Effects of dexamethasone on glucose dynamics and insulin sensitivity in healthy horses

OBJECTIVE: To determine effects of dexamethasone on glucose dynamics and insulin sensitivity in healthy horses. ANIMALS: 6 adult Standardbreds. PROCEDURES: In a balanced crossover study, horses received dexamethasone (0.08 mg/ kg, IV, q 48 h) or an equivalent volume of saline (0.9% NaCl) solution (control treatment) during a 21-day period. Horses underwent a 3-hour frequently sampled IV glucose tolerance test (FSIGT) 2 days after treatment. Minimal model analysis of glucose and insulin data from FSIGTs were used to estimate insulin sensitivity (Si), glucose effectiveness (Sg), acute insulin response to glucose (AIRg), and disposition index. Proxies for Si (reciprocal of the inverse square of basal insulin concentration [RISQI]) and beta-cell responsiveness (modified insulin-to-glucose ratio [MIRG]) were calculated from basal plasma glucose and serum insulin concentrations. RESULTS: Mean serum insulin concentration was significantly higher in dexamethasone-treated horses than control horses on days 7, 14, and 21. Similarly, mean plasma glucose concentration was higher in dexamethasone-treated horses on days 7, 14, and 21; this value differed significantly on day 14 but not on days 7 or 21. Minimal model analysis of FSIGT data revealed a significant decrease in Si and a significant increase in AIRg after dexamethasone treatment, with no change in Sg or disposition index. Mean RISQI was significantly lower, whereas MIRG was higher, in dexamethasone-treated horses than control horses on days 7, 14, and 21. CONCLUSIONS AND CLINICAL RELEVANCE: The study revealed marked insulin resistance in healthy horses after 21 days of dexamethasone administration. Because insulin resistance has been associated with a predisposition to laminitis, a glucocorticoid-induced decrease in insulin sensitivity may increase risk for development of laminitis in some horses and ponies.     

Effects of phenylbutazone on glucose tolerance and on secretion of insulin in healthy geldings

The effect of phenylbutazone (4.4 mg/kg of body weight, IV, q 24 h, for 5 days) on glucose tolerance and on secretion of insulin in 6 healthy geldings was determined. Phenylbutazone significantly lowered fasting concentrations of glucose in plasma but did not significantly change the concentration of insulin in serum. There was no significant effect of phenylbutazone on glucose tolerance, on secretion of insulin, or on the area under the insulin/glucose ratio vs time curve in healthy geldings, as determined by paired t test analysis.     

Repeatability of 2 methods for assessment of insulin sensitivity and glucose dynamics in horses

Both the euglycemic-hyperinsulinemic clamp (EHC) and minimal model analysis of the frequently sampled intravenous glucose tolerance test (FSIGT) have been applied for measurement of insulin sensitivity in horses. However, no published data are available on the reproducibility of these methods. Therefore, the objective of this study was to evaluate the variation and repeatability of measures of glucose dynamics and insulin sensitivity in horses derived from minimal model analysis of the FSIGT and from the EHC method. Six healthy horses underwent both the FSIGT and EHC on 2 occasions over a 4-week period, with a minimum of 5 days between tests. Coefficient of variation (CV) and intraclass correlation coefficient (ICC) were calculated for measures of glucose metabolism and insulin sensitivity derived from each test. In the EHC, insulin sensitivity, expressed as the amount of metabolized glucose (M) per unit of serum insulin (I) (M/I ratio), averaged 0.19 +/- 0.06 x 10(-4) mmol/kg/min x (pmol/L)(-1) with an average interday CV of 14.1 +/- 5.7% (range, 7-20%) and ICC of 0.74. Minimal model analysis of the FSIGT demonstrated mean insulin sensitivity (Si) of 0.49 +/- 0.17 x 10(-4)/min x (pmol/L)(-1) with an average interday CV of 23.7 +/- 11.2% (range, 9-35%) and ICC of 0.33. Mean CV and ICC for minimal model glucose effectiveness (Sg) and acute insulin response (AIRg) were, respectively, 26.4 +/- 11.2% (range 13-40%) and 0.10 and 11.7 +/- 6.5% (range 7-21%) and 0.98. Insulin sensitivity measured by the EHC has lower interday variation when compared with the minimal model estimate derived from the FSIGT.     

