Insulin dysregulation (ID) is the hallmark of equine metabolic syndrome, a constellation of clinical and laboratory features that result in an increased risk of laminitis.1 This form of laminitis was named hyperinsulinemia-associated laminitis (HAL) due to the role of insulin in its development and is now recognized as the most common form of laminitis, representing more than 90% of laminitis cases.2 Despite its high prevalence, the pathophysiology of HAL is incompletely understood and warrants further explorations.
As ID is not a fixed trait, changing with diet, season, or age, maintaining a stable herd of horses or ponies with ID is challenging; therefore, experimental models are required.3,4 Current models to study HAL include the infusion of insulin for 48 to 72 hours with a euglycemic hyperinsulinemic clamp.5–8 This clamp has been shown to be a reliable and repeatable model of HAL, reproducing the histologic findings of spontaneous cases.9,10 This model is, however, limited to terminal studies and is not useful for studying the mechanisms of ID that eventually lead to HAL or for evaluating pharmaceuticals for the treatment of ID. Due to the antagonistic role of glucocorticoids on insulin receptors, dexamethasone has been used as a model of tissue insulin resistance (IR) in several studies.11–15 Administration of dexamethasone every 24 to 48 hours for 7 days decreases tissue insulin sensitivity as demonstrated by an increased insulin concentration 45 minutes after a combined glucose insulin tolerance test, lower quantitative insulin sensitivity check index, reciprocal of the square root of insulin, and fasting glucose-to-insulin ratio.13 Longer administration of dexamethasone, extending to 14 days, showed decreased insulin sensitivity as calculated after a frequently sampled IV glucose tolerance test and an increased risk of developing laminitis14,15; however, inconsistencies in insulin and glucose concentrations among subjects raised questions about the predictability of dexamethasone as a model of ID and about the role of glucocorticoids in the exacerbation of ID leading to laminitis.15,16
With a better understanding of insulin and glucose dynamics in horses, the concept of ID was shown to extend beyond IR.17 In fact, ID is now characterized by the presence of hyperinsulinemia (resting or postprandial or postnonstructural carbohydrate challenge), IR, or a combination of these elements.18 The importance of each component varies in individual cases; however, hyperinsulinemia has been shown to play a crucial role in the risk of HAL development, requiring further attention.19–21 Blood glucose is the primary stimulus for insulin secretion in equine pancreatic beta cells, accounting for approximately 70% of beta cell activity. Incretins, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), contribute the remaining 30%, and recent studies22 suggest that these hormones might have increased activity in ponies with ID. While dexamethasone has been used to experimentally induce IR, there are no data published regarding its specific effect on insulin secretion and on its activity on the enteroinsular axis. Therefore, the current study aimed to describe the effects of dexamethasone administration on the insulin and incretin response to an oral carbohydrate challenge in horses to further characterize its suitability as a model for ID and understand how glucocorticoid administration exacerbates ID.
Methods
The experimental protocol was approved by the institutional animal ethics committee.
Horses
Eight Standardbreds (5 to 13 years old; 467 to 548 kg) were used for the study. The horses were clinically healthy and sound at the walk when examined on a hard surface. Lateromedial radiographs of the feet obtained before the study did not yield evidence of laminitis. Horses enrolled in the study were housed in dirt yards, with ad libitum access to lucerne (alfalfa) hay (analysis in Supplementary Table S1) and water.
