IN-DEPTH: GERIATRIC MEDICINE/METABOLICS 3. IR and Hyperinsulinemia


Although our understanding of the etiology and pathophysiology of EMS is far from complete, it seems likely that IR and/or hyperinsulinemia play an important role. From a biological viewpoint, IR is usually defined in terms of the reduced ability of a given concentration of insulin to lower blood glucose levels. There has been much discussion about IR in the context of EMS; however, very few studies have reported quantitative data on insulin sensitivity and other aspects of glucose and insulin dynamics in affected animals.8–10 Furthermore, the clinical definition and recognition of IR in equine medicine are not straightforward because “gold standard” methods for assessment of insulin sensitivity cannot be readily applied in clinical practice while simpler methods are either highly labile (eg, measurement of fasting insulin and glucose concentrations) or have not been thoroughly evaluated as valid surro- gate indicators of insulin sensitivity (eg, fasting in- sulin; combined glucose-insulin tolerance test). The recognition of significant breed differences in insulin sensitivity, fasting insulin concentrations, and insulin responses during an oral sugar test (OST) further complicates development of a univer- sal clinical definition of IR in horses. The majority of reports have used “fasting” or “resting” measures of insulin and glucose and/or indices derived from these measurements (eg, the reciprocal of the square root of insulin concentra- tion) as surrogate indicators of IR. Hyperinsulin- emia has been shown to be a feature in the EMS phenotype in ponies5–7 and Morgan horses,8 al- though there is wide variation in values among stud- ies that may in part be explained by differences in sampling conditions (eg, feed withholding versus pasture grazing before collection of blood samples). The current consensus view is that a fasting insulin concentration 20 mIU/L indicates IR. In a sam- ple of 300 healthy, nonlaminitic horses in southwest Virginia, the prevalence of basal hyperinsulinemia (defined as insulin concentration 20 mIU/L) was 18%,11 whereas another study in Australia reported a 28% prevalence of hyperinsulinemia (same cutoff value) in randomly selected ponies.12 In the pony study, age, body condition score (BCS), supplemen- tary feeding, and a history of laminitis were identi- fied as risk factors for hyperinsulinemia.12 Fasting hyperinsulinemia is typically (but not always) accompanied by normoglycemia, which sug- gests compensated IR, that is, an increase in pan- creatic insulin secretion occurs in response to reduced tissue insulin sensitivity, resulting in maintenance of glucose homeostasis. Two studies in ponies that used minimal model analysis of a frequently sampled glucose tolerance test have pro- vided evidence of compensated IR, indicated by lower insulin sensitivity, higher acute insulin re- sponse to glucose administration (a measure of insulin secretion), and no difference in glucose tol-


erance when comparing laminitis-prone to nonlami- nitic ponies.9,10 In the early stages of type 2 diabetes of humans, hyperinsulinemia is also con- sidered to be a compensatory response to IR. How- ever, there also are some data suggesting that hyperinsulinemia per se can induce IR.13 Thus, it may be questioned whether hyperinsulinemia in EMS is the “cart or the horse.” Mechanisms other than a compensatory increase


in pancreatic secretion to counter tissue insensi- tivity may contribute to the fasting hyperinsulin- emia and exaggerated insulinemic response to glucose administration observed in EMS animals. The plasma or serum concentration of insulin is primarily determined by its rate of secretion and clearance, with approximately 80% of endogenous insulin removed by the liver.14 In humans and some animal species, there is evidence of decreased insulin clearance in insulin-resistant states (eg, di- abetes mellitus, obesity, nonalcoholic fatty liver dis- ease).15,16 This reduction in insulin clearance is thought to be a mechanism to preserve -cell func- tion and also to maintain peripheral insulin levels in the face of IR.16 One recent study in horses has shown that reduced insulin clearance contributes to higher blood insulin concentrations in obesity,17 and it is also possible that decreased insulin clearance is a factor in the hyperinsulinemia observed in EMS animals. Other hormones may contribute to an “upregula-


tion” of insulin secretion in EMS, for example, the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) which are secreted by the gut in response to nutrient cues. GLP-1 and GIP are labeled incretin hormones because they potentiate glucose-mediated insulin secretion and account for the higher insulin secretory response that is elicited by oral when com- pared with IV administration of glucose.18 The in- sulinotropic action of GLP-1 was augmented in high- fat–fed obese and insulin-resistant mice compared with normal mice.19 Studies in humans have yielded conflicting information regarding the effects of obesity and type 2 diabetes on incretin hormone secretion and the incretin effect.20,21 One view, however, is that these conditions result in impair- ment in secretion and/or action of incretin hor- mones, and current studies are focused on the potential benefits of incretin-based therapy in type 2 diabetes.20 At present, there is no published infor- mation on incretin hormone secretion or action in EMS.


There may be breed and/or genetic variation in


insulin sensitivity and dynamics that affects sus- ceptibility to EMS. Several review articles have raised the possibility of breed predisposition to EMS, with Welsh and Dartmoor ponies, Morgans, Tennessee Walking Horses (TWH), Saddlebreds, Arabian, and Paso Fino breeds thought to be more susceptible.1,2,22 Affected horses and ponies ap- pear to have high metabolic efficiency, meaning


AAEP PROCEEDINGS  Vol. 59  2013 299


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