Insulin Resistance vs Dysregulation – A Distinction without a DifferenceEleanor M. Kellon, VMDEquine Cushing’s and Insulin Resistance Group, Inc.2307 Rural Road, Tempe, AZ 85282, [email protected] 2014, the term insulin dysregulation was introduced in an article by Frank and Tadros, published in EVE. It purported to cover all causes of “excessive insulin response to oral sugars, fasting hyperinsulinemia and insulin resistance” 1 . This was precipitated by interest in the enteroinsular axis and whether incretins might play a role in the excessive response to oral sugars, as well as decreased insulin clearance contributing to hyperinsulinemia. The paper also mentioned the stress response to illness, sepsis and injury as causing hyperinsulinemia but this is well recognized to be a physiological insulin resistance response to preserve glucose for critical tissues like heart and brain. Similarly, the hyperinsulinemia of pregnancy was recognized as a physiological response to allow ample access of the glucose to the fetus. The hyperinsulinemia of PPID is also recognized to be a combination of genetic predisposition and insulin resistance in response to the POMC hormones. This leaves only incretins and reduced insulin clearance as possible causes of hyperinsulinemia without insulin resistance.Higher insulin response to oral than intravenous glucose is a well recognized physiological response in all species, including the horse. Interest in incretins traces back to a 2001 study which determined higher insulin response to oral glucose than intravenous in both horses and Shetland ponies. There was one pony in the study with an exaggerated insulin response and higher GIP incretin (glucose-dependent insulinotropic polypeptide). However, that pony also had elevated absorption of glucose and insulinresistance status was unknown. In a 2016 study 2 , 31 ponies previously identified as hyperinsulinemic were evaluated to determine their active GLP-1 (glucagon-like peptide-1 incretin) and insulin responses to feeding glucose and compare that to the response to intravenous glucose. In phase one of the trial, 22 ponies determined to have hyperinsulinemic responses to oral feeding were subjected to a CGIT (combined insulin-glucose tolerance test). Only 15 of the 22 were determined to be IR by CGIT criteria. However, it has been shown that the diagnostic sensitivity of the insulin phase of CGIT is only 28.5%3 . In phase two, 9 other ponies were utilized. Those that had previously been identified as high responders to oral glucose were found to have the same insulin response to intravenous glucose as the normal ponies. However, they were also found to absorb more glucose orally than the normal ponies i.e., higher AUC glucose. AUC insulin following the oral tests was not correlated with AUC GIP but was correlated with AUC active GLP-1 while total GLP-1 did not change. Given the increased glucose absorption in those ponies, elevated GLP-1 is not an unexpected finding but rather was a normal and appropriate physiologic response to the enhanced glucose absorption, as was the higher insulin – not a dysregulation.Four studies since then have looked for a correlation between elevated levels of GLP-1 or GIP and a hyperinsulinemic response to oral carbohydrates in both normal and hyperinsulinemic horses but failed to find a significant difference. Most notably, one study 4 found the 75 minute insulin response to oral glucose was negatively correlated to GLP-1 and adiponectin levels were positively correlated to GLP-1, the exact opposite of what would be expected if exaggerated incretin responses could cause hyperinsulinemia without insulin resistance or could lead to insulin resistance.To further add to the confusion, both a GLP-1 mimetic and GLP-1 receptor antagonist have been reported to decrease the insulin response to a meal. Interestingly, in the case of the mimetic, the reduced insulin response was due to an increase in whole body insulin sensitivity, again directly contradicting the idea that incretins could cause hyperinsulinemia without there being insulin resistance.As for reduced insulin clearance, one study has documented reduced insulin clearance in horses with metabolic syndrome and hyperinsulinemia. This is a well-recognized component of human insulin resistance in metabolic syndrome and type 2 diabetes mellitus. The reduced insulin clearance helps spare the beta cells and compensate for cellular insulin resistance by maintaining higher circulating insulin levels and is thus an adaptive physiological response, not a dysregulation. There are no studies in any species documenting reduced insulin clearance without concurrent insulin resistance.In contrast, since the 2005 publication of insulin sensitivity quintiles using minimal model analysis of FSIGT (frequently sampled intravenous glucose tolerance test) data, over 40 articles have been formally published describing diagnosis of insulin resistance by intravenous response to glucose, insulin or their combination in various protocols, sometitmes with greater sensitivity than oral testing.It appears possible, but by no means proven, that some animals, particularly ponies, may over-absorb glucose, possibly under the influence of GLP-2, leading to exaggerated GLP-1 and insulin responses to meals and that this repeated exposure to high levels of insulin would lead to insulin resistance. However, even if this is shown to be true, it is not the insulin response that is dysregulated but rather glucose absorption. The GLP-1 and insulin responses to the enhanced glucose load are appropriate and physiological. The end result is likely insulin resistance from repeated exposure to high levels of insulin, as also described by Frank and Tadros, and could be considered an early stage of insulin resistance. They certainly wouldn’t be treated any differently than an animal with insulin resistance confirmed by intravenous testing.By creating an artificial distinction between horses and all other species with insulin resistance there is the potential to reduce interest in collaboration and funding. It also encourages avenues of research which are unlikely to ever benefit the horse or increase understanding of equine insulin resistance. The term insulin dysregulation should be abandoned as the other proposed mechanisms for hyperinsulemia have either not been proven, lead to insulin resistance or are known to be an inherent physiological response to insulin resistance.References:1. N. Frank and E.M. Tadros, Insulin dysregulation, Equine Vet J 46 (2014), pp. 103-112.2. M.A. de Laat, J.M. McGree and M.N. Sillence, Equine hyperinsulinemia: investigation of the enteroinsular axis during insulin dysregulation,Am J Physiol Endocrinol Metab 310 (2016), pp. E61-72.3. L.K. Dunbar, K.A. Mielnicki, K.A. Dembek, R.E. Toribio and T.A. Burns, Evaluation of Four Diagnostic Tests for Insulin Dysregulation in Adult Light-Breed Horses, J Vet Intern Med 30 (2016), pp. 885-891.4. N. Frank and D.M. Walsh, Repeatability of Oral Sugar Test Results, Glucagon-Like Peptide-1 Measurements, and Serum High-Molecular-Weight Adiponectin Concentrations in Horses, J Vet Intern Med 31 (2017), pp. 1178-1187.5. K.H. Treiber, D.S. Kronfeld, T.M. Hess, R.C. Boston and P.A. Harris, Use of proxies and reference quintiles obtained from minimal model analysis for determination of insulin sensitivity and pancreatic beta-cell responsiveness in horses, Am J Vet Res 66 (2005), pp. 2114-2121.