Effect of phenylbutazone on insulin secretion in horses with insulin dysregulation.

BACKGROUND: Phenylbutazone is often prescribed to manage pain caused by hyperinsulinemia-associated laminitis, but in diabetic people nonsteroidal anti-inflammatory drugs increase insulin secretion and pancreatic activity. HYPOTHESIS/OBJECTIVES: Investigate the effect of phenylbutazone administration on insulin secretion in horses. It was hypothesized that phenylbutazone will increase insulin secretion in horses with insulin dysregulation (ID). ANIMALS: Sixteen light breed horses, including 7 with ID. METHODS: Randomized cross-over study design. Horses underwent an oral glucose test (OGT) after 9 days of treatment with phenylbutazone (4.4 mg/kg IV q24h) or placebo (5 mL 0.9% saline). After a 10-day washout period, horses received the alternative treatment, and a second OGT was performed. Insulin and glucose responses were compared between groups (ID or controls) and treatments using paired t test and analyses of variance with P < .05 considered significant. RESULTS: In horses with ID, phenylbutazone treatment significantly decreased glucose concentration (P = .02), glucose area under the curve (2429 ± 501.5 vs 2847 ± 486.1 mmol/L × min, P = .02), insulin concentration (P = .03) and insulin area under the curve (17 710 ± 6676 vs 22 930 ± 8788 µIU/mL × min, P = .03) in response to an OGT. No significant effect was detected in control horses. CONCLUSION AND CLINICAL IMPORTANCE: Phenylbutazone administration in horses with ID decreases glucose and insulin concentrations in response to an OGT warranting further investigation of a therapeutic potential of phenylbutazone in the management of hyperinsulinemia-associated laminitis beyond analgesia.

The effect of pre-dosing with metformin on the insulin response to oral sugar in insulin-dysregulated horses.

BACKGROUND: A single dose of metformin administered 1 h prior to oral glucose challenge was previously shown to reduce insulinaemic responses in horses with experimentally-induced insulin dysregulation (ID). Targeted administration could be useful for controlling post-prandial hyperinsulinaemia in horses with naturally-occurring ID. OBJECTIVES: The objective was to compare the insulinaemic and glycaemic responses to oral sugar testing (OST) performed at different intervals after a single dose of metformin in horses with naturally-occurring ID. We hypothesised that pre-treatment with one dose of metformin would significantly decrease the insulinaemic response to OST. STUDY DESIGN: Randomised cross-over in vivo experiment. METHODS: Eight university-owned adult horses with naturally-occurring ID underwent OST 1, 2 and 6 h following a single oral dose of metformin (30 mg/kg) or 1 h after placebo (240 mL water) with a 7-day washout between treatments over a period of 3 weeks. Plasma insulin, C-peptide and glucose concentrations were measured at 0, 60 and 90 min after 0.45 mL/kg light corn syrup and the effect of treatment (and the interval since dosing) examined using a mixed effects linear regression model. RESULTS: Metformin treatment had no significant effect on plasma glucose, insulin or C-peptide concentrations at any time point compared with placebo (p > 0.05). For OST 1 h post metformin, median (IQR) plasma insulin was 91.3 (62.4-114.9) µIU/mL at 60 min versus 76.2 (59.1-134.5) for placebo (p = 0.8) and 62.7 (31.4-109.7) at 90 min versus 51.8 (29.2-126.3) for placebo (p = 0.9). MAIN LIMITATIONS: Small sample size may limit identification of more subtle decreases in insulin concentration with metformin pre-dosing. The results of this study are relevant only for one pre-treatment dose (30 mg/kg) which limits extrapolation to predictions about the effects of longer-term metformin administration on insulin and glucose dynamics in the horse. CONCLUSIONS AND CLINICAL IMPORTANCE: The results do not support the use of targeted metformin treatment to reduce post-prandial hyperinsulinaemia in horses with naturally-occurring ID.

Effect of 5'-adenosine monophosphate-activated protein kinase agonists on insulin and glucose dynamics in experimentally induced insulin dysregulation in horses.

