Effect of canagliflozin on insulin sensitivity in insulin-dysregulated horses as assessed by euglycemic hyperinsulinemic clamp: a randomized, placebo-controlled trial
Elin Svonni, Peter Michanek, Peter Bergsten, Sanna Lindåse, Johan BröjerAbstract
Background
Insulin resistance, enhanced β-cell responsiveness, and lower insulin clearance contribute to hyperinsulinemia in horses with insulin dysregulation. Canagliflozin (CAN) reduces hyperinsulinemia in horses, but its effect on insulin sensitivity (IS) remains unclear.
Hypothesis/Objectives
Evaluate the effects of CAN on IS and insulin clearance using a euglycemic hyperinsulinemic clamp (EHC) and on β-cell responsiveness using a graded glucose infusion test (GGI) in insulin-dysregulated (ID) horses.
Animals
Twenty privately owned ID mares.
Methods
In this randomized, double-blind, placebo-controlled study, horses received CAN (0.4 mg/kg, n = 10) or placebo (PBO, n = 10) PO once daily for 4 weeks. Insulin sensitivity and insulin metabolic clearance rate (MCR) were assessed by EHC, and β-cell responsiveness by GGI.
Results
Insulin sensitivity (M/I) was lower with CAN than PBO (1.5 ± 0.2 vs 2.7 ± 0.2 [mg/kg/min × 103]/[μIU/mL]; LS mean difference,—1.3 [95% CI, -1.9 to -0.6]; P < .001), whereas insulin MCR was higher (6.5 ± 0.3 vs 5.4 ± 0.3 mL/kg/min; LS mean difference, 1.0 [95% CI, 0.3-1.8]; P = .01). Beta-cell responsiveness (ΔI vs ΔG) was 43.3% lower with CAN (20.8 [95% CI, 16.9-25.5] vs 36.7 [29.9-45.1] mIU/mmol; ratio of geometric LS means, 0.57 [95% CI, 0.42-0.76]; P < .001).
Conclusions and clinical importance
Beta-cell responsiveness was lower and insulin clearance higher in CAN-treated ID mares, despite apparently lower IS. Higher endogenous glucose production in CAN-treated mares might have contributed to an underestimation of IS.