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Abstract Background Equine endocrinopathic laminitis is common and can be associated with an underlying endocrinopathy, such as equine metabolic syndrome (EMS), pituitary pars intermedia dysfunction (PPID), pasture consumption, or any combination of these factors. Objectives The aim of the study was to improve the risk assessment capabilities of clinicians, and to inform management strategies, for acute endocrinopathic laminitis by prospectively examining the phenotypic, hormonal, and clinical characteristics of the disease in a large cohort. Animals Privately owned horses and ponies (n = 301) of any age, sex, or breed diagnosed with laminitis by a veterinarian. A history of laminitis was acceptable. Methods This was a prospective cohort study. Veterinarians provided information on each case via an online questionnaire after informed consent from the animal's owner, and all data were de-identified before analysis. Serum insulin and plasma adrenocorticotrophic hormone concentrations were measured in each case. Results Most cases were recruited in spring (109/301; 36.2%). Concurrent EMS and PPID resulted in higher basal insulin concentrations (49 [21.5-141]; P < .02) than if an animal had a single underlying cause for their laminitis. The insulin concentration was negatively correlated (r2 = −0.38; P < .001) with the animal's height, being higher in ponies (33[10-14]; P < .001) than horses (9.5 [3-25.7]) and was positively correlated (r2 = 0.12; P = .05) with their grade (severity) of laminitis. Conclusions and Clinical Importance Horses and ponies with concurrent endocrinopathies have more marked hyperinsulinemia. Higher basal insulin concentrations were associated with more severe lameness.

There are no registered veterinary drugs for treating insulin dysregulation and preventing insulin-associated laminitis in horses. Velagliflozin is a sodium-glucose co-transport 2 inhibitor that reduces renal glucose reabsorption, promotes glucosuria, and consequently, decreases blood glucose and insulin concentrations. This study aimed to determine if velagliflozin reduced hyperinsulinemia and prevented laminitis in insulin-dysregulated ponies fed a challenge diet high in non-structural carbohydrates (NSC). An oral glucose test (1 g dextrose/kg BW) was used to screen 75 ponies for insulin dysregulation, of which 49 ponies with the highest insulin concentrations were selected. These animals were assigned randomly to either a treated group (n = 12) that received velagliflozin (0.3 mg/kg BW, p.o., s.i.d.) throughout the study, or a control group (n = 37). All ponies were fed a maintenance diet of alfalfa hay for 3 weeks, before transferring to a challenge diet (12 g NSC/kg BW/d) for up to 18 d. Blood glucose and serum insulin concentrations were measured over 4 h after feeding, on d 2 of the diet. The maximum glucose concentration was 22% lower (P = 0.014) in treated animals, with a geometric mean (95% CI) of 9.4 (8.0-11.0) mM, versus 12.1 (10.7-13.7) mM in the controls. This was reflected by lower (45%) maximum insulin concentrations in the treated group (P = 0.017), of 149 (97-228) μIU/mL, versus 272 (207-356) μIU/mL for controls. The diet induced Obel grade 1 or 2 laminitis in 14 of the 37 controls (38%), whereas no velagliflozin-treated pony developed laminitis (P = 0.011). Velagliflozin was well-tolerated, with no hypoglycemia or any clinical signs of adverse effects. The main limitation of this study was the sample size. Velagliflozin shows promise as a safe and effective compound for treating insulin dysregulation and preventing laminitis by reducing the hyperinsulinemic response to dietary NSC.

Abstract Background Endocrinopathic laminitis is common in horses and ponies, but the recurrence rate of the disease is poorly defined. Objectives To determine the incidence of, and risk factors for, the recurrence of endocrinopathic laminitis. Animals Privately owned horses and ponies with acute laminitis (n = 317, of which 276 cases with endocrinopathic laminitis were followed up to study completion). Methods This prospective cohort study collected data on veterinary-diagnosed cases of acute laminitis for 2 years. Each case was classified on acceptance to the study as endocrinopathic or non-endocrinopathic using data collected in a questionnaire completed by the animal's veterinarian. Follow-up data were collected at regular intervals to determine whether the laminitis recurred in the 2-year period after diagnosis. Results The recurrence rate for endocrinopathic laminitis was 34.1%. The risk of recurrence during the 2-year study period increased with basal, fasted serum insulin concentration (P ≤ .05), with the probability of recurrence increasing markedly as the insulin concentration increased beyond the normal range (0-20 μIU/mL) to over the threshold for normal (up to approximately 45 μIU/mL). Being previously diagnosed with laminitis (before the study; P = .05) was also a risk factor for recurrent laminitis. Cases with a higher Obel grade of laminitis were likely (P = .05) to recur sooner. Conclusions and clinical importance Knowing that hyperinsulinemia and being previously diagnosed with laminitis are significant risk factors for recurrence will enable clinicians to proactively address these factors, thereby potentially reducing the risk of recurrence of laminitis.