BACKGROUND: 5'-adenosine monophosphate-activated protein kinase (AMPK) agonists, particularly resveratrol (RES), have not been extensively evaluated for their effect on insulin dysregulation (ID) in horses. OBJECTIVES: Evaluate the effects of treatment with RES (10 mg/kg PO q12h), metformin (MET; 30 mg/kg PO q12h), and aspirin (ASP; 20 mg/kg PO q24h) on experimentally induced ID. ANIMALS: Thirty-three healthy, adult, light-breed horses. METHODS: Unblinded, placebo-controlled, experimental trial evaluating effects of AMPK agonists (RES, MET, and ASP) on experimentally induced ID. Horses were randomly assigned to a treatment group (RES, MET/ASP, RES/ASP, RES/MET/ASP, or placebo [CON]) after induction of ID with dexamethasone (0.08 mg/kg PO q24h for 7 days). Frequently sampled insulin-modified IV glucose tolerance tests (FSIGTT) and oral sugar tests (OST) were performed at baseline, 7 days after ID, and ID plus 7 days of treatment. Minimal model and OST variables were compared between (1-way ANOVA) and within (1-way ANOVA for repeated measures) groups over time to determine effects of treatment on ID. RESULTS: Administration of dexamethasone for 14 days resulted in significantly altered insulin and glucose dynamics (SI, DI, basal [glucose], and [insulin]) and produced clinical signs of laminitis in 5 out of 33 (15%) of horses included in the study. Combination therapy with RES, MET, and ASP did not significantly improve insulin and glucose dynamics in horses with experimentally induced ID. CONCLUSIONS AND CLINICAL IMPORTANCE: Metabolic testing before glucocorticoid administration should be considered in horses with clinical signs of metabolic syndrome.

Comparison of one novel and four established diagnostic tests for insulin dysregulation in ponies.

Several tests have been advocated for diagnosis of insulin dysregulation (ID). Tests using simple sugars may not reflect the response to naturally ingested carbohydrates. This study aimed to evaluate agreement between the oral glucose test (OGT), the oral sugar test (OST), a novel oral test using a proprietary cereal (WEET), the IV combined glucose-insulin tolerance test (CGIT) and fasted basal insulin (FI) for diagnosis of ID. Each of the five tests above was performed on a group of six normal and six insulin dysregulated mixed-breed ponies in a randomised crossover study. Area under the curve (AUC) and maximum concentration of insulin from OGT, OST and WEET showed strong to very strong bivariate correlations (r = 0.85-0.94, and r = 0.87-0.92, respectively; P ≤ 0.001) and were significantly different between tests (associated with dose of carbohydrate) and between CGIT-positive and -negative ponies. Dichotomous results showed substantial agreement between OST and both WEET (κ = 0.65; P = 0.02) and OGT (κ = 0.67; P = 0.01) and between CGIT and both OST (κ = 0.63; P = 0.03) and OGT (κ = 0.67; P = 0.01), and no agreement between FI, which had low sensitivity, and all other tests (κ = 0.15 - 0.31; P > 0. 05). Palatability of WEET was variable, resulting in one pony being excluded for analysis of WEET data. Further work on development of an oral test using a more palatable feedstuff and appropriate cut-offs or diagnostic thresholds for tests of ID is warranted.

Evaluation of field-testing protocols to diagnose insulin dysregulation in ponies using a Bayesian approach.

Field tests and their association with laminitis have not been evaluated in large cohorts. The objectives of this study were to evaluate the performance of basal insulin (BI), the oral sugar test (OST) and the insulin tolerance test (ITT) to diagnose ID and investigate their association with laminitis. Insulin dysregulation status was determined in 146 ponies using BI (insulin concentration >20 µIU/mL), an OST (insulin concentration >65 µIU/mL at 60 or 90 min after oral administration of 0.45 mL/kg corn syrup) and an ITT (< 50% reduction in glucose concentration 30 min after intravenous administration of 0.1 IU/kg insulin). Laminitis was identified using modified-Obel scores. A Bayesian approach was used to define the characteristics of the tests and receiver operating characteristic curves were used to assess their association with laminitis. All tests were well tolerated and laminitis was diagnosed in 9% of ponies. Insulin dysregulation was diagnosed in 15% of ponies using BI, 38% using the OST and 54% using the ITT with 11% of ponies positive for all three tests. The sensitivities and specificities of BI, the OST and the ITT to diagnose ID were 0.52 (95% confidence interval [CI], 0.35-0.79) and 0.97 (95% CI, 0.91 - 1.00), 0.84 (95% CI, 0.70 - 0.94) and 0.60 (95% CI, 0.49 - 0.71), and 0.85 (95% CI, 0.68-0.96) and 0.88 (95% CI, 0.75 - 0.97), respectively. Only BI and the OST were associated with laminitis (P = 0.003 and 0.015, respectively).

Comparison of a modified 2-step insulin response test performed with porcine zinc insulin and an oral glucose test to detect hyperinsulinemic Icelandic horses.

Both, oral and intravenous (IV) testing protocols, are recommended and still used to detect insulin dysregulation (ID) in equids. However, IV tests mainly focus on peripheral insulin resistance (IR), while oral tests assess hyperinsulinemia (HI), which are different aspects of ID. The objective of this study was to describe if horses with HI also demonstrate IR and consequently can be detected by a modified 2-step insulin response test (2-step IRT) performed with a veterinary approved porcine zinc insulin (PZI). Twelve Icelandic horses were subjected to an OGT and 2-step IRT in a crossover study. Serum insulin concentrations during the OGT revealed that six horses were hyperinsulinemic (HI) while six were not (NON-HI). To describe the glucose response to IV injected PZI, the decline of plasma glucose concentration within the first 30 min was analyzed. Glucose reduction was similar in horses with and without HI during the 2-step IRT over time. Additionally, none of the horses reached a glucose reduction of ≥ 50% at 30 min. The results of the present study indicated that a comparable insulin mediated glucose uptake may be observed in horses with and without HI during a modified 2-step IRT. While six out of twelve horses were identified as HI by the OGT, all twelve horses were identified as IR by the modified 2-step IRT performed with PZI underlining the importance, but difficulty in choosing the right diagnostic tool in clinical settings to assess ID.