Insulin sensitivity and glucose dynamics during pre-weaning foal development and in response to maternal diet composition

Nutritional management of animals during pregnancy can affect glucose and insulin dynamics in the resulting offspring through influences on fetal development. Additionally, high starch feeding in mature horses is associated with reduced insulin sensitivity and an increased risk for diseases such as obesity and laminitis. However, no study has yet evaluated the effect of feeding a high starch diet to pregnant mares on glucose and insulin dynamics in their offspring. Twenty late-gestation mares maintained on pasture were provided two-thirds of digestible energy requirements from isocaloric, isonitrogenous low starch (LS, n = 10) or high starch (HS, n = 10) feed. Their foals were assessed with an insulin-modified frequently sampled intravenous glucose tolerance test at 5, 40, 80, and 160 d of age. Baseline glucose concentrations, insulin sensitivity, and insulin-independent glucose clearance in 5-d foals were all greater than values observed in mature horses and declined towards mature values as foals reached 160 d of age. Baseline glucose concentrations were all within normal range, but higher in foals born from HS mares through 80 d of age. Insulin sensitivity was not different between dietary groups until a trend for lower insulin sensitivity in HS foals emerged at 160 d of age. These data are the first to characterize decreasing insulin sensitivity and glucose tolerance in Thoroughbred foals from 5 to 160 d of age. This study also presents the first data examining glucose and insulin dynamics in developing foals in response to maternal high starch diet.     

Effects of diet and weight gain on circulating tumour necrosis factor‐α concentrations in Thoroughbred geldings

Low‐grade inflammation precedes the development of obesity‐related metabolic disorders in humans, but whether the same is true in the horse is not known. The objective of this study was to examine the effects of weight gain and diet on the inflammatory state of horses as determined by serum concentrations of tumour necrosis factor‐α (TNF), an inflammatory cytokine. Fifteen mature Thoroughbred geldings with an initial body weight (BW) of 519 ± 12 kg and body condition score (BCS) of 4.3 ± 0.1 were fed a diet of hay plus a concentrate that was either high in non‐structural carbohydrates (NSC) (i.e. starch and sugar), similar to those commercially available (CON) or one that had the energy source replaced with fat and fibre (FAT) for 32 weeks. Weight gain was achieved by feeding an additional 20 Mcal/day in excess of digestible energy maintenance requirements and resulted in a final BW of 608 ± 12 kg and BCS of 6.9 ± 0.1. Horses were exercised twice daily at a walk during the weight gain period. Horses were assessed bi‐weekly for BW and BCS. Serum TNF was analysed from blood samples collected at 4‐week intervals. Although treatment groups began the study with similar mean serum TNF concentrations, 12 weeks of FAT feeding promoted a decrease in circulating TNF that was maintained throughout the study with the exception of weeks 20 and 32. For either diet, there were no linear correlations between serum TNF concentration and BCS when horses increased in BCS from four to seven. The higher level of TNF observed in horses fed the CON diet indicates an increase in some level of systemic inflammation that was independent of their weight gain from a moderately thin to fleshy condition. The influence of diet on serum TNF concentrations should be investigated in horses fed to maintain body condition.     

Evaluation of glucose tolerance and insulin sensitivity in Ilama crias

OBJECTIVE: To investigate glucose tolerance and insulin sensitivity in llama crias. ANIMALS: 7 llamas (age range, 14 to 30 days). PROCEDURE: On each of 2 sequential days, crias were administered glucose (0.5 g/kg) via rapid i.v. injection. On 1 day (randomly determined for each cria), regular insulin (0.2 U/kg) or 0.9% NaCl solution (0.002 mL/kg) was administered i.v. 15 minutes after glucose administration. Blood samples were collected before (baseline) and at 5, 15, 30, 45, 60, 90, 120, 180, and 240 minutes after glucose administration for determination of plasma glucose and insulin concentrations; fractional turnover rates and plasma half-life of glucose were calculated. The data were compared over time and between days (ie, between glucose treatments with and without insulin administration). RESULTS: A peak plasma glucose concentration of 342 +/- 47 mg/dL was detected at 5 minutes after glucose administration and llamas cleared glucose from plasma within 60 minutes; at 15 minutes, plasma insulin concentration attained a peak value of 33 +/- 13 microU/mL (ie, triple the baseline value). During the 15- to 45-minute interval, fractional turnover rate of glucose was 1.10 +/- 0.24%/min and plasma half-life was 65.7 +/- 13.4 minutes. Insulin significantly increased glucose turnover and resulted in hypoglycemia within 75 minutes of administration. CONCLUSIONS AND CLINICAL RELEVANCE: Healthy immature llamas have glucose tolerance and insulin sensitivity superior to that of adults. However, whether sick crias retain the pancreatic sufficiency and tissue responsiveness that are likely responsible for the rapid glucose clearance in healthy individuals is not known.     

