The effect of pre-dosing with metformin on the insulin response to oral sugar in insulin-dysregulated horses

Background: A single dose of metformin administered 1 h prior to oral glucose challenge was previously shown to reduce insulinaemic responses in horses with experimentally-induced insulin dysregulation (ID). Targeted administration could be useful for controlling post-prandial hyperinsulinaemia in horses with naturallyoccurring ID. Objectives: The objective was to compare the insulinaemic and glycaemic responses to oral sugar testing (OST) performed at different intervals after a single dose of metformin in horses with naturally-occurring ID. We hypothesised that pre-treatment with one dose of metformin would significantly decrease the insulinaemic response to OST. Study design: Randomised cross-over in vivo experiment. Methods: Eight university-owned adult horses with naturally-occurring ID underwent OST 1, 2 and 6 h following a single oral dose of metformin (30 mg/kg) or 1 h after placebo (240 mL water) with a 7-day washout between treatments over a period of 3 weeks. Plasma insulin, C-peptide and glucose concentrations were measured at 0, 60 and 90 min after 0.45 mL/kg light corn syrup and the effect of treatment (and the interval since dosing) examined using a mixed effects linear regression model. Results: Metformin treatment had no significant effect on plasma glucose, insulin or C-peptide concentrations at any time point compared with placebo (p > 0.05). For OST 1 h post metformin, median (IQR) plasma insulin was 91.3 (62.4-114.9) mu IU/mL at 60 min versus 76.2 (59.1-134.5) for placebo (p = 0.8) and 62.7 (31.4-109.7) at 90 min versus 51.8 (29.2-126.3) for placebo (p = 0.9). Main limitations: Small sample size may limit identification of more subtle decreases in insulin concentration with metformin pre-dosing. The results of this study are relevant only for one pre-treatment dose (30 mg/kg) which limits extrapolation to predictions about the effects of longer-term metformin administration on insulin and glucose dynamics in the horse. Conclusions and clinical importance: The results do not support the use of targeted metformin treatment to reduce post-prandial hyperinsulinaemia in horses with naturally-occurring ID.