Effect of sirolimus on insulin dynamics in horses.

BACKGROUND: Sirolimus, a mechanistic target of rapamycin inhibitor, suppresses insulin production in other species and has therapeutic potential for hyperinsulinemia in horses. HYPOTHESIS/OBJECTIVE: Determine the pharmacokinetics (PKs) of sirolimus and evaluate its effect on insulin dynamics in healthy and insulin dysregulation (ID) horses. ANIMALS: Eight Standardbred geldings. METHODS: A PK study was performed followed by a placebo-controlled, randomized, crossover study. Blood sirolimus concentrations were measured by liquid chromatography-mass-spectrometry. PK indices were estimated by fitting a 2-compartment model using nonlinear least squares regression. An oral glucose test (OGT) was conducted before and 4, 24, 72, and 144 hours after administration of sirolimus or placebo. Effects of time, treatment and animal on blood glucose and insulin concentrations were analyzed using mixed-effects linear regression. Sirolimus was then administered to 4 horses with dexamethasone-induced ID and an OGT was performed at baseline, after ID induction and after 7 days of treatment. RESULTS: Median (range) maximum sirolimus concentration was 277.0 (247.5-316.06) ng/mL at 5 (5-10) min and half-life was 3552 (3248-4767) min. Mean (range) oral bioavailability was 9.5 (6.8-12.4)%. Sirolimus had a significant effect on insulin concentration 24 hours after a single dose: median (interquartile range) insulin at 60 min (5.0 [3.7-7.0] µIU/mL) was 37 (-5 to 54)% less than placebo (8.7 [5.8-13.7] µIU/mL, P = .03); and at 120 min (10.2 [8.4-12.2] µIU/mL) was 28 (-15 to 53)% less than placebo (14.9 [8.4-24.8] µIU/mL, P = .02). There was minimal effect on glucose concentration. Insulin responses decreased toward baseline in ID horses after 7 days of treatment. CONCLUSION AND CLINICAL IMPORTANCE: Sirolimus decreased the insulinemic response to glucose and warrants further investigation.

Palatability, glycemic, and insulinemic responses to various carbohydrate formulations: Alternatives for the diagnosis of insulin dysregulation in horses?

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.

Carbohydrate pellets to assess insulin dysregulation in horses.

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.

Comparación de los valores de glucosa en caninos obtenidos con glucómetros portátiles y la prueba estándar de laboratorio / Comparação dos valores de glicose em caninos obtidos com glicômetros portáteis e o teste laboratorial padrão / Comparison of glucose values in dogs obtained with portable glucometers and the standard laboratory test

La medición de glucosa en caninos es un procedimiento habitual en la clínica diaria, actualmente este valor se puede obtener mediante dispositivos portátiles y pruebas laboratoriales. Se realizó esta investigación con el fin de aportar mayor conocimiento sobre la importancia de la medición de glucosa, ya que en los últimos años ha perdido valor entre las pruebas hematológicas a considerar debido a que solo se relaciona con determinadas patologías como la diabetes u otras enfermedades metabólicas. El presente trabajo tiene como objetivo comparar los valores de glucosa en caninos obtenidos mediante un glucómetro portátil de uso humano (Accu-chek® Active, Roche Diagnostic, Mannheim, Alemania); veterinario (aLcose® Vet Glu, jjPlus Corporation, New Taipei, Taiwán) y la prueba estándar de laboratorio, esto nos indicará la fiabilidad de los resultados obtenidos mediante estos métodos. Se realizó la toma de muestras de sangre de 50 caninos clínicamente sanos, de los cuales se obtuvo el resultado de glucemia mediante estos tres métodos. Los resultados de nuestra investigación evidenciaron que las tres formas de evaluación de la glucosa sanguínea en perros brindaban resultados estadísticamente diferentes (p < 0.05). Se obtuvo valores de glucosa diferentes entre los tres métodos de medición, teniendo como promedios finales 84.14 mg/dL, 101.12 mg/dL y 91.12 mg/dL correspondientes al glucómetro portátil de uso humano, veterinario y a la prueba estándar de laboratorio respectivamente. En conclusión, los glucómetros portátiles de uso humano subestiman los valores reales de glucosa, mientras que los de uso veterinario lo sobreestiman, comparados con la prueba estándar de laboratorio.

