Dexamethasone administration transiently increases insulin response to an oral carbohydrate challenge in horses.

Overview

• This study investigated how the administration of dexamethasone affects insulin secretion and related metabolic responses during an oral carbohydrate challenge in healthy horses.
• The researchers found that dexamethasone transiently increased insulin secretion and altered related metabolic parameters, but these effects diminished after prolonged treatment.

Background and Purpose

• Dexamethasone is a corticosteroid commonly used in research to experimentally induce insulin resistance, a condition where the body’s cells respond poorly to insulin.
• While dexamethasone’s role in inducing insulin resistance is well known, its impact on insulin secretion—the pancreas’s ability to produce insulin—had not been clearly established prior to this study.
• This study aimed to clarify how dexamethasone affects insulin secretion and related metabolic hormones in horses subjected to an oral carbohydrate challenge.

Study Design and Methodology

• The study used eight healthy Standardbred horses, all untreated and in good health.
• Dexamethasone was administered intramuscularly at a dose of 0.08 mg/kg every 48 hours for 14 days, during the Southern Hemisphere winter (June 2022).
• Oral glucose tests (OGT) were performed on three key days: before dexamethasone treatment (Day 1), midway through treatment (Day 8), and after completing treatment (Day 15).
• Measurements taken included: blood glucose, insulin, triglycerides (a type of fat in the blood), and gut-derived hormones involved in insulin secretion—total and active glucagon-like peptide-1 (tGLP-1 and aGLP-1) and glucose-dependent insulinotropic polypeptide (GIP).
• Samples were taken at baseline and at multiple time points up to 240 minutes after the oral glucose challenge.
• Data analysis was conducted using a mixed-effects linear regression model, which can evaluate changes over time within subjects.

Key Findings

• By Day 8 of dexamethasone treatment:
  • There were significant increases in the areas under the curve (AUC) for glucose (+139.1 mg/dL·min), insulin (+297.6 µIU/mL·min), triglycerides (+4854.3 mg/dL·min), tGLP-1 (+2.58 pmol/L·min), and GIP (+65.56 pg/mL·min), showing enhanced responses to the oral glucose challenge.
  • The increased insulin response indicates that dexamethasone temporarily boosts insulin secretion despite its association with insulin resistance.
  • The rise in triglycerides suggests increased lipid mobilization during dexamethasone treatment.
  • The elevated gut hormone levels (tGLP-1 and GIP) indicate stimulation of the enteroinsular axis, which helps regulate insulin secretion.
• By Day 15, after extended dexamethasone administration:
  • The insulin, glucose, and active GLP-1 AUCs were significantly reduced compared to Day 8, indicating a partial return towards baseline levels.
  • For tGLP-1, triglycerides, and GIP, the AUC values were not significantly different from Day 1 (pre-treatment), indicating that the earlier increases were no longer present.
  • No horses developed clinical laminitis, an important safety observation since laminitis is a risk associated with insulin dysregulation in horses.

Interpretation and Implications

• Dexamethasone administration initially enhances insulin secretion in response to an oral glucose challenge, accompanied by increases in lipid mobilization and gut hormone activity.
• This transient increase in insulin secretion suggests that the pancreatic beta cells initially compensate for dexamethasone-induced insulin resistance by secreting more insulin.
• However, with prolonged dexamethasone administration, this compensatory increase in insulin secretion diminishes, potentially indicating beta cell desensitization or exhaustion.
• The stimulation of the enteroinsular axis, demonstrated by increased gut hormones, supports the mechanism by which dexamethasone influences insulin secretion during early treatment.
• These findings indicate that while dexamethasone consistently induces insulin resistance over time, its effect on insulin secretion is transient and may wane with longer treatment durations.
• Clinically, this study helps to clarify how corticosteroids like dexamethasone modulate metabolic function in horses, informing veterinary approaches to managing insulin resistance and related conditions.