Experimental protocol
The experiments were conducted in June 2022 (winter in the Southern hemisphere). After 2 weeks of acclimatization, all horses underwent an oral glucose test (OGT) consisting of administration through a nasogastric tube of 0.75 g/kg of dextrose dissolved in 2 L of warm water (day 1 OGT).23 The use of a nasogastric tube was selected to ensure the complete administration of dextrose and a reliable timeline. Blood samples were collected from a jugular catheter placed 1 hour before the start of the experiments at 0, 15, 30, 60, 90, 120, 150, 180, 210, and 240 minutes in serum, heparin, and EDTA tubes. Serum tubes were left to clot for 45 minutes at room temperature and centrifuged for 10 minutes at 450 X g, with serum collected and stored at −80 °C until analysis. Heparin and EDTA samples were centrifuged immediately, and plasma was stored at −80 °C until analysis. The day after day 1 OGT, horses received 0.08 mg/kg of dexamethasone IM every 48 hours for 14 days. The administration of dexamethasone every 48 hours rather than every 24 hours was used to limit the risk of inducing laminitis while still dysregulating insulin metabolism.12,13,15 Oral glucose tests were repeated after 7 and 14 days of treatment (day 8 OGT and day 15 OGT, respectively). For each testing, horses were fasted for about 10 hours (the last hay was provided at 10 pm the night before, and testing started between 8 am and 10 am) and were not offered feed during the test.3
Sample analysis
Blood glucose concentrations were measured at all sample time points immediately using a glucometer validated for use with horses (AlphaTRAK2; Zoetis Inc).19 Serum insulin concentrations were measured using a chemiluminescent assay (Siemens Immulite 1000; Bayswater) previously validated for use with horses.24 Plasma active GLP-1 (aGLP-1) was measured using a commercial ELISA kit (#EGLP-35K; EMD Millipore) previously validated for use with horses.25 Plasma total GLP-1 (tGLP-1) was measured using a commercial ELISA kit (#EZGLP1T-36K; EMD Millipore) previously validated for use with horses.22 Plasma total GIP was measured using a commercial ELISA kit (#EZHGIP-54K; EMD Millipore) previously validated for use with horses.22 Triglycerides concentrations were determined on a commercial biochemical analyzer (AU480 Chemistry Analyzer; Beckman Coulter) as previously described.26
Statistical analysis
In addition to actual analyte concentrations, areas under the curve (AUC) were calculated with the trapezoidal method, and maximum concentrations (Cmax) were determined for each OGT. Tests of normal distribution (Shapiro-Wilk) were performed to determine the extent of skewness. Data with normal distributions were reported as the mean and 95% CI, whereas significantly skewed data were reported as the median and IQR. For the outcome variables (glucose, insulin, triglyceride, and incretin concentrations as well as AUC and Cmax), analysis was based on a linear mixed-effects model, with the fixed effects of the interaction between time after dextrose administration (0 to 240 minutes of the OGT) and dexamethasone administration (no treatment [day 1 OGT], 7 days of dexamethasone [day 8 OGT], and 14 days of dexamethasone [day 15 OGT]). Random effects were set on the level of the horse. Post hoc analysis was used for calculating the marginal (model adjusted) means and to calculate the pairwise effects. All marginal means and effects are reported with their respective 95% CI. Statistical analyses were performed using Stata/MP (version 18; StataCorp), with 2-sided tests and P < .05 as the criterion for statistical significance. Figures were generated using Prism, version 10 (GraphPad).
Results
All horses tolerated the experiments well, and none developed clinical laminitis.
Glucose
Blood glucose concentrations are shown in Figure 1. After 7 days of dexamethasone, the baseline (day 8 OGT time = 0 minutes) blood glucose was increased by 56.9 (95% CI, 43.6 to 70.3) mg/dL compared to day 1 OGT (P < .0001). There were also significant increases in under the glucose curve (AUCglucose) and maximum concentration in glucose (Cmaxglucose, +28,833.4 [95% CI, 25,495.1 to 32,171.7] mg/dL·min; +139.1 [95% CI, 124.0 to 154.1] mg/dL; both P < .0001) during day 8 OGT compared to day 1 OGT. These effects were, however, blunted after 14 days of dexamethasone, with AUCglucose and Cmaxglucose significantly lower on day 15 OGT than on day 8 OGT (−22,556.6 [95% CI, −25,971.4 to −19,141.8] mg/dL·min; −90.4 [95% CI, −107.4 to −73.4] mg/dL; both P < .0001) but still significantly higher than on day 1 OGT (+6,276.8 [95% CI, 2,979.5 to 9,574.1] mg/dL·min; 48.7 [95% CI, 31.6 to 65.7] mg/dL; both P < .0001). Furthermore, the baseline blood glucose was not significantly different at day 15 OGT compared to day 1 OGT (P < .2).
Marginal means and 95% CI for blood glucose concentration over time in 8 Standardbred horses during an oral glucose test (OGT) after 0 (day 1 OGT; black circles), 7 (day 8 OGT; blue circles), and 14 (day 15 OGT; red circles) days of dexamethasone administration.
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.24.12.0373
Insulin
Serum insulin concentrations are displayed in Figure 2. Seven days of dexamethasone administration (day 8 OGT time = 0 minutes) increased baseline serum insulin by 68.4 (95% CI, 40.5 to 96.3) µIU/mL compared to day 1 OGT (P < .0001). Increases in area under the insulin curve (AUCinsulin) and maximum concentration in insulin (Cmaxinsulin, +53,172.8 [95% CI, 38,845.9 to 67,499.7] µIU/mL·min; +297.6 [95% CI, 214.6 to 380.8] µIU/mL; both P < .0001) were also detected at day 8 OGT; however, these effects were reduced after 14 days of dexamethasone administration, with baseline serum insulin, AUCinsulin, and Cmaxinsulin significantly lower on day 15 OGT than on day 8 OGT (−58.9 [95% CI, −77.7 to −30.0] µIU/mL; −37,599.1 [95% CI, −49,030.9 to −26,167.3] µIU/mL·min; −206.3 [95% CI, −272.3 to −140.4] µIU/mL; all P < .0001) but still significantly higher than on day 1 OGT (+15,573.7 [95% CI, 10,644.7 to 20,502.7] µIU/mL·min; 91.3 [95% CI, 58.0 to 124.7] µIU/mL; both P < .0001).