A medição de glicose nos cães é um procedimento habitual realizado no atendimento clínico. Atualmente este valor pode ser obtido por meio de dispositivos portáteis e testes laboratoriais. Esta pesquisa foi realizada com a finalidade de destacar a importância da medição de glicose, visto que nos últimos anos esta avaliação não tem sido muito valorada entre os testes hematológicos, sendo considerada relevante apenas em relação a patologias como a diabetes e outras doenças metabólicas. O presente estudo teve como objetivo comparar os valores de glicose em cães obtidos com glicômetro portátil de uso humano; veterinário e o teste padrão de laboratório. Esta comparação poderá indicar a confiabilidade dos resultados obtidos mediante os métodos avaliados. Foi realizada a amostragem do sangue de 50 caninos clinicamente sadios os quais foram submetidos a avaliação de glicose mediante os três métodos. Os resultados de nossa investigação evidenciaram que as três formas de avaliação da glicose sanguínea têm resultados estatisticamente diferentes (p < 0,05). Os valores de glicose tiveram medias finais de 84,14 mg/dL, 101,12 mg/dL e 91,12 mg/dL para o glicômetro portátil de uso humano (Accu-chek® Active, Roche Diagnostic, Mannheim, Alemanha), veterinário (aLcose® Vet Glu, jjPlus Corporation, Nova Taipei, Taiwan) e o teste padrão de laboratório, respectivamente. Ao concluir, os glicômetros portáteis de uso humano subestimam os valores reais de glicose e os de uso veterinário os superestimam quando comparados com o teste padrão de laboratório.

The measurement of glucose in canines is a common procedure in daily clinical practice. Currently this value can be obtained by use of portable devices and laboratory tests. This research was carried out in order to provide more knowledge about the importance of glucose measurement, since in recent years it has lost value among the hematological tests to be considered because it is only related to certain pathologies such as diabetes or other metabolic diseases. The present study aimed to compare the glucose values in dogs obtained with a portable glucometer for human use, veterinarian use, and the standard laboratory test. This comparison may indicate the reliability of the results obtained through the evaluated methods. A blood sampling of 50 clinically healthy canines was taken and submitted to glucose evaluation using the three methods. Our investigation showed that the three ways of assessing blood glucose have statistically different results (p < 0.05). Glucose values had final averages of 84.14 mg/dL, 101.12 mg/dL, and 91.12 mg/dL for the portable glucometer for human use (Accu-chek® Active, Roche Diagnostic, Mannheim, Germany), veterinary (aLcose® Vet Glu, jjPlus Corporation, New Taipei, Taiwan) and the standard laboratory test, respectively. In conclusion, portable glucometers for human use underestimate the glucose values, and those for veterinary use overestimate them compared to the standard laboratory test.

Diagnostic evaluation of insulin and glucose dynamics in light-breed horses receiving dexamethasone.

Objective: Insulin dysregulation is a hallmark of equine metabolic syndrome (EMS) and increases the risk for development of laminitis. Accurate diagnosis of insulin dysregulation is crucial for implementation of preventative strategies in this population. The objective was to assess the effects of dexamethasone administration on insulin and glucose dynamics in light-breed horses and assess the agreement of various diagnostic tests for insulin dysregulation [basal [insulin] (BI), oral sugar test (OST), and combined glucose-insulin test (CGIT)]. Animal: Fourteen adult light-breed horses. Procedure: Prospective, experimental study to assess insulin and glucose dynamics by performing basal insulin, OST, and CGIT before (baseline) and post-dexamethasone administration (0.08 mg/kg, PO, q24h) for 7 d. Insulin and glucose dynamics were assessed by the BI, OST, CGIT, and insulin sensitivity proxy measurements (RISQI, QUICKI, FGIR, HOMA-IR, IG) at the baseline and post-dexamethasone time points. Results: The OST area under the insulin and glucose curves were increased following dexamethasone treatment (P < 0.001 and P < 0.01, respectively). Basal insulin, OST [insulin] at 60 min and CGIT [insulin] at 45 min were increased at the post-dexamethasone time point (P < 0.001, < 0.001, and < 0.01). Similarly, time spent in the positive glucose phase during the CGIT was longer at the post-dexamethasone time point (P < 0.001). The proxy measurements for insulin sensitivity (RISQI, QUICKI, FGIR) were decreased (P < 0.01) and the proxy measurements for insulin resistance (HOMA-IR) and ß-cell function (IG) were increased after dexamethasone administration (P < 0.01). More horses were classified with following dexamethasone administration, based on the diagnostic criteria for basal insulin (P = 0.03), OST (P = 0.01), and CGIT (P < 0.01). Kappa coefficients, measuring agreement between basal insulin, OST, and CGIT, showed none to moderate agreement at the baseline time point. Conclusion: Dexamethasone administration at 0.08 mg/kg, PO, q24h for 7 d worsened insulin dysregulation in adult light-breed horses based on findings of a basal insulin, OST, CGIT, and insulin sensitivity proxy measurements. There was none to moderate agreement between the basal insulin, OST, CGIT for the diagnosis of insulin dysregulation. Clinical relevance: Horses administered dexamethasone at a dose of 0.08 mg/kg, PO, q24h for 7 d should be considered insulin dysregulation and appropriate preventative strategies should be implemented. The variability of diagnostic performance of common tests for insulin dysregulation (basal insulin, OST, CGIT) may affect clinical decisions; therefore, performing multiple tests, including proxy measurements, may improve diagnostic accuracy of insulin dysregulation.

