Effect of canagliflozin on insulin sensitivity in insulin-dysregulated horses as assessed by euglycemic hyperinsulinemic clamp: a randomized, placebo-controlled trial.

Overview

• This study investigated how the drug canagliflozin affects insulin sensitivity, insulin clearance, and pancreatic beta-cell responsiveness in horses with insulin dysregulation.
• Using controlled testing methods, the researchers found that while canagliflozin increased insulin clearance and decreased beta-cell responsiveness, it appeared to reduce insulin sensitivity, though this may be influenced by other metabolic effects.

Background

• Horses with insulin dysregulation exhibit abnormal insulin metabolism characterized by:
• Insulin resistance (reduced ability of tissues to respond to insulin)
• Increased beta-cell responsiveness (greater insulin release from the pancreas)
• Lower insulin clearance (slower removal of insulin from the bloodstream)
• These factors contribute to hyperinsulinemia, which is associated with conditions like equine metabolic syndrome and laminitis.
• Canagliflozin is a drug known to reduce hyperinsulinemia in horses, but its impact on insulin sensitivity and related metabolic parameters needed clarification.

Study Objectives

• To evaluate the effect of canagliflozin on three key aspects in insulin-dysregulated horses:
• Insulin sensitivity (IS)
• Insulin metabolic clearance rate (MCR)
• Beta-cell responsiveness to glucose
• These parameters were assessed using gold-standard techniques:
• Euglycemic hyperinsulinemic clamp (EHC) to measure IS and insulin clearance
• Graded glucose infusion test (GGI) to assess beta-cell responsiveness

Methods

• The study enrolled 20 privately owned mares diagnosed with insulin dysregulation.
• Design: Randomized, double-blind, placebo-controlled trial.
• Intervention: Horses received either canagliflozin (0.4 mg/kg) or placebo once daily, orally, for 4 weeks.
• Measurements:
• Insulin sensitivity (M/I) calculated during EHC—measuring glucose infusion rate relative to plasma insulin.
• Insulin metabolic clearance rate (MCR)—the rate at which insulin is cleared per kilogram of body weight.
• Beta-cell responsiveness calculated from the change in insulin relative to the change in glucose concentrations during GGI (ΔI vs ΔG).

Results

• Insulin Sensitivity (IS):
• Decreased in canagliflozin-treated horses compared to placebo (mean difference -1.3, statistically significant with P < .001).
• Measured as M/I values: 1.5 ± 0.2 vs. 2.7 ± 0.2 (mg/kg/min × 10³)/(μIU/mL).
• Insulin Metabolic Clearance Rate (MCR):
• Increased in canagliflozin group (6.5 ± 0.3 vs. 5.4 ± 0.3 mL/kg/min, P = .01).
• Beta-cell Responsiveness:
• Significantly lower in canagliflozin-treated horses by 43.3% compared to placebo (20.8 vs. 36.7 mIU/mmol, P < .001).
• This indicates reduced insulin secretion response to glucose stimulation.

Interpretation and Conclusions

• Canagliflozin treatment in insulin-dysregulated mares lowers pancreatic beta-cell responsiveness, which likely reduces the excessive insulin secretion characteristic of the condition.
• The treatment also increases insulin clearance, meaning insulin is removed from circulation more rapidly.
• Interestingly, insulin sensitivity appeared to be lower with treatment, which is contrary to expectations since reducing hyperinsulinemia typically improves insulin sensitivity.
• The authors suggest that increased endogenous glucose production in treated horses might have confounded the assessment of insulin sensitivity, potentially underestimating the true effect.
• Overall, canagliflozin modifies multiple facets of insulin metabolism in these horses, which may have therapeutic implications for managing insulin dysregulation and preventing complications like laminitis.

Implications for Veterinary Medicine

• Canagliflozin has potential as a pharmacologic option in managing equine insulin dysregulation, by reducing hyperinsulinemia via increased insulin clearance and diminished beta-cell activity.
• Further research may be needed to fully understand its effects on insulin sensitivity and glucose metabolism over longer treatment periods or in different equine populations.
• Using precise clinical tests like the euglycemic hyperinsulinemic clamp remains valuable to evaluate metabolic interventions in horses.