Marginal means and 95% CI for serum insulin concentration over time in 8 Standardbred horses during an OGT after 0 (day 1 OGT; black circles), 7 (day 8 OGT; blue circles), and 14 (day 15 OGT; red circles) days of dexamethasone administration.
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.24.12.0373
At day 1 OGT, 1 of 8 horses had an insulin concentration > 80 µIU/mL within 120 minutes and would have been considered hyperinsulinemic in clinical practice. During day 8 OGT, 8 of 8 horses had insulin concentrations > 80 µIU/mL, and after day 15 OGT, 5 of 8 horses had insulin concentrations > 80 µIU/mL.
Glucagon-like peptide-1
Plasma tGLP-1 concentrations are presented in Figure 3. Although significant increases in area under the tGLP-1 curve (AUCtGLP-1) and maximum concentration in tGLP-1 (CmaxtGLP-1, +399.5 [95% CI, 12.1 to 786.9] pmol/L·min; P = .04; +2.58 [95% CI, 0.23–4.93] pmol/L; P = .03) were detected after 7 days of dexamethasone (day 8 OGT), these effects were no longer detected after 14 days of dexamethasone, with AUCtGLP-1 and CmaxtGLP-1 not significantly different on day 15 OGT than on day 1 OGT (P = .6 and P = .9, respectively). No significant effect of dexamethasone administration was detected on baseline plasma tGLP-1 during any OGT (P = .05 for all comparisons).
Marginal means and 95% CI for plasma total glucagon-like peptide 1 (tGLP-1) concentration over time in 8 Standardbred horses during an OGT after 0 (day 1 OGT; black circles), 7 (day 8 OGT; blue circles), and 14 (day 15 OGT; red circles) days of dexamethasone administration.
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.24.12.0373
Plasma aGLP-1 concentrations are shown in Figure 4. Unlike its total fraction, no significant increase in area under the aGLP-1 curve (AUCaGLP-1) or maximum concentration in aGLP-1 (CmaxaGLP-1) was detected after 7 days of dexamethasone (day 8 OGT; P = .2 and P = .3, respectively). Significant decreases were, however, detected after 14 days of dexamethasone, with AUCaGLP-1 and CmaxaGLP-1 significantly lower on day 15 OGT than on day 1 OGT (−767.9 [95% CI, −1,263.4 to −272.5] pmol/L·min; P = .002; −3.52 [95% CI, −5.92 to −1.12] pmol/L; P = .004). No significant effect of dexamethasone administration was detected on baseline plasma aGLP-1 during any OGT (P = .05 for all comparisons).
Marginal means and 95% CI for plasma active glucagon-like peptide 1 (aGLP-1) concentration over time in 8 Standardbred horses during an OGT after 0 (day 1 OGT; black circles), 7 (day 8 OGT; blue circles), and 14 (day 15 OGT; red circles) days of dexamethasone administration.
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.24.12.0373
Glucose-dependent insulinotropic polypeptide
Plasma GIP concentrations are plotted in Figure 5. After 7 days of dexamethasone, significant increases in area under the GIP curve (AUCGIP) and maximum concentration in GIP (CmaxGIP, +13,479.4 [95% CI, 8,108.9 to 18,849.9] pg/mL·min; +65.56 [95% CI, 40.98 to 90.16] pg/mL; both P < .0001) were detected after day 8 OGT. These effects were, however, blunted after 14 days of dexamethasone, with AUCGIP and CmaxGIP not significantly different on day 15 OGT than on day 1 OGT (both P = .1). No significant effect of dexamethasone administration was detected on baseline plasma GIP during any OGT (P > .05 for all comparisons).
Marginal means and 95% CI for plasma glucose-dependent insulinotropic polypeptide (GIP) concentration over time in 8 Standardbred horses during an OGT after 0 (day 1 OGT; black circles), 7 (day 8 OGT; blue circles), and 14 (day 15 OGT; red circles) days of dexamethasone administration.