Abstract Background Testing for insulin dysregulation (ID) in horses is commonly performed to guide management and therapeutic strategies. Objectives To evaluate a newly developed glycemic pellets challenge (GPC) and compare results to those obtained using the low-dose oral sugar test (OST). Animals Twenty-four adult horses with unknown insulin status. Methods A randomized crossover trial was performed. Horses underwent GPC (0.5 g glycemic carbohydrates/kg body weight) and OST (0.15 mL corn syrup/kg body weight) 7 days apart. Feed was withheld before testing and blood samples were collected at T0, T60, T120, and T180 minutes for GPC and at T0, T60, and T90 minutes for OST. Blood glucose concentration was measured using a point-of-care glucometer and insulin by radioimmunoassay. Comparisons were made using nonparametric tests, linear regression, and Bland-Altman agreement analysis. Results Eighteen horses consumed >85% of the GPC pellets within 10 minutes and had acceptable OST results. Maximum glucose (P = .02) and insulin (P = .007) concentrations were significantly higher for GPC compared with OST. Time to maximum insulin concentration (Tmax[ins]) varied within and between tests and neither Tmax[ins] (P = .28) nor maximum insulin concentration (P = .46) was correlated with the time horses took to consume pellets. Conclusions The GPC is well tolerated and may offer another diagnostic testing modality for ID. Blood glucose and insulin concentrations increase during GPC and reach higher concentrations than observed with low-dose OST. The Tmax[ins] varied for GPC and OST, emphasizing the importance of identifying the optimal time range for the collection of samples to capture diagnostically relevant changes in insulin concentration.

Abstract Background A glycemic challenge test is used for the diagnosis of insulin dysregulation (ID) in horses and ponies. Different forms of the test exist where the administrative route and dose of glucose vary, which makes interpretation of results challenging. Hypothesis/Objectives To evaluate the palatability of, and blood glucose and insulin responses to, carbohydrate pellets fed as an oral glucose test (OGT), and to establish the diagnostic threshold for ID when using the pellets. Animals University and privately-owned horses and ponies (n = 157) comprised of 31 breeds and both sexes. Methods Multicenter cohort study. A custom-produced glycemic pellet was offered for free intake at 0.5 g/kg BW soluble carbohydrate and serum insulin and blood glucose concentrations measured before and after (60, 120, and 180 minutes) the pellets were offered. Pellet acceptance and intake time (those that finished within 10 minutes) were determined to assess palatability. Results The pellets were palatable to 132/157 animals, and ponies found the pellets more (P = .004) palatable than horses. The median intake time (4 [3-6] minutes) was positively correlated with acceptance grade (r = .51; P < .0001). Consumption of the pellets elicited peak blood glucose (6.6 [5.8-7.8] mmol/L) and serum insulin (40.5 [19-99.8] μIU/mL) responses at 120 minutes. At 120 minutes the optimal cut-off was 83 μIU/mL (95% CI: 70-99 μIU/mL) for the IMMULITE 2000XPi assay. Conclusions and Clinical Importance The pellets were palatable and a suitable, novel carbohydrate source for the OGT.

Background Insulin dysregulation (ID) is a key risk factor for equine endocrinopathic laminitis, but in many cases ID can only be assessed accurately using dynamic tests. The identification of other biomarkers could provide an alternative or adjunct diagnostic method, to allow early intervention before laminitis develops. The present study characterised the metabolome of ponies with varying degrees of ID using basal and postprandial plasma samples obtained during a previous study, which examined the predictive power of blood insulin levels for the development of laminitis, in ponies fed a high-sugar diet. Samples from 10 pre-laminitic (PL – subsequently developed laminitis) and 10 non-laminitic (NL – did not develop laminitis) ponies were used in a targeted metabolomic assay. Differential concentration and pathway analysis were performed using linear models and global tests. Results Significant changes in the concentration of six glycerophospholipids (adj. P  ≤ 0.024) and a global enrichment of the glucose-alanine cycle (adj. P  = 0.048) were found to characterise the response of PL ponies to the high-sugar diet. In contrast, the metabolites showed no significant association with the presence or absence of pituitary pars intermedia dysfunction in all ponies. Conclusions The present results suggest that ID and laminitis risk are associated with alterations in the glycerophospholipid and glucose metabolism, which may help understand and explain some molecular processes causing or resulting from these conditions. The prognostic value of the identified biomarkers for laminitis remains to be investigated in further metabolomic trials in horses and ponies.