Effects of high and moderate non-structural carbohydrate hay on insulin, glucose, triglyceride, and leptin concentrations in overweight Arabian geldings

The objective of this study was to determine the effects of high and moderate non-structural carbohydrates (NSC) hay on insulin, glucose, triglyceride, and leptin concentrations in overweight Arabian geldings. Eight adult overweight (average BCS 7 [9-point scale]) Arabian geldings were fed each of two orchardgrass hays, high NSC (18% DM) and moderate NSC (12% DM), in a cross over design during two 28-day periods. Body weight and body condition score assessment along with blood sampling to measure insulin, glucose, leptin, and triglyceride concentrations were performed on days 0, 7, 14, 21 and 28 of each period. Effects of hay, period, day, and day*hay on plasma glucose and serum leptin were not detected. Serum insulin was influenced by hay (p = 0.001), day (p = 0.03), and day*hay (p = 0.04). Insulin concentrations were higher on day 7 in the high NSC group (15.6 μIU/ml) than the moderate NSC group (9.5 μIU/ml), but not by day 14 (p = 0.0007). Plasma triglyceride was influenced by period (p = 0.0003), day*period (p < 0.0001), and day*hay (p = 0.02). Hyperinsulinaemia was not observed in the overweight Arabian geldings fed either a moderate or high NSC hay.     

Plasma glucose and insulin responses of Thoroughbred mares fed a meal high in starch and sugar or fat and fiber

Plasma concentrations of glucose and insulin following a meal were compared in twelve Thoroughbred mares fed a pelleted concentrate (PC), a traditional sweet feed high in sugar and starch (SS), or a feed high in fat and fiber (FF). The feeds had similar DE and CP but differed in fat (19, 32, and 166 g/kg DM, respectively), NDF (199, 185, and 369 g/kg DM, respectively) and nonstructural carbohydrates (574, 645, and 247 g/kg, respectively). Mares were randomly assigned to two groups balanced for foaling date and weight. All mares received PC in late gestation; then, after foaling, one group was fed SS and the other FF for trials in early and late lactation. Mares were placed in stalls and deprived of feed overnight. A series of blood samples was collected via a jugular catheter from 0 (baseline) to 390 min after consumption of 1.82 kg of feed. Plasma was analyzed for glucose and insulin. Baseline values, peak values, and areas under curves (AUC) were compared by ANOVA. Baseline values were 74.7 +/- 10.9 mg/dL for glucose and 5.86 +/- 1.80 mIU/L for insulin for all diets and stages. Responses to PC did not differ between the two groups (P > 0.34), indicating the groups were metabolically similar. Peak plasma glucose and insulin concentrations were higher (P < 0.001) in the SS group than in the FF group during early and late lactation. Similarly, glucose and insulin AUC were larger (P < 0.003) in SS than in FF during early and late lactation. These results indicate that metabolic fluctuations are moderated by the replacement of sugar and starch with fat and fiber. This replacement may reduce the risk of certain digestive and metabolic disorders that have been linked to feeding meals of grain-based concentrates to pregnant or lactating mares.     

The effects of dietary nitrate on plasma glucose and insulin sensitivity in sheep

