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.

Introduction : The dentigerous cyst is a well-known congenital malformation usually found in the temporal region. This is the first case report of a large maxillary sinus cyst with ectopic teeth in an adult horse. Methods: A 14-year-old warmblood gelding was presented for evaluation of chronic right nasal discharge. After imaging exploration, surgery was performed on the standing horse with a conchofrontal sinus trephination and a large maxillary bone (MB) sinutomy. Results : The examinations revealed a sinusal mass in the right maxillary sinus covered by sinusal mucosa and around the infraorbital canal. The mass contained three ectopic tooth structures. The dental table was complete and normal. Both approaches (right frontal trephination, and maxillary sinutomy) showed adhesion between the dental structures, the infraorbital canal and the MB. The two simultaneous approaches allowed extraction with preservation of all sinus and nerve structures. Conclusions: The loss of integrity in the MB and the attachment to the infraorbital canal suggests that there could have been subsequent damage to the infraorbital canal, seen at the time of the examination and the surgery, leading to neurological symptoms in the future. The extraction of these completed structures in the standing horse has not been described and the use of both approaches allowed good visualization and preservation of the integrity of the sinus structures whilst allowing complete removal of the mass.

Lameness in the horse is one of the most common reasons a horse is seen by a veterinarian. As the foot is frequently the source of lameness, research utilizing reversible methods of foot lameness induction are vital to improvements of the knowledge in this area. This literature review aims to describe published methods of reversible foot lameness induction, identify any limitations of these methods, and summarize findings of research where these methods have been utilized.

Background: Injury resulting in proliferative new bone formation on the dorsal aspect of the middle phalanx (P2) has been recognised by equine veterinarians and is generally referred to as capsulitis. Objectives: Describe the clinical features, treatment, and outcomes of this condition. Study Design: Case series (n=19) Methods: Clinical cases in which the horse presented for lameness and were diagnosed with acute formation of proliferative bone on the dorsal aspect of P2 were included in the study (cases collected from 2005-2022). Signalment, history, presenting clinical signs, diagnostics, treatments administered, and outcome were evaluated. Results: Horses presented with unilateral lameness that were all classified as either a moderate lameness at a trot (n=6), or a moderate to severe lameness at a walk (n=13). The presentation of lameness was recorded as acute in 15/19 horses and not reported in the remainder. Bone proliferation on the dorsal aspect of P2 was diagnosed on radiographic evaluation in all horses (as part of the inclusion criteria). In horses with sequential radiographs made from the time of acute presentation, the bone production developed rapidly over a period of a few weeks to 2 months. A variety of therapeutic options were implemented, and 13/19 (68%) of the cases were subject to humane euthanasia with only one horse returning to its previous athletic function. Milder cases were more likely to have better outcomes. Main Limitations: Small sample size. Conclusions: Acute new bone proliferation on the dorsal aspect of P2 may be associated with moderate to severe lameness and carries a poor prognosis for return to athletic performance and survival.

A recently castrated 4-year-old Selle Français gelding was presented for evaluation of a renal failure. Abdominal and transrectal ultrasonography revealed a large volume of anechoic free fluid within the peritoneal cavity with high creatinine concentration and a tear at the cranial pole of the bladder. Medical management was initiated for two days, then a standing laparoscopy was performed to close the defect using barbed suture. After a transient acute renal injury, the gelding recovered and was discharged from the hospital 13 days post-operatively. To our knowledge, this case is the first report using barbed sutures on the equine bladder.

Summary: A rare case of bilateral perineal hernia was reported in a 24-year-old Italian Trotter mare. This condition is described as a protrusion of retroperitoneal fat, and/or the abdominal or pelvic viscera through the pelvic diaphragm which supports the rectal wall. It is commonly observed in olduncastrated old male dogs, but occurs very rarely in large ruminants; to the Authors’ knowledge, it has never been described in horses. Chronic weight loss is the main clinical sign, even if the main concern regards the entrapment and the strangulation of the bowel content. Reaching a diagnosis involves clinical signs, palpation, ultrasound evaluation and rectal examination. The approach chosen in all the cases of perineal hernia described in large ruminants is appositional herniorrhaphy; for this reason, it was utilised as the first surgical choice in the present case. Due to its failure, a new surgical approach was used The second procedure involved the transposition of the semimembranosus muscle. The short-term outcome after the second surgery presented no recurrence or complications. It is therefore necessary to consider perineal hernia among the various differential diagnosis of perineal swellings in horses. Additional cases are required to determine its benefits.

