Insulin Resistance and Inflammatory Challenges

AN ASSOCIATION BETWEEN OBESITY AND the development of insulin resistance in humans and laboratory animals has led to a marked interest in adipose tissue as a source of hormones and small proteins that function as signaling molecules. Of particular interest is the recognition that fat cells produce the inflammatory cytokine tumor necrosis factor-alpha (TNF-a). This cytokine plays a key role as a pro-inflammatory agent in inflammatory/immune challenges and is produced predominantly by circulating blood monocytes. However, in obese subjects, there is now compelling evidence that fat cells significantly contribute to increased circulating concentrations of TNF-a.

An initial response to an inflammatory challenge is the development of transient insulin resistance and thus redirection of available energy towards the immune system. The development of insulin resistance during inflammation and immune challenges is caused by TNF-a acting on the insulin receptor of target cells and leads to decreased glucose uptake by peripheral tissues. In obesity, circulating concentrations of TNF-a also are elevated, and there is growing support for the proposal that TNF-a plays a role in the development of insulin resistance associated with obesity. Indeed, the similarity of the mechanisms that lead to development of insulin resistance during an inflammatory challenge and obesity has led to proposal that the development of insulin resistance with obesity is representative of a mild inflammatory response.

Insulin resistance in the horse has been associated with the development of laminitis, osteochondrosis dissecans lesions (OCD), Cushing's disease, and hyperlipidemia. In previous studies we observed that equine adipose tissue is a source of TNF-a. Further, we proposed that this cytokine may play a key role in the development of insulin resistance associated with obesity. In consideration of the observation that in other species an inflammatory/immune challenge leads to profound insulin resistance, an investigation was undertaken to identify whether a similar relationship may exist for the horse. Insulin resistance was determined using the euglycemic hyperinsulinemic clamp procedure before and after administration of endotoxin to induce a mild inflammatory response. Within 24 hours after administration of endotoxin, profound insulin resistance was identified by a marked reduction in the ability of insulin to promote glucose uptake by peripheral tissues. The development of insulin resistance in the horse following administration of a bacterial endotoxin is similar to that found in other species, including humans. Insulin resistance also occurs in humans following sepsis, surgery, and hemorrhage. This injury/infection-induced resistance is often referred to as "stress diabetes." The development of insulin resistance in these stress conditions serves to ensure a high flow of glucose to the predominantly glucose-consuming cells, such as the wound, the inflammatory and immune cells, and all insulin-independent cells. On the other hand, an elevated circulating concentration of insulin, a characteristic feature of insulin resistance, promotes protein catabolism in muscle tissue and thus muscle wasting if the insulin-resistant state is maintained. The consequences of insulin resistance in the horse remain relatively unknown, but strong associations with particular diseases have long been proposed. A question arising from the plethora of perturbations leading to insulin resistance is whether these stressors predispose the animal to further pathological conditions, including the development of laminitis and OCD lesions.

Dr. Barry Fitzgerald, (859) 257-4757,
Department of Veterinary Science, University of Kentucky, Lexington, Kentucky