Development of Laminitis -- Possible Role of Adipose Tissue

Laminitis is associated with obesity as well as sepsis and post-operative conditions in horses where levels of inflammation are elevated. The precise mechanisms that lead to laminitis are unknown; however, several studies document the involvement of inflammation in the pathogenesis of laminitis. In addition, recent studies utilizing an in vitro approach to studying laminitis using hoof wall explants have shown that removal of glucose from the culture medium leads to rapid separation of hoof lamella tissue when subject to stress forces. A similar mechanism might occur in natural cases of laminitis where there is insulin resistance--a suppressed ability of insulin to induce glucose uptake into the cell. 

While numerous mechanisms contribute to the development of insulin resistance, growing evidence points to both a correlative and causative relationship between inflammation and insulin resistance. In addition to sepsis and surgery, obesity is also considered an inflammatory state that some studies relate to a localized form of Cushing's syndrome. Circulating concentrations of inflammatory molecules--including acute phase proteins and inflammatory cytokines--are elevated in obese humans, with even higher elevations in obese patients with insulin resistance and type II diabetes. Further evidence indicating an inflammatory role in insulin resistance is derived from studies demonstrating a reversal of insulin resistance by administration of anti-inflammatory salicylates, such as aspirin.

Several key molecules involved in the development of insulin resistance have come to the forefront in recent years and have led researchers to investigate adipose tissue as a major player in the regulation of insulin sensitivity. Adipose tissue, once considered only a reservoir for energy storage, has emerged as an endocrine organ and an active participant in whole body energy homeostasis. A number of factors directly contributing to insulin resistance, such as the inflammatory cytokine TNF-alpha, are synthesized and secreted by adipose tissue. Additionally, studies have shown that adipose tissue contribute a considerable percentage of the circulating inflammatory molecules IL-6 and TNF-alpha, with degree of contribution correlating to degree of obesity in humans. Thus, the significance of excess adipose tissue as a major contributor to the development of insulin resistance cannot be understated.

Preliminary studies in our laboratory have employed a model for inducing inflammation. This model investigates a) the relationship between inflammation and insulin resistance, and b) the possible role of adipose tissue as a contributor of inflammatory molecules in insulin resistance in the horse. Administration of lipopolysaccharide (LPS), part of the cell wall of the bacteria E. coli, is a commonly used model for inducing inflammation. LPS induces an acute but transient inflammatory response characterized by elevation in heart rate, temperature, respiration, and insulin levels over a period of several hours. It is also well documented that administration of LPS in the horse induces increased circulating levels of the inflammatory cytokine TNF-alpha in blood. The objectives of the study were to determine whether insulin resistance results from a direct inflammatory stimulus in the horse and measure inflammatory cytokine mRNA expression in adipose tissue in response to LPS.

Mares treated with an inflammatory stimulus not only developed a dramatic decrease in insulin sensitivity, but also had marked increases in the levels of cytokine gene expression in adipose tissue. These results suggest that inflammation is associated with reduced insulin sensitivity in the horse and that adipose tissue might be a significant contributor of inflammatory cytokines in obese horses. It is clear that laminitis can be triggered in a number of different situations involving a number of different factors. However, growing evidence points to both insulin resistance and inflammation as major players in the onset of this severely debilitating disease. Impaired glucose uptake associated with inflammation in obesity and post-operative conditions might weaken the layers of the hoof lamellae and predispose the horse to laminitis. In the future, therapeutic drugs that increase insulin sensitivity and those that act as anti-inflammatory agents might work in concert to effectively treat laminitis.

Author: Mandi Vick, Graduate Research Assistant, 859/257-4757, mmvick2@uky.edu, or Dr. Barry Fitzgerald, 859/257-4757, bfitz@uky.edu, Maxwell H. Gluck Equine, Research Center, University of Kentucky, Lexington, Ky.

Reprinted from Equine Disease Quarterly, Department of Veterinary Science,Maxwell H. Gluck Equine Research Center, University of Kentucky, Lexington, Ky. 40546; 859/257-4757; www.uky.edu/Agriculture/VetScence/gluck1.htm.

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Equine Disease Quarterly

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