Objectif: La dysrégulation de l'insuline est une caractéristique du syndrome métabolique équin (EMS) et augmente le risque de développement de la fourbure. Un diagnostic précis de la dysrégulation de l'insuline est crucial pour la mise en oeuvre de stratégies préventives dans cette population. L'objectif était d'évaluer les effets de l'administration de dexaméthasone sur la dynamique de l'insuline et du glucose chez les chevaux de race légère et d'évaluer la concordance de divers tests de diagnostic pour le dérèglement de l'insuline [insuline basale] (BI), test de sucre oral (OST) et un test glucose-insuline combiné (CGIT). Animal: Quatorze chevaux adultes de race légère. Procédure: Étude prospective et expérimentale pour évaluer la dynamique de l'insuline et du glucose en effectuant l'insuline basale, l'OST et le CGIT avant (valeur de base) et après l'administration de dexaméthasone (0,08 mg/kg, PO, q24h) pendant 7 jours. La dynamique de l'insuline et du glucose a été évaluée par les mesures indirectes de BI, de l'OST, du CGIT et de la sensibilité à l'insuline (RISQI, QUICKI, FGIR, HOMA-IR, IG) aux points temporels de base et post-dexaméthasone. Résultats: La zone OST sous les courbes d'insuline et de glucose a augmenté après le traitement à la dexaméthasone (P < 0,001 et P < 0,01, respectivement). L'insuline basale, l'OST [insuline] à 60 minutes et le CGIT [insuline] à 45 minutes ont augmenté au point temporel post-dexaméthasone (P < 0,001, < 0,001 et < 0,01). De même, le temps passé dans la phase de glucose positif pendant le CGIT était plus long au moment post-dexaméthasone (P < 0,001). Les mesures indirectes de la sensibilité à l'insuline (RISQI, QUICKI, FGIR) ont diminué (P < 0,01) et les mesures indirectes de la résistance à l'insuline (HOMA-IR) et de la fonction des cellules ß (IG) ont augmenté après l'administration de dexaméthasone (P < 0,01). Plus de chevaux ont été classés avec l'administration suivante de dexaméthasone, sur la base des critères de diagnostic de l'insuline basale (P = 0,03), OST (P = 0,01) et CGIT (P < 0,01). Les coefficients Kappa, mesurant la concordance entre l'insuline basale, l'OST et le CGIT, ont montré une concordance nulle à modérée au point de référence. Conclusion: L'administration de dexaméthasone à 0,08 mg/kg, PO, toutes les 24 h pendant 7 jours a aggravé la dysrégulation de l'insuline chez les chevaux adultes de race légère d'après les résultats d'une insuline basale, d'OST, de CGIT et de mesures indirectes de la sensibilité à l'insuline. Il n'y avait aucun accord à modéré entre l'insuline basale, l'OST, le CGIT pour le diagnostic de dysrégulation de l'insuline. Pertinence clinique: Les chevaux ayant reçu de la dexaméthasone à une dose de 0,08 mg/kg, PO, q24h pendant 7 jours doivent être considérés comme ayant un dérèglement de l'insuline et des stratégies préventives appropriées doivent être mises en oeuvre. La variabilité des performances diagnostiques des tests courants de dysrégulation de l'insuline (insuline basale, OST, CGIT) peut affecter les décisions cliniques; par conséquent, la réalisation de plusieurs tests, y compris des mesures indirectes, peut améliorer la précision du diagnostic du dérèglement de l'insuline.(Traduit par Dr Serge Messier).

Seasonal Insulin Responses to the Oral Sugar Test in Healthy and Insulin Dysregulated Horses.