Nitrate (NO₃^¯) is an effective non‐protein nitrogen source for gut microbes and reduces enteric methane (CH₄) production in ruminants. Nitrate is reduced to ammonia by rumen bacteria with nitrite (NO₂^¯) produced as an intermediate. The absorption of NO₂^¯ can cause methaemoglobinaemia in ruminants. Metabolism of NO₃^¯ and NO₂^¯ in blood and animal tissues forms nitric oxide (NO) which has profound physiological effects in ruminants and has been shown to increase glucose uptake and insulin secretion in rodents and humans. We hypothesized that absorption of small quantities of NO₂^¯ resulting from a low‐risk dose of dietary NO₃^¯ will increase insulin sensitivity (S_I) and glucose uptake in sheep. We evaluated the effect of feeding sheep with a diet supplemented with 18 g NO₃^¯/kg DM or urea (Ur) isonitrogenously to NO₃^¯, on insulin and glucose dynamics. A glucose tolerance test using an intravenous bolus of 1 ml/kg LW of 24% (w/v) glucose was conducted in twenty sheep, with 10 sheep receiving 1.8% supplementary NO₃^¯ and 10 receiving supplementary urea isonitrogenously to NO₃^¯. The MINMOD model used plasma glucose and insulin concentrations to estimate basal plasma insulin (I_b) and basal glucose concentration (G_b), insulin sensitivity (S_I), glucose effectiveness (S_G), acute insulin response (AIRg) and disposition index (DI). Nitrate supplementation had no effect on I_b (p > .05). The decrease in blood glucose occurred at the same rate in both dietary treatments (S_G; p = .60), and there was no effect of NO₃^¯ on either G_b, S_I, AIRg or DI. This experiment found that the insulin dynamics assessed using the MINMOD model were not affected by NO₃^¯ administered to fasted sheep at a low dose of 1.8% NO₃^¯ in the diet.     

Effects of an intravenous endotoxin challenge on glucose and insulin dynamics in horses

OBJECTIVE: To evaluate the effects of endotoxin administered IV on glucose and insulin dynamics in horses. ANIMALS: 16 healthy adult mares. PROCEDURES: Each week of a 2-week randomized crossover study, each horse received an IV injection (duration, 30 minutes) of Escherichia coli O55:B5 lipopolysaccharide (LPS) in 60 mL of sterile saline (0.9% NaCl) solution (20 ng/kg) or sterile saline solution alone (control treatment). Frequently sampled IV glucose tolerance test procedures were performed at 24 hours before (baseline) and 24 and 48 hours after injection; glucose and insulin dynamics were assessed via minimal model analysis. RESULTS: 13 of 16 horses had a clinical response to LPS, which was characterized by mild colic and leukopenia. Before treatment, mean +/- SD insulin sensitivity was 2.9 +/- 1.9 x 10(4) L x min(1) x mU(1); this significantly decreased to 0.9 +/- 0.9 x 10(4) L x min(1) x mU(1) 24 hours after treatment (69% reduction) and was 1.5 +/- 0.9 x 10(4) L x min(1) x mU(1) 48 hours after treatment. At baseline, mean +/- SD acute insulin response to glucose was 520 +/- 196 mU x min x L(1); this significantly increased to 938 +/- 620 mU x min x L(1) (80% increase) and 755 +/- 400 mU x min x L(1) (45% increase) at 24 and 48 hours after LPS treatment, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with baseline values, insulin sensitivity was decreased for 24 hours after IV injection of LPS, and affected horses had a compensatory pancreatic response. These disturbances in glucose and insulin dynamics may contribute to development of laminitis in horses.     

Combined effects of diet and cold exposure on insulin responsiveness to glucose and tissue responsiveness to insulin in sheep.

Hyperglycemic clamp and hyperinsulinemic euglycemic clamp techniques were used to investigate effects of diet and cold exposure on insulin responsiveness to glucose and tissue responsiveness and sensitivity to insulin in adult rams. The sheep were fed a high-concentrate diet (80% concentrate and 20% roughage) and a high-roughage diet (20% concentrate and 80% roughage), both 70% above the ME requirement for maintenance, and were exposed to a thermoneutral environment (20 degrees C) and a cold environment (0 degrees C) for 2 wk. The estimated ME intake was greater (P < .01) for the high-concentrate diet than for the high-roughage diet. In the hyperglycemic clamp experiment, the ratio of the plasma insulin increment to the glucose infusion rate (insulin responsiveness to glucose) was lower during cold exposure than in the thermoneutral environment in sheep fed the high-concentrate diet but was unchanged in sheep fed the high-roughage diet. In the hyperinsulinemic euglycemic clamp experiment, the glucose infusion rate (tissue responsiveness to insulin) was higher (P < .01) for the high-concentrate diet than for the high-roughage diet, and it was also higher (P < .01) during cold exposure than in the thermoneutral environment, indicating that tissue responsiveness to insulin was intensified in sheep fed the high-concentrate diet during cold exposure associated with the higher energy intake. These results suggest that both reduced insulin responsiveness and enhanced tissue responsiveness to insulin in sheep exposed to cold were dependent on the type of diet.