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.24.12.0373
Triglycerides
Triglyceride concentrations are presented in Figure 6. After 7 days of dexamethasone, the baseline (day 8 OGT time = 0 minutes) triglyceride concentration was increased by 21.6 (95% CI, 12.1 to 31.2) mg/dL compared to day 1 OGT (P < .0001). There was also a significant increase in area under the triglyceride curve (AUCTrig) and maximum concentraion in triglycerides (CmaxTrig, +4,854.3 [95% CI, 2,181.3 to 7,527.3] mg/dL·min; +23.38 [95% CI, 12.84 to 33.91] mg/dL; both P < .0001) detected after day 8 OGT. These effects were, however, blunted after 14 days of dexamethasone, with baseline triglycerides, AUCTrig, and CmaxTrig not significantly different on day 15 OGT than on day 1 OGT (P = .4, P = .9, and P = .1, respectively).
Marginal means and 95% CI for plasma triglyceride concentration over time in 8 Standardbred horses during an OGT after 0 (day 1 OGT; black circles), 7 (day 8 OGT; blue circles), and 14 (day 15 OGT; red circles) days of dexamethasone administration.
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.24.12.0373
Discussion
This study shows the effects of dexamethasone administration on the equine enteroinsular axis, with a significant increase in incretin and insulin secretion as well as a significant increase in triglyceride mobilization after 7 days of treatment, all subsequently blunted after 14 days of treatment.
Dexamethasone primarily impacts glucose metabolism by reducing tissue insulin sensitivity. In people, dexamethasone impairs insulin-mediated glucose disposal by decreasing intracellular glucose oxidation independently of glucose transporter 4 activity.27 This decreased glucose oxidation is associated with a shift in fatty acid delivery to insulin-sensitive tissues and increased activity of lipoprotein lipase, suggesting that dexamethasone promotes lipids as a source of energy over glucose.28 This is consistent with our findings at day 8 OGT with an initial increase in triglyceride mobilization, suggesting that this metabolic shift also occurs in horses treated with dexamethasone.
The dexamethasone-induced decrease in glucose uptake results in hyperglycemia and a proportionate increase in insulin secretion. The resulting hyperinsulinemia increases glucose uptake and inhibits the release of free fatty acids and triglycerides from adipose tissue by inhibition of the hormone-sensitive lipase, leading to a hyperinsulinemic compensation of hyperglycemia over time, also consistent with our findings on day 15 OGT.29
In previous studies,12 IV dexamethasone administration to horses has resulted in tissue IR as demonstrated by a 70% decrease in glucose infusion rate during a euglycemic hyperinsulinemic clamp. Interestingly, no change in glucose transporter 4 or glycogen concentration was detected in that study, confirming that the mechanisms described in humans on peripheral tissues could apply to horses.
At the level of the pancreas, the mechanisms of action of dexamethasone are less well understood, with evidence of some opposing effects. In cultured pancreatic islets, dexamethasone treatment impairs the release of insulin vesicles independently of changes in beta cell glucose metabolism, whereas in other studies,30–35 dexamethasone administration resulted in a time-dependent beta cell apoptosis preceded by a concentration-dependent beta cell hyperplasia and hypertrophy. Taken together these findings would suggest that dexamethasone treatment induces an initial hyperinsulinemic response characterized by beta cell hyperactivity followed by a proapoptotic phase leading to hypoinsulinemia. Through this mechanism, chronic administration of dexamethasone has been recognized as a cause of type 2 and type 1 diabetes in people.34,36
In our horses, a similar mechanism might explain the initial increase in insulin secretion detected during day 8 OGT, with all horses becoming severely hyperinsulinemic, but a relative decrease in insulin secretion detected during day 15 OGT, with only 5 horses still considered hyperinsulinemic. The timeline for the changes described in people is unclear, with the hyperinsulinemic phase occurring within hours of dexamethasone administration and the hypoinsulinemic phase only occurring with chronic treatment. The degree of beta cell apoptosis was not assessed in our horses since functional assessment of pancreatic mass is challenging with no imaging or biopsy protocol available. Nevertheless, our data might indicate that beyond its effect on peripheral tissues, dexamethasone could directly impact the equine beta cells with an initial increase in insulin secretion, combining compensation of tissue IR and beta cell hyperplasia, followed by a decrease in insulin secretion, possibly associated with decreased pancreatic mass or a compensated hyperglycemia. This timing is consistent with what is observed in clinical practice, where administration of dexamethasone is associated with the development of HAL in at-risk cases shortly after treatment initiation, whereas other cases can tolerate long-term treatment with dexamethasone without laminitis.10,37