Seasonal effects on the oral sugar test (OST), used to monitor insulin dysregulation (ID) status to help reduce laminitis risk, are poorly understood in the ID horse. Resting, (basal) insulin (T0) and 60-minute (T60) OST (0.15 mL/Kg BW Karo Light Corn Syrup) insulin responses were evaluated, once per each season over 2 years, in ID (n = 11 14.9 ± 4.3 years; mean ± SD) and non-insulin dysregulated (NID: n = 11 16.4 ± 5.3 years; mean ± SD) horses housed on the same farm. Seasonal morphometric measurements were collected: bodyweight (BW), body-condition scores (BCS), and cresty neck scores (CNS). Seasonal forage from paddocks and hay were collected and analyzed. Insulin was measured by RIA. Data were analyzed via Minitab Software 20.2 (mixed effects model). Season had no effect on BW (P = .99); however, BCS and CNS were higher in ID versus NID in the spring, summer and fall (P < .02). Paddock (P < .05) but not hay (P > .2) analytes varied across season. ID horses consistently had higher T0, T60 insulin concentrations versus NID (P < .02). Season had no effect on NID T0 insulins (P = .31), but T60 values were higher in the spring versus summer (P = .01). ID horses' T0 & T60 insulins were higher in spring than fall and summer (P < .01 & P < .05) and winter T60 was higher than fall (P = .04). ID horses changed their ID categorization across season, with T0 confirming ID status only 56% of the time whilst T60 confirmed 94% of the time. Therefore, regardless of seasonal changes, if the OST was used, ID diagnosis would be more consistent.

Comparison of insulin sensitivity between healthy neonatal foals and horses using minimal model analysis.

The equine neonate is considered to have impaired glucose tolerance due to delayed maturation of the pancreatic endocrine system. Few studies have investigated insulin sensitivity in newborn foals using dynamic testing methods. The objective of this study was to assess insulin sensitivity by comparing the insulin-modified frequently sampled intravenous glucose tolerance test (I-FSIGTT) between neonatal foals and adult horses. This study was performed on healthy neonatal foals (n = 12), 24 to 60 hours of age, and horses (n = 8), 3 to 14 years of age using dextrose (300 mg/kg IV) and insulin (0.02 IU/kg IV). Insulin sensitivity (SI), acute insulin response to glucose (AIRg), glucose effectiveness (Sg), and disposition index (DI) were calculated using minimal model analysis. Proxy measurements were calculated using fasting insulin and glucose concentrations. Nonparametric statistical methods were used for analysis and reported as median and interquartile range (IQR). SI was significantly higher in foals (18.3 L·min-1· µIU-1 [13.4-28.4]) compared to horses (0.9 L·min-1· µIU-1 [0.5-1.1]); (p < 0.0001). DI was higher in foals (12 × 103 [8 × 103-14 × 103]) compared to horses (4 × 102 [2 × 102-7 × 102]); (p < 0.0001). AIRg and Sg were not different between foals and horses. The modified insulin to glucose ratio (MIRG) was lower in foals (1.72 µIUinsulin2/10·L·mgglucose [1.43-2.68]) compared to horses (3.91 µIU insulin2/10·L·mgglucose [2.57-7.89]); (p = 0.009). The homeostasis model assessment of beta cell function (HOMA-BC%) was higher in horses (78.4% [43-116]) compared to foals (23.2% [17.8-42.2]); (p = 0.0096). Our results suggest that healthy neonatal foals are insulin sensitive in the first days of life, which contradicts current literature regarding the equine neonate. Newborn foals may be more insulin sensitive immediately after birth as an evolutionary adaptation to conserve energy during the transition to extrauterine life.

Variation in insulin response to oral sugar test in a cohort of horses throughout the year and evaluation of risk factors for insulin dysregulation.

BACKGROUND: The oral sugar test (OST) is commonly used to diagnose insulin dysregulation (ID) and equine metabolic syndrome; however, possible seasonal changes in OST results have not been evaluated. OBJECTIVE: To determine the possible variation in insulin response to OST throughout the year and risk factors associated with maximum insulin concentration (InsMax) and ID. STUDY DESIGN: Prospective, longitudinal cohort study. METHODS: The OST was performed on 29 Finnhorses every other month six times. Serum total adiponectin concentration and phenotypic variables related to obesity were also measured. Changes in InsMax, adiponectin, scale weight, body condition score, cresty neck score (CNS), and fasting glucose concentration were assessed. Risk factor analyses were performed on InsMax and ID status, and ID groups were compared with each other. RESULTS: Fourteen horses were categorised with non-ID each time and 15 as having ID at least once during the follow-up period. The ID status of 12 horses varied throughout the year, but neither the insulin variables measured during the OST nor adiponectin expressed significant seasonal variation. Increasing age and CNS, and decreasing adiponectin were observed as risk factors for a high InsMax after OST. The risk of ID was higher in horses with no exercise compared to horses with exercise (OR 7.6, 95% CI 1.2-49.3, P = .03). Horses with ID had lower serum adiponectin concentrations, longer neck circumference and larger height than horses in the non-ID group. MAIN LIMITATIONS: The environmental conditions (feeding, exercise) were not constant for all horses throughout the study and only one breed was used. CONCLUSIONS: Neither OST results nor adiponectin varies with season; however, there were a substantial number of horses with variable ID status throughout the year, in which repeated OSTs may be beneficial. Lack of exercise was a risk factor for ID.

Characterisation of the oral glucose and sugar tolerance tests and the enteroinsular axis response in healthy adult donkeys.