Buyers expect much from the veterinarian examining a prospective horse for purchase. To compound this, the veterinarian is the gatekeeper in a highly unregulated transaction. The examining veterinarian must determine precisely what the buyer’s expectations are for the examination and their prospective new horse. How we communicate our findings to them is critical for helping them make an informed purchasing decision.

Background: The importance of intra-articular corticosteroid treatment for osteoarthritis with its possible adverse effects requires a comprehensive review. Objectives: This review answers the following questions: 1) What evidence is available regarding the symptom-modifying and disease-modifying changes related to a single intra-articular corticosteroid injection for treating osteoarthritis? Moreover, 2) What evidence suggests corticosteroids are detrimental to equine joint health? Study design: Systematic review. Methods: A systematic search was conducted in June/2022 in PubMed, CAB, and the Web of Science. Inclusion criteria were applied to titles and abstracts. For each question, further criteria were applied. The risk of bias was assessed according to the study design. Results: We generated 6,417 titles, and 23 articles fit all inclusion criteria for single-injection corticosteroid treatments; 21 were included regarding corticosteroid effects on joint health. Studies were usually rated as having an unclear risk of bias. Single-injection protocols lead to short-term symptom-modifying osteoarthritic changes with conflicting results regarding disease-modifying osteoarthritis. Healthy joints demonstrated disturbances in metabolism and tissue changes, with dose-dependent effects found in vitro. Main limitations: There is a lack of studies regarding the topics–primarily for equine species. Conclusions: Symptom-modifying osteoarthritic changes after a single injection are short-term; however, a consistent disease-modifying osteoarthritis effect is yet to be established. Joint health appears to be disturbed by corticosteroids as their effects on normal joints show adverse changes in tissues and metabolism.

A 17-year-old Quarter Horse broodmare was taken to surgery for signs of colic unresponsive to medical management. The small colon was strangulated by a pendulous ovarian pedicle. The strangulation was freed, and the affected ovary was removed. The mare developed signs of a small colon obstruction 4 days after surgery. The mare was euthanized 6 days after surgery for signs of a GI rupture. A post-mortem examination revealed necrosis of the affected portion of small colon.

An 8-year-old Thoroughbred gelding presented for evaluation and investigation for recurrent unilateral epistaxis. Computer tomography (CT) confirmed the presence of an invasive and expansive progressive ethmoid hematoma (PEH) located in the right paranasal sinuses. The mass invaded the right paranasal sinuses compartments causing moderate leftward displacement of the nasal septum with subsequent collapse of the left nasal passages, complete obliteration of the right ethmoid turbinate, right infraorbital canal, and nasolacrimal duct. Also, impingement of the axial margin of the right orbit. A large frontonasal maxillary bone flap was performed standing under sedation and local anesthesia and the PEH was removed successfully with minimal surgical complications. The gelding made an unremarkable recovery from surgery and progressed well after recovering from post operative pleuropneumonia. Follow-up (25 months post operative) confirmed the reoccurrence of the PEH, but the horse remained healthy in pasture turn out.

Background: Colic is the commonest emergency in first opinion equine practice. Early referral is important for horses requiring surgery. Fast localised abdominal ultrasonography of horses (FLASH) is frequently used as a diagnostic tool in the investigation of colic at referral hospitals, but its use in first opinion practice has not been evaluated. Objective: To assess the value of FLASH scanning in the primary assessment of horses with colic in the field, using a portable wireless ultrasound system. Study design: Prospective study (2018-2021). Methods: Any horse examined for colic as an emergency in a first opinion ambulatory practice was eligible for inclusion in the study. A FLASH examination was performed using a wireless handheld ultrasound scanner, with the images displayed on a smartphone or tablet. The findings on FLASH scans and outcome of the case (recovered, referred for surgery or euthanised without referral) were recorded. Results: 135 equids with acute colic were evaluated. Of the 135 horses, 49 (36%) had an abnormal finding on FLASH scanning, including distended loops of small intestine (n=34), thickened small intestinal walls (n=23) and/or distension of the stomach (n=7). Reduced small intestinal motility was recorded in 52 animals (38%). Follow-up information was available in all animals: 50 (37%) were euthanised due to clinical deterioration and the owners’ decision not to undertake surgery; 85/135 (63%) survived, including 5/85 (6%) that underwent surgery and 80/85 (94%) that resolved with medical management. Main limitations: Small number of cases. Lack of results of post-mortem examination of horses that were euthanised. Potential selection bias. Conclusion: The FLASH technique can be valuable in the primary assessment of horses with colic in first opinion ambulatory practice. Further evaluation with more cases is required.