The contribution of incretins to stimulation of the equine pancreatic beta cells remains unclear, with some studies22,38 showing limited impact and others39,40 indicating a potential key role in the development of equine hyperinsulinemia. Incretins are secreted from the proximal duodenum after ingestion of carbohydrates, and higher incretin concentrations lead to higher insulin concentrations.32 This is in agreement with our data, with incretin concentrations mirroring insulin concentrations, suggesting a possible role of incretins in dexamethasone-associated hyperinsulinemia. Dexamethasone increases the absorption of glucose in the proximal duodenum, which would stimulate the secretion of incretins.41 Since incretins have an effect on beta cell growth, they could therefore have a role in the initial proliferative phase of dexamethasone-associated pancreatic hyperplasia.32 In this way, the increases in tGLP-1 and GIP observed in our study on day 8 OGT could mediate this effect. On the other hand, chronic glucocorticoid administration has been shown to reduce intestinal proliferation and nutrient absorption, including glucose.42 Although speculative, this decrease in intestinal glucose absorption would reduce the stimulus for incretin secretion. This is consistent with our findings as we observed decreased glucose and incretin concentrations during day 15 OGT, indicating that the effect on insulin concentration observed during that OGT could be mediated by a combination of decreased glucose absorption and a decreased stimulation of the pancreatic beta cells by incretins. That being said, the magnitude of the changes in incretin concentrations after dexamethasone treatments was relatively small; therefore, this mechanism might only have a minimal contribution to the observed effect.
Altogether, our results indicate that dexamethasone has a biphasic effect on insulin and glucose dynamics. We propose that dexamethasone initially induces hyperinsulinemia by direct stimulation of the pancreatic beta cells, by indirect stimulation through incretin secretion potentiated by an increase in intestinal glucose absorption, and by compensation of tissue IR. In the later stages, dexamethasone mitigates insulin secretion by possible apoptosis of pancreatic beta cells and decreased intestinal glucose absorption. Although the dose of dexamethasone used in this study is higher than what would typically be used in practice, these findings might be of particular importance for horses at risk of ID (eg. specific breeds, those affected by obesity or pituitary pars intermedia dysfunction, or those being fed a high-carbohydrate diet) treated with glucocorticoids at lower dose rates. These horses could develop hyperinsulinemia by multiple mechanisms and therefore increase their risk of developing HAL. On the other hand, these findings might also have some impact on the relevance of dexamethasone administration as a model of ID to test specific treatments.15,43 The dexamethasone model might not be as stable for ID induction as initially considered, and the beneficial effect of tested compounds observed in some studies might be attributed to a dexamethasone-induced decrease in insulin secretion rather than to an actual effect of treatment. That being said, other studies15 that have used a daily administration of dexamethasone demonstrated a sustainedly high AUCinsulin, whereas we administered dexamethasone every 48 hours and demonstrated variable results. A different regimen was elected in this study to reduce the risk of inducing laminitis while still disturbing insulin regulation, but it could suggest that more frequent administration of dexamethasone could produce different effects.12
There are several limitations to this study, including the relatively low number of horses and the inclusion of Standardbreds, which are less likely to represent an at-risk population for HAL. In addition, our inability to completely assess de novo insulin secretion by measuring C-peptide limited our description of the mechanism. Measuring C-peptide would have allowed us to better characterize the role of dexamethasone on beta cell activity and to describe its role on insulin clearance.44 This approach was attempted; however, despite the use of multiple assays (ELISA #ab178641; Abcam; human double-antibody radioimmunoassay; Diabetes Research Core at the University of Pennsylvania, Institute for Diabetes, Obesity, and Metabolism), no trustable and publishable results were obtained.44–46 Another way to more completely investigate insulin dynamics would have been to conduct a modified frequently sampled IV glucose tolerance test.15 This test would have allowed the calculation of the insulin sensitivity index, acute insulin response to glucose, disposition index, and glucose effectiveness and completed our assessment of the effect of dexamethasone on insulin sensitivity and secretion.
In conclusion, dexamethasone disrupts the insulin and glucose dynamics affecting both tissue insulin sensitivity and insulin secretion. This confirms the potential for increased laminitis risk with dexamethasone treatment, especially in horses with preexisting ID or those at risk of developing ID. The results also question the relevance of dexamethasone treatment as a reliable model of ID for clinical research where effects of therapy are measured over periods > 7 days.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org.
Acknowledgments
None reported.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the composition of this manuscript.
Funding
This work was funded by a grant from the Grayson Jockey Club Research Foundation.
ORCID
F. R. Bertin https://orcid.org/0000-0002-2820-8431
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