The impact of low dose gliclazide on the incretin effect and indices of beta cell function.

Abstract

AIMS/HYPOTHESIS\nStudies in permanent neonatal diabetes suggest that sulphonylureas lower blood glucose without causing hypoglycaemia, in part by augmenting the incretin effect. This mechanism has not previously been attributed to sulphonylureas in patients with type 2 diabetes (T2DM). We therefore aimed to evaluate the impact of low dose gliclazide on beta-cell function and incretin action in patients with T2DM.\n\n\nMETHODS\nPaired oral glucose tolerance tests and isoglycaemic infusions were performed to evaluate the difference in the classical incretin effect in the presence and absence of low dose gliclazide in 16 subjects with T2DM (HbA1c <64mmol/mol, 8.0%) treated with diet or metformin monotherapy. Beta-cell function modelling was undertaken to describe the relationship between insulin secretion and glucose concentration.\n\n\nRESULTS\nA single dose of 20mg gliclazide reduced mean glucose during the OGTT from 12.01 ± 0.56 to 10.82 ± 0.5 mmol/l (p=0.0006) (mean ± SEM). The classical incretin effect was augmented by 20mg gliclazide, from 35.5% (LQ 27.3, UQ 61.2) to 54.99% (34.8, 72.8) (p=0.049). Gliclazide increased beta-cell glucose sensitivity by 46% (Control 22.61 ± 3.94, Gliclazide 33.11 ± 7.83 (p=0.01)) as well as late-phase incretin potentiation (Control 0.92 ± 0.05, Gliclazide 1.285 ± 0.14 (p=0.038).\n\n\nCONCLUSIONS/INTERPRETATION\nLow dose gliclazide reduces plasma glucose in response to oral glucose load, with concomitant augmentation of the classical incretin effect. Beta-cell modelling shows that low plasma concentrations of gliclazide potentiate late phase insulin secretion and increase glucose sensitivity by 50%. Further studies are merited to explore whether low dose gliclazide, by enhancing incretin action, could effectively lower blood glucose without risk of hypoglycaemia.