Insulin Resistance in Equids: Possible Role in Laminitis
Insulin resistance was first implicated in the pathogenesis of laminitis in the 1980s using oral glucose and i.v. insulin tolerance tests (1,2). These tests indicated relative glucose intolerance and resistance to exogenous insulin in ponies that had previously experienced laminitis, compared with ponies with no history of laminitis. Field and Jeffcott (3) proposed a mechanism of insulin resistance–mediated vasoconstriction in laminitis. Since then, our understanding of insulin resistance in laminitis has improved, due largely to technological advances in measurement. Advancements include the use of specific and quantitative techniques to characterize the dynamic glucose and insulin system and more convenient proxies that statistically predict specific quantitative parameters (4,5). Using such techniques can better define the roles of insulin signaling and insulin resistance in the development of equine laminitis. Here we provide the background of insulin resistance and its assessment, present existing data connecting insulin resistance to equine laminitis, and discuss possible mechanisms. Our goal is to promote a better understanding of the role of insulin resistance in the development of equine laminitis, ultimately to improve management to avoid the disease.
Insulin resistance is a general term for the inability of a normal concentration of insulin to produce a normal response from target tissues (6). Insulin resistance is a characteristic of type 2 diabetes and is different from a reduction in insulin action due to reduced circulating insulin as occurs in type 1 diabetes. Insulin signaling refers to the stimulation of a response by insulin.
Insulin resistance could pertain to a breakdown in insulin-signaling mediators prior to the insulin receptor, which reduce circulating insulin or downregulate insulin-receptors. More commonly observed, however, are alterations in the postbinding signal transduction associated with decreased insulin receptor-autophosphorylation and decreased tyrosine kinase activity, resulting in decreased insulin-receptor substrate-1 phosphorylation and reduced activation of phosphatidylinositol 3-kinase (7–9). In addition, disruption of intracellular glucose metabolism regulated by enzymes such as hexokinase and glycogen synthase could reduce insulin-mediated glucose uptake and storage (7–10). To distinguish receptor-level and intracellular inhibition of insulin action we adopted 2 terms: insulin sensitivity, which describes reduced insulin-mediated glucose transport into the cell, and insulin ineffectiveness, which describes a failure of insulin-facilitated intracellular glucose metabolism (11).
Assessment of insulin sensitivity
Various types of evidence have been used to document insulin insensitivity in horses. Analogy to human metabolic syndrome provides a tempting cornucopia of possible disease associations, mechanisms, and interventions, but care should be taken to avoid the danger of unsupported assumptions. Similarly, association with risk factors such as obesity or equine Cushing's disease that suggest insulin resistance is an insufficient basis for establishing genuine insulin resistance.