5 years ago

Sodium-Glucose Cotransporter-2 Inhibition Improves Incretin Sensitivity of Pancreatic β-cells in Patients with Type 2 Diabetes

Chang Ho Ahn, Soo Heon Kwak, Tae Jung Oh, Young Min Cho
Aims The β-cell response to glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), at their physiologic concentrations, is reduced in patients with type 2 diabetes mellitus (T2DM). We hypothesized that dapagliflozin improves β-cell responses to incretin hormones (or β-cell incretin sensitivity) by alleviating glucose toxicity. Materials and Methods Nineteen patients with T2DM underwent a 3-hour hyperglycemic clamp study with incretin infusion before and after 8-week treatment with dapagliflozin added to the background treatment. Ten subjects with normal glucose tolerance (NGT) underwent a single hyperglycemic clamp study. The hyperglycemic clamp was targeted at 15.5 mmol/L for 3 hours with synthetic GLP-1 and GIP infusion over a 60-180 minute and a 120-180 minute period, respectively. Results Compared to baseline, the C-peptide response to GLP-1 [incremental area under the curve (iAUC) of C-peptide60-120min] significantly increased (83.6 ± 42.1 to 106.6 ± 45.7 nmol/L×min, P = 0.011), and that to GIP/GLP-1 (iAUC of C-peptide120-180min) tended to increase after dapagliflozin treatment (82.5 ± 58.4 to 101.