The Impact of Low-dose Gliclazide on the Incretin Effect and Indices of Beta-cell Function

Abstract

Aims/hypothesis: Studies in permanent neonatal diabetes suggest that sulphonylureas lower blood glucose without causing hypoglycemia, 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.

Methods: Paired oral glucose tolerance tests and isoglycemic 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 (hemoglobin A1c < 64 mmol/mol, 8.0%) treated with diet or metformin monotherapy. Beta-cell function modeling was undertaken to describe the relationship between insulin secretion and glucose concentration.

Results: A single dose of 20 mg gliclazide reduced mean glucose during the oral glucose tolerance test from 12.01 ± 0.56 to 10.82 ± 0.5mmol/l [P = 0.0006; mean ± standard error of the mean (SEM)]. The classical incretin effect was augmented by 20 mg gliclazide, from 35.5% (lower quartile 27.3, upper quartile 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)].

Conclusions/interpretation: Low-dose gliclazide reduces plasma glucose in response to oral glucose load, with concomitant augmentation of the classical incretin effect. Beta-cell modeling 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 hypoglycemia.

Trial registration: ClinicalTrials.gov NCT03705195.

Keywords: GIP; GLP-1; KATP channel; beta-cell modeling; beta-cell physiology; gliclazide; incretin effect; incretins; sulphonylureas; type 2 diabetes.

© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.

Study design comprising paired OGTT and IIGI in the presence (blue) and absence (red) of low-dose gliclazide.

Figure 2.

Mean (SEM) plasma glucose (A) and gliclazide (B) and median (interquartile range) insulin (C) and C-peptide (D) concentrations during OGTT (solid lines) and IIGI (dashed lines) in control (red lines) and gliclazide intervention visits (blue lines) in phase 2 (n = 16). For interventions involving gliclazide (B), low-dose gliclazide suspension was administered 60 min prior to the start of the OGTT and IIGI.

Figure 3.

Linear regression analysis of mean insulin secretion against mean plasma glucose levels from phase 2 (n = 16) shows insulin secretion to be significantly augmented in response to oral glucose load (A) compared to intravenous glucose (B) following the addition of low-dose gliclazide (blue lines) vs control (red lines). (A) Slope increased from 33.6 to 80.97 (P < 0.0001), and (B) slope increased from 13.63 to 25.2 (P < 0.01).

Figure 4.

Incretin secretion profiles 0 to 240 min in response to (A) oral glucose and (B) intravenous glucose (mean ± SEM) in phase 2 (n = 16).

Figure 5.

Incretin potentiation profiles from 0 to 240 min for control (red) and gliclazide intervention (blue) in phase 2 (n = 16).