Projects per year
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.
Original language | English |
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Pages (from-to) | 2036-2046 |
Number of pages | 11 |
Journal | Journal of Clinical Endocrinology and Metabolism |
Volume | 106 |
Issue number | 7 |
Early online date | 8 Mar 2021 |
DOIs | |
Publication status | Published - Jul 2021 |
Keywords
- Sulphonylureas
- Gliclazide
- Incretins
- Incretin Effect
- Beta Cell Physiology
- Type 2 Diabetes
- KATP Channel
- GLP-1
- Beta Cell Modelling
- incretins
- beta-cell modeling
- sulphonylureas
- GIP
- gliclazide
- type 2 diabetes
- beta-cell physiology
- incretin effect
- KATP channel
ASJC Scopus subject areas
- Biochemistry, medical
- Endocrinology
- Biochemistry
- Clinical Biochemistry
- Endocrinology, Diabetes and Metabolism
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- 1 Finished
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Stratified Medicine in Type 2 Diabetes: Insights from the Study of Drug Response (New Investigator Award)
Pearson, E. (Investigator)
16/02/15 → 15/08/21
Project: Research
Student theses
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Modernising the Use of Sulphonylureas in Type 2 Diabetes Mellitus
Cordiner, R. L. M. (Author), Pearson, E. (Supervisor) & McCrimmon, R. (Supervisor), 2022Student thesis: Doctoral Thesis › Doctor of Philosophy