BACKGROUND: Insulin dysregulation (ID) is diagnosed in horses and ponies using oral glucose (OGTT) and oral sugar (OSTT) tolerance tests. The enteroinsular axis plays a major role in postprandial glucose disposal and insulin response in horses, ponies and foals. The insulin and incretin response to oral carbohydrate challenges has not been characterised in donkeys. OBJECTIVES: (a) To characterise OGTT and OSTT, and (b) to assess the plasma incretin response to OGTT and OSTT in healthy donkeys. STUDY DESIGN: In vivo experiments. METHODS: Six healthy adult female Andalusian donkeys were challenged with OGTT (1 g/kg glucose, 20% solution by nasogastric tube) and OSTT (0.45 mL/kg corn syrup orally by syringe) with a 1-week washout. Blood samples were collected for glucose (spectrophotometry), insulin (radioimmunoassay), glucose-dependent insulinotropic polypeptide (GIP, ELISA) and active glucagon-like peptide-1 (aGLP-1, ELISA) determination over 6 hours. Curves were analysed and proxies calculated. RESULTS: Glucose and insulin concentrations peaked at 180 minutes in OGTT, but at 300 and 150 minutes in OSTT, respectively. Plasma GIP concentrations increased in the OGTT and OSTT (peaked at 180 and 360 minutes, respectively), but aGLP-1 increased only in OGTT (240 minutes). MAIN LIMITATIONS: Single breed, narrow age and sample, diet, season and not having donkeys with evidence of ID to provide clinical validation. CONCLUSIONS: Donkeys have a functional enteroinsular axis that is activated by enteral carbohydrates. Donkeys have evident endocrine differences with horses, supporting the validation of the OSTT and OGTT to assess insulin sensitivity in this species to avoid extrapolation from horses.

Evaluation of the combined glucose-insulin and intravenous glucose tolerance tests for insulin dysregulation diagnosis in donkeys.

BACKGROUND: Insulin dysregulation (ID) and donkey metabolic syndrome (DMS) are common in this species. Contrary to horses, diagnostic guidelines compiling insulin cut-offs values and dynamic testing interpretations have not been reported for this species. OBJECTIVES: To evaluate resting serum insulin concentrations, the combined glucose-insulin test (CGIT) and the glucose intravenous tolerance test (IVGTT) for the diagnosis of DMS with ID suspicion. STUDY DESIGN: Diagnostic test comparison. METHODS: Six of 80 mix-breed adult donkeys fulfilled the inclusion criteria for DMS based on history or clinical evidence of recurrent laminitis, body condition >6 and neck score >2 or baseline insulin and leptin concentrations >20 µIU/mL and >12 ng/mL respectively. CGIT and IVGTT were performed in all donkeys within a week and interpreted following guidelines reported for equine metabolic syndrome (EMS). Insulin and glucose curves were analysed, proxies calculated and correlations and multivariate analysis assessed. RESULTS: Following EMS guidelines, CGIT classified 2 (using glucose-positive phase duration) or 3 (using insulin concentration) and IVGTT classified 5 donkeys as ID. ID donkeys showed a lower glucose/insulin ratio, QUICKI and RISQI, and a higher insulin/glucose ratio, MIRG and HOMA-B%. MAIN LIMITATIONS: Comparison of these tests with additional dynamic testing including a larger number of ID donkeys is necessary. CONCLUSIONS: This is the first study evaluating dynamic tests to assess ID/DMS in DMS-suspected donkeys. IVGTT detected more ID donkeys than CGIT. EMS recommendations could also be used for DMS diagnosis, although a baseline insulin cut-off value is needed.

Effect of Dose and Fasting on Oral Sugar Test Responses in Insulin Dysregulated Horses.

The oral sugar test (OST) is frequently used to identify insulin dysregulated (ID) equines. The effect of fasting and varying sugar dose for the OST has been investigated in the pony but little work has been done in the horse. This study aimed to investigate (1) an OST response with access to forage continued until the time of the OST or prevented for 3 hours prior to the OST and (2) responses of ID and non-insulin dysregulated (NID) horses to two different OST doses. Twenty-one mixed-breed horses (14.8 ± 3.2 years; 574.3 ± 83.3 kg) were used in two randomized crossover studies. Seven ID and seven NID horses were used in study A, and eight ID and eight NID in study B. Study A horses underwent an OST (0.15 mL/kg BW) either after a fast (FA) or directly off pasture (FE). Study B horses received either a low (LD; 0.15 mL/kg BW) or high dose (HD; 0.45 mL/kg BW) OST on one occasion each. Blood was collected at basal (T0), and post-60 minute (T60) for later determination of insulin (RIA). Data were analyzed via ANOVA with repeated measures. ID horses had significantly (P < 0.05) greater insulin responses than NID for all OSTs. There was no statistical difference between LD versus HD mean insulin concentrations (T0, T60, delta insulin) for either ID or NID horses. ID had higher T0 (P < 0.01) for FE compared to FA; however, FE and FA did not significantly affect T60 or delta insulins (DI) concentrations.

