin Resistance in the Horse: Significance and Pharmacologic Management

Obesity and insulin resistance: Insulin resistance can be defined simply as an inability of the body to remove blood sugar or glucose from the circulation. In an effort to decrease blood sugar levels, pancreatic insulin output increases, but continued hypersecretion eventually leads to complete failure of insulin secretion, and type-2 diabetes prevails. While insulin resistance is normally associated with obesity, it is has been recognized for many years that temporary insulin resistance may also occur in conditions of inflammation, infection, injury, and several non-pathological conditions, including pregnancy and puberty. As with obese humans, excess bodyweight may predispose the horse to develop insulin resistance and lead to the development of several related diseases, most notably equine Cushing’s disease and laminitis. Additionally in the pre-pubertal animal, insulin resistance has been associated and perhaps implicated as a causal factor in the development of osteochondritis dessicans (OCD) lesions.

Identification of insulin resistance: Two methods are currently employed by physicians to identify insulin resistance in humans. The first approach is to measure blood glucose and insulin levels following a period of fasting. The second test involves oral administration of a glucose solution and identifies the clearance rate from the circulation (glucose tolerance test). Both tests—elevated levels of glucose and insulin and prolonged insulin responses to glucose administration—are indicative of insulin resistance. While each test offers an inexpensive and practical assessment of insulin sensitivity, a more accurate test may frequently be employed, namely the euglycemic, hyperinsulinemic clamp procedure. The clamp procedure utilizes a basic principle of maintaining a steady-state blood level of insulin and glucose via constant infusion. The total amount of glucose infused over time is an index of insulin action on glucose metabolism. Because insulin actively causes glucose uptake by peripheral tissues, primarily muscle and fat cells, an insulin-sensitive individual requires glucose to be infused at a high rate to maintain constant blood levels. In contrast, the insulin-resistant patient requires much less glucose to maintain basal plasma glucose levels, since peripheral tissues fail to utilize glucose as rapidly as occurs in sensitive individuals.

The mechanism whereby insulin resistance leads to certain disease states in horses remains largely unknown. However, lessons learned from human studies suggest that insulin resistance represents a condition of low-grade inflammation. As a result, insulin resistance may be accompanied by elevated blood levels of several chemical signals (cytokines) related to inflammation. In turn, some cytokines may predispose the individual to changes in local blood flow of tissues and release of inflammatory agents that lead to tissue injury. The exact mode of this relationship is unclear.

Development of a model to induce transient insulin resistance—what can we learn? To further understand the relationship between insulin resistance and some disease conditions, our laboratory has recently developed a simple method to induce a transient insulin resistance condition that may provide an opportunity to investigate changes in the release of cytokines potentially involved in the etiology of some diseases, including laminitis. This method utilizes infusion of a 20% lipid emulsion containing heparin (to facilitate enzymatic production of free fatty acids) for four hours. The change in sensitivity to insulin before and after infusion of a lipid solution is illustrated in Figure 3. Prior to infusion of the lipid solution, glucose infusion rates were higher, indicating a more insulin-sensitive state. Immediately following infusion of the solution, glucose infusion rates were lower, indicating a decreased response to insulin.

Potential methods to block insulin resistance—physical and pharmacological: In humans physical exercise can improve insulin sensitivity through different mechanisms, including increased glucose uptake in muscle cells and improved insulin action on target tissues. A forthcoming report (VI International Conference on Equine Exercise Physiology, Lexington, Ky., Sept. 2002) demonstrates that increased insulin sensitivity occurs without an alteration in body weight or condition in horses subjected to short-term, low intensity exercise (1 week at 30 minutes per day). This finding is useful because many obese, insulin-resistant horses are older, and high intensity exercise may be too demanding.

Currently, many therapeutic drugs effectively improve insulin sensitivity in humans, including two families of drugs, thiazolidinediones and biguanides. These drugs function like exercise, by reducing glucose production in the liver and increasing muscle glucose utilization. An investigation is currently under way to determine whether one of these therapeutic drugs is effective in the horse.

CONTACT:
Dr. Barry P. Fitzgerald, bfitz@uky.edu;
Dawn R. Sessions, graduate research assistant; Mandi M. Vick, graduate research assistant; (859) 257-3757
Department of Veterinary Science, University of Kentucky, Lexington, Kentucky.