Article ; Online: The Impact of Low-dose Gliclazide on the Incretin Effect and Indices of Beta-cell Function.
The Journal of clinical endocrinology and metabolism
2021 Volume 106, Issue 7, Page(s) 2036–2046
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 ... ...
| 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. |
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| MeSH term(s) | Aged ; Blood Glucose/drug effects ; C-Peptide/metabolism ; Diabetes Mellitus, Type 2/blood ; Diabetes Mellitus, Type 2/drug therapy ; Dose-Response Relationship, Drug ; Female ; Gliclazide/administration & dosage ; Glucose/metabolism ; Glucose Tolerance Test ; Glycated Hemoglobin A/metabolism ; Humans ; Hypoglycemic Agents/administration & dosage ; Incretins/metabolism ; Insulin/blood ; Insulin Secretion/drug effects ; Insulin-Secreting Cells/drug effects ; Male ; Middle Aged ; Proof of Concept Study |
| Chemical Substances | Blood Glucose ; C-Peptide ; Glycated Hemoglobin A ; Hypoglycemic Agents ; Incretins ; Insulin ; Gliclazide (G4PX8C4HKV) ; Glucose (IY9XDZ35W2) |
| Language | English |
| Publishing date | 2021-03-06 |
| Publishing country | United States |
| Document type | Evaluation Study ; Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 3029-6 |
| ISSN | 1945-7197 ; 0021-972X |
| ISSN (online) | 1945-7197 |
| ISSN | 0021-972X |
| DOI | 10.1210/clinem/dgab151 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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