Effects of maternal obesity in an ovine model on metabolic outcomes in F2 adults and F3 neonates.

Accumulating evidence suggests that indications of metabolic syndrome can be inherited through the germline as a result of maternal obesity. We hypothesized that diet-induced maternal obesity during gestation would program metabolic consequences for multiple generations of offspring, even when first, second, and third generation offspring (F1, F2, F3, respectively) were fed only to requirements. Control (CON) and obese (OB) ewes (generation 0; F0) were bred to a single ram to produce the first generation of offspring (F1). From 60 d prior to conception through term, CONF0 ate 100% National Research Council recommendations (NRC), while OBF0 ewes ate 150% NRC. All F1, F2, and F3 ate 100% NRC after weaning. All mature F1 ewes were bred to a single ram to generate CONF2 (n = 6) and OBF2 (n = 10). All mature F2 ewes were bred to a single ram to produce CONF3 (n = 6) and OBF3 (n = 10). OBF2 ewes exhibited greater (P < 0.0001) plasma cortisol than CONF2 throughout gestation. A glucose tolerance test at 90% gestation revealed OBF2 ewes had higher (P < 0.05) insulin response with similar glucose, resulting in greater (P < 0.05) insulin resistance. OBF3 neonates had similar weight, lean mass, and body fat mass to CONF3 neonates. These data suggest that multigenerational programming of adverse metabolic phenotypes occur in association with F0 maternal obesity, yet adiposity may return to CON levels in F3 neonates.

Effects of dietary antioxidants on glucose and insulin responses to glucose tolerance test in transition dairy cows.

Oxidative stress occurs during the transition period and causes insulin resistance, which may be reduced by the use of antioxidants in this period. Twenty-four multiparous Holstein dairy cows, at 8 wk before parturition, were divided into 4 equal groups, namely control (Ctrl), vitamin E (VE), selenium (Se), and vitamin E plus selenium (VE + Se) groups. On a daily basis, VE and Se cows received dietary 1.5 IU vitamin E/kg BW and 0.3 mg/kg DM selenium, respectively, from 8 wk before to 3 wk after parturition. Vitamin E plus selenium group received doses similar to VE and Se groups. Insulin sensitivity was evaluated through intravenous glucose tolerance test (ivGTT) at weekly intervals from 3 wk before to 3 wk after parturition. Serum concentrations of total antioxidant status (TAS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), nonesterified fatty acid (NEFA), and beta-hydroxybutyric acid (BHBA) were assayed weekly before the commencement of ivGTT. Based on the results of ivGTT, the lowest and the highest degrees of insulin sensitivity were detected in Ctrl and VE + Se groups, respectively. The highest and the lowest concentrations of NEFA and BHBA were observed in Ctrl and VE + Se groups, respectively. Total antioxidant status, SOD, and GPx values were significantly lower in Ctrl cows and significantly higher in VE + Se-received cows compared with other groups. However, MDA values in Ctrl and VE + Se cows were significantly higher and lower than the other groups, respectively. Collectively, our results show that dietary administration of vitamin E and selenium ameliorates oxidative stress and lipid mobilization and increases insulin sensitivity in transition cows.

The effect of the ghrelin-receptor agonist capromorelin on glucose metabolism in healthy cats.

Somatostatin secretion from islet delta cells is important in maintaining low glycemic variability (GV) by providing negative feedback to beta cells and inhibiting insulin secretion. Capromorelin is a ghrelin-receptor agonist that activates the growth hormone secretagogue receptor on delta cells. We hypothesized that in cats, capromorelin administration will result in decreased GV at the expense of reduced insulin secretion and glucose tolerance. Seven healthy cats were treated with capromorelin from days 1-30. After the first day, fasting blood glucose increased (+13 ± 3 mg/dL, P < 0.0001), insulin decreased (+128 ± 122 ng/dL, P = 0.03), and glucagon was unchanged. Blood glucose was increased throughout an intravenous glucose tolerance test on day 1 with blunting of first-phase insulin response ([FPIR] 4,931 ± 2,597 ng/L/15 min) compared with day -3 (17,437 ± 8,302 ng/L/15 min, P = 0.004). On day 30, FPIR was still blunted (9,993 ± 4,285 ng/L/15 min, P = 0.045), but glucose tolerance returned to baseline. Mean interstitial glucose was increased (+19 ± 6 mg/dL, P = 0.03) on days 2-4 but returned to baseline by days 27-29 (P = 0.3). On days 2-4, GV was increased (SD = 9.7 ± 3.2) compared with baseline (SD = 5.0 ± 1.1, P = 0.02) and returned to baseline on days 27-29 (SD = 6.1 ± 1.1, P = 0.16). In summary, capromorelin caused a decline in insulin secretion and glycemic control and an increase in glucose variability early in the course of treatment, but these effects diminished toward the end of 30 d of treatment.