Laminitis associated with hyperinsulinemia a significant cause of morbidity and mortality in horses with equine metabolic syndrome. The diagnosis and management of insulin dysregulation are therefore critical to prevent the development of hyperinsulinemia-associated laminitis. This review article aims to help primary care clinicians manage patients with insulin dysregulation by providing an overview of diagnostics, management strategies and new therapies that are available.

Background: The conjunctiva of the eye is a mucosal surface that is colonized by various bacteria. Following surgeries, trauma, or other underlying conditions the normal flora of these bacteria may cause some eye infections such as conjunctival, corneal infections, or endophthalmitis. Objectives: This study aimed to investigate the bacterial population and antibiotic resistance of the conjunctiva in healthy horses. Study design: Random sampling of ocular samples from 20 horse during the winter (2019). Methods: Swab samples were collected from the eyes of 20 healthy horses of different breeds, ages, and sexes in Tehran province, Iran. The swabs were cultured on blood agar and MacConkey agar and incubated at 37°C for 24-48 hours. The isolated bacteria were characterized using cellular morphology, gram-staining, and biochemical tests. Sensitivity and resistance to 10 different antibiotics were measured using an antibiogram test. Results: Results showed that the bacterial population consisted of various species, with Bacillus cereus being the most frequent. There were no significant differences in the frequency of isolated bacteria between sexes and age groups. There were no significant differences in the sensitivity of bacterial flora of the eyes to Colistin, ceftiofur, florfenicol, amoxicillin, and ampicillin between neither different age groups nor different sexes of the horses (P>0.05). However, sensitivity to enrofloxacin and ciprofloxacin was significantly correlated with the age groups of the horses (P>0.05). Significant difference in sensitivity to trimethoprim-sulfamethoxazole between various sexes of horses was observed. Main limitations: The non-uniformity of the follow-up examination reliance owners or caregiver of the horse for follow-up information and Lack of adequate financial resources to study more horses. Conclusions: The study suggests that the frequency of bacterial flora in horses’ eyes is influenced by housing and management conditions rather than age and sex. Keywords: Microbial flora, Conjunctiva, Eyes, Horse, Mucosal surface.

The inclusion of thoracolumbar radiographs in a pre-purchase examination (PPE) is a topic of current and intense debate, subsequent to a statement from the Federation of European Equine Veterinary Associations (FEEVA) advocating the exclusion of spinous process radiography from the PPE. This review will consider the reasons behind the addition of such radiographs into PPEs, the limitations of radiography in ambulatory practice and therefore the diagnostic limitations to the practitioner, the diagnostic benefit of a complete radiographic examination, and discussion of common and less-frequent thoracolumbar pathologies. We will focus on laterolateral radiographs of the spinous processes as these are most commonly acquired during the PPE. The lack of consistent and repeatable grading systems highlights the subjective nature and variability in assessing this region radiographically. Coupled with the sparse evidence of correlation between clinical symptoms and radiographic abnormalities of the thoracolumbar spine leads us to conclude that taking radiographs of the back during PPEs should not be performed unless the clinical examination indicates otherwise.