Background Although several studies have investigated factors associated with the onset and occurrence of hyperinsulinaemia-associated laminitis (HAL), few have examined the factors associated with the rate of improvement during recovery from an acute bout of the disease. This observational study sought to discover if a range of demographic, morphologic, hormonal and metabolic variables are associated with the improvement rate from HAL in 37 naturally-occurring cases identified by 16 clinics across Germany. Each case was evaluated for laminitis severity on the day of inclusion in the trial (d 0), then after 4, 9, 14, 25 and 42 d. The horses were managed according to best clinical practice including restricting exercise and prescribing a diet of hay-only, for a minimum of 9 d. Blood samples were also collected during each evaluation, except on d 9, and analysed for glucose, insulin, ACTH and leptin. Results Based on individual clinical laminitis scores plotted against time, most horses improved markedly within 2 weeks, with a ‘fast group’ ( n  = 27) having a median (interquartile range) score on a 12-point scale of 0 (0–2) by d 14. However, there was a clear disparity within the total cohort, as ~ 1 in 4 horses demonstrated much slower improvement, with a median score of 5 (4–7) by d 14, or a marked relapse thereafter (‘slow group’, n  = 10). Horses in the slow improvement group were younger (12.5 (8.8–16.3) vs 17 (14–24) yr; P  = 0.008), but were not more likely to be heavier, male, very fat, to have presented with a previous history of laminitis or elevated ACTH concentrations, or to be receiving pergolide treatment. Of the hormonal and metabolic parameters measured, glucose and insulin concentrations were within the normal range following transition to the hay-only diet, but were higher in the group that failed to improve quickly, with a small but significant difference being evident on d 4, 14 and 25 for glucose (11 to 16%; P  < 0.05), and a larger difference for insulin on d 14 and 25 (51 to 55%; P  < 0.05). There was no difference between the groups in ACTH or leptin concentrations throughout the study. The main limitations of this study were the small number of slow-improvement horses and an inability to control or measure certain variables, such as feed quality. Conclusions Young age and a modest increase in blood glucose and insulin concentrations are associated with delayed laminitis improvement.

Laminitis is a common equine disease characterized by foot pain, and is commonly diagnosed using a five-grade Obel system developed in 1948 using sepsis-related cases. However, endocrinopathic laminitis is now the most common form of the disease and clinical signs may be mild, or spread across two Obel grades. This paper describes a modified method which assigns scores to discreet clinical signs, providing a wider scale suitable for use in a research setting. The \"modified Obel\" method was developed using an iterative process. First, a prototype method was developed during the detailed observation of 37 ponies undergoing a laminitis induction experiment. The final method was refined and validated using video footage taken during the induction study and from a clinical trial of naturally occurring endocrinopathic laminitis cases. The Obel method was deconstructed and key laminitis signs were evaluated to develop a three-stage, five criteria method that employs a severity scale of 0-12. Veterinarians ( = 28) were recruited to watch and assess 15 video recordings of cases of varying severity, using the Obel and \"modified Obel\" methods. The inter-observer agreement (reproducibility) was determined using Kendall's coefficient of concordance (Kendall ) and Krippendorf's alpha reliability coefficient. A total of 14 veterinarians repeated the exercise 2-4 weeks after their original assessment, to determine intra-observer agreement (repeatability), assessed using a weighted kappa statistic ( ). Agreement between methods was calculated by converting all \"modified Obel\" scores to Obel grades and calculating the mean and distribution of the differences. The \"modified Obel\" and Obel methods showed excellent and similar inter-observer agreement based on the Kendall value (0.87, < 0.001 vs. 0.85, < 0.001) and Krippendorf's alpha (95% CI) value (0.83 [0.53-0.90] vs. 0.77 [0.55-0.85]). Based on the value, the \"modified Obel\" method also had substantial repeatability, although slightly less than the Obel method, (0.80 vs. 0.91). Excellent agreement between the methods was found, with the mean difference (95% CI), comparing the Obel grade, with the \"modified Obel\" score converted to an Obel grade, being -0.12 (-0.19 to -0.06) grades. The Obel and converted \"modified Obel\" grades were identical 62% of the time (259/420) and a difference of one grade (higher or lower) occurred in 35% of cases (148/420). Both methods show excellent agreement, reproducibility and repeatability when used to diagnose endocrinopathic laminitis. The \"modified Obel\" method is a three-step examination process for severity-scoring of endocrinopathic laminitis, initially proposed for use within a research setting. When using the modified method a diagnosis of laminitis also requires clinical acumen. The allocation of scores for specific clinical signs should be particularly useful in research trials monitoring laminitis recovery.

