Evaluation of the tolerance and effects of 1-deoxynojirimycin on insulin and glucose dynamics in healthy horses and horses at risk for insulin dysregulation.

Overview

• This study evaluated the safety and effectiveness of 1-deoxynojirimycin (DNJ), a compound derived from mulberry leaf extract (Reducose®), in reducing insulin responses in healthy horses and horses at risk for insulin dysregulation (ID).
• The research demonstrated that DNJ was well-tolerated and dose-dependently lowered insulin peaks and overall insulin secretion following oral sugar challenges, suggesting its therapeutic potential for managing ID in horses.

Background and Importance

• Insulin dysregulation (ID) is a common metabolic disorder in horses that negatively affects their welfare.
• Current management approaches include diet control and exercise but these can have inconsistent results and few medical treatments are available.
• Alpha-glucosidase inhibitors (AGIs), such as DNJ, inhibit enzymes involved in carbohydrate digestion, potentially blunting glucose absorption and insulin spikes following sugar intake.
• Reducing insulin responses is important since high insulin levels can exacerbate ID and contribute to laminitis, a painful hoof condition.

Study Objective

• To examine the tolerability of escalating doses of DNJ in healthy horses and horses at risk of ID.
• To assess the effects of DNJ on insulin and glucose dynamics during oral sugar tests (OSTs), which simulate sugar intake and measure insulin responses.
• Hypothesis: DNJ would be safe and reduce insulin peaks and total insulin exposure (area under the curve, AUC) after OSTs in a dose- and time-dependent manner.

Study Design and Methods

• Prospective, three-phase clinical trial with 27 horses divided into groups:
  • Phase I: 6 healthy horses to assess tolerance to increasing DNJ doses (0 to 5000 mg twice daily; 7 days per dose).
  • Phase II: 5 horses at risk of ID to evaluate dose-dependent effects of DNJ on OST insulin response (same dosing regimen).
  • Phase III: 16 horses at risk of ID to evaluate duration of DNJ effects when given 2500 or 5000 mg twice daily for 28 days, with OSTs at different times post-administration (0 and 3 hours).
• Primary outcomes measured were peak insulin concentration and insulin area under the curve (AUC) during OSTs.
• DNJ used was Reducose®, a standardized extract from Morus alba leaves containing 5% 1-deoxynojirimycin.

Key Results

• Tolerability:
  • DNJ caused no adverse effects at doses up to 5000 mg twice daily over the study periods.
• Insulin Response:
  • DNJ reduced peak insulin and insulin AUC in a dose-dependent manner.
  • At the highest dose (5000 mg twice daily), peak insulin decreased from 33.4 ± 15.1 μIU/mL to 18.8 ± 9.2 μIU/mL representing a significant reduction.
  • Insulin AUC was reduced by -18.6 μIU·h/mL (95% confidence interval: -31.7 to -5.5), indicating less overall insulin secretion.
• Duration of Effect:
  • In Phase III, 5000 mg DNJ significantly reduced peak insulin when the OST was performed up to 1 hour post-treatment (peak insulin reductions of -13.1 and -7.4 μIU/mL at 0 and 1 hour respectively).
  • These effects diminished by 3 hours post-DNJ administration.

Conclusions and Implications

• DNJ via Reducose® was well-tolerated in both healthy and at-risk horses over up to 28 days of administration.
• DNJ effectively decreased insulin responses to sugar intake, reducing both the peak levels and total insulin release in a dose- and time-dependent fashion.
• These results support the potential use of DNJ as an adjunctive medical therapy to complement diet and exercise in managing insulin dysregulation in horses.
• Further studies may be warranted to evaluate long-term clinical benefits, optimal dosing regimens, and impacts on metabolic health and laminitis risk.