This report describes the successful treatment of a cutaneous hemangiosarcoma of a 12 years old horse presented for evaluation of a cutaneous mass on the left gluteal region. Hemangiosarcoma is a rare life-threatening neoplasia that can be successfully managed when diagnosed and treated at early stages. Unfortunately, they are often diagnosed at later stages, leading to a poor outcome and low survival rates. In this report, the horse has been treated with a complete large surgical excision of the neoplastic tissue. A good cosmetic outcome as well as a short recovery time has been achieved with an autologous skin grafting split thickness modified meek technique. A long-term follow-up of the patient showed no reoccurrence of the hemangiosarcoma, and successful return to athletic performance. In the authors knowledge, this is the first equine primary cutaneous hemangiosarcoma treated with complete excision and subsequently autologous skin grafting with a long-term follow-up and good outcome despite the poor prognosis.

Whilst there are limited data on the environmental impact of administering parasiticide drugs to horses, evidence from other species treated with identical drugs indicates significant negative ecological effects. Anthelmintic drugs may be excreted unchanged or metabolised to other active and/or toxic metabolites that enter the environment through direct excretion during grazing. These chemicals can have significant toxic effects on non-target insects, such as dung beetles, earthworms and aquatic animals. Of the anthelmintics frequently used in horses, ivermectin appears to be the most ecotoxic; available evidence indicates that moxidectin is less toxic. Fenbendazole appears to have little impact on dung-colonising insects but may be toxic to aquatic organisms and fungi. There is very little data regarding the ecotoxicity of pyrantel and praziquantel, although their ecotoxic effects are thought to be low. Pasture hygiene reduces pharmaceutical contamination and also helps to break the endoparasitic cycle of infectivity, thus reducing reliance on anthelmintics. Judicious use of endoparasiticides, along with pasture hygiene measures, will limit the ecotoxic effects of these drugs and reduce the selection pressure that drives anthelmintic resistance. Anthelmintics may also impact the equine gastrointestinal microbiota.Following topical treatment with ectoparasiticides (such as fipronil, permethrin or cypermethrin), there is a risk of contamination of both the immediate environment and water courses. The half-life of fipronil in the environment is variable, but it degrades into compounds which are more toxic; it is highly toxic to bees, and is reported to bioaccumulate in fish and can be toxic to birds. Of the synthetic pyrethroids, permethrin degrades at a faster rate than cypermethrin and may therefore have a lower ecotoxic effect. The ecotoxic effects of injectable doramectin are likely to be similar to oral ivermectin, although persistence in faeces may be significantly prolonged compared to the oral treatment route.

A seven year old Slovak warmblood gelding, used as a police horse, initially presented to the refferal clinic when it was five years old, with an itching keloid on the distal limb, requiring surgical removal. After surgical removal of the keloid and successful closure of the skin, it was necessary to maintain bandaging the healed wound to prevent self mutilation as the healed surgical site remained pruritic post operatively. After two years, the horse presented to the clinic again with pruritic and alopetic regions of the head, neck, limbs and base of the tail. Attempts to find the cause of dermal iritation included dermatological, parazitological, microbiological and ultrasonographic examination. Treatment with corticosteroids, antiparasitics and antibiotics were not succesfull. Further investigation due to the horse's worsening general status led to the finding of marked pleural effusion. Cytology of the pleural fluid confirmed there was, as suspected, neoplastic changes in the thoracic cavity. Furthermore there were gross pathological changes of the lymphatic tissue of the cranial mediastinum, surroundings of the aorta in the thoracic cavity and lymph nodes of the abdominal cavity. Histolology of the lymphatic nodes found poorly differentiated round cell tumours. Histopathological findings confirmed there was a very aggressive form of lymphoma. The pruritus, generalised moth-eaten alopecia and self-mutilation were the first symptoms of the terminal disease in this case.

This case report describes successful conservative management of a comminuted fracture of the atlas. To the authors knowledge, fracture of the atlas in the horse and intrathecal corticosteroid injection in the standing sedated patient has not been previously reported. Clinical signs included acute onset ataxia, proprioceptive deficits and neck stiffness; which developed immediately post trauma during assisted recovery from general anaesthesia. Radiographic examination was not diagnostic immediately post trauma and computed tomographic (CT) imaging subsequently identified a fracture of the atlas. Treatment included ultrasound guided intrathecal medication of the cerebrospinal fluid and intra-articular medication of the atlantooccipital joint under standing sedation. Medication resulted in a marked improvement in clinical signs (grade 4 ataxia to grade 1 ataxia).