Background Culicoides hypersensitivity (CH) is induced in horses by salivary allergens of Culicoides midges. In Iceland, the causal Culicoides species for CH are not present. Previous epidemiological data indicated that Icelandic horses are more susceptible to CH when they are exported from Iceland and first exposed to Culicoides at adult age. Horses born in countries where Culicoides is endemic, develop the disease less frequently. Here, we established a longitudinal allergy model to identify predictive and diagnostic serological biomarkers of CH. Results Sixteen adult Icelandic horses from Iceland were imported to the Northeastern United States (US) during the winter and were kept in the same environment with natural Culicoides exposure for the next two years. None of the horses showed clinical allergy during the first summer of Culicoides exposure. In the second summer, 9/16 horses (56%) developed CH. Allergen specific IgE and IgG isotype responses in serum samples were analysed using nine potential Culicoides allergens in a fluorescent bead-based multiplex assay. During the first summer of Culicoides exposure, while all horses were still clinically healthy, Cul o 2 specific IgG3/5 antibodies were higher in horses that developed the allergic disease in the second summer compared to those that did not become allergic ( p  = 0.043). The difference in Cul o 2 specific IgG3/5 antibodies between the two groups continued to be detectable through fall ( p  = 0.035) and winter of the first year. During the second summer, clinical signs first appeared and Cul o 3 specific IgG3/5 isotypes were elevated in allergic horses ( p  = 0.041). Cul o 2 specific IgG5 (p = 0.035), and Cul o 3 specific IgG3/5 (p = 0.043) were increased in late fall of year two when clinical signs started to improve again. Conclusions Our results identified IgG5 and IgG3/5 antibodies against Cul o 2 and Cul o 3, respectively, as markers for CH during and shortly after the allergy season in the Northeastern US. In addition, Cul o 2 specific IgG3/5 antibodies may be valuable as a predictive biomarker of CH in horses that have been exposed to Culicoides but did not yet develop clinical signs.

Abstract Background Oral glycemic challenge (GC) tests are recommended for diagnosis of insulin dysregulation (ID). Various protocols are used, but all have limitations in terms of palatability, ease of use, variable composition, geographic availability, or some combination of these. Hypothesis/Objective To evaluate newly developed formulations with defined carbohydrate composition for use as oral GCs. Animals Thirty-four horses and ponies in various metabolic states. Methods Our objectives were carried out in 2 separate cross-over experiments. First, the palatability and acceptance of various GCs (2 syrups, 1 granulate) offered for free intake were compared to glucose mixed in a chaff-based diet. Subsequently, syrups were administered by syringe and compared to an oral glucose test using naso-gastric tubing (tube OGT) to investigate the glycemic and insulinemic responses. Second, these variables were compared in the best performing GC-formulations (granulate further optimized to pelleted formulation and 1 syrup) and a tube OGT. All GCs were administered with equivalent amounts of 0.5 g glycemic carbohydrates per kg body weight. Results Only the GC pellets were consumed completely by all horses (consumption time 5 ± 2 min). When administered by syringe, the GC syrup also was well accepted. The insulin concentrations at 120 min correlated significantly between tube OGT and GC pellets (r = .717; P < .001) or GC syrup (r = .913; P < .001). The new GC syrup and GC pellets discriminate between healthy and ID horses. Conclusions and Clinical Significance The GC pellets (DysChEq)™ and GC syrup can be used as palatable and well-accepted oral GC tests for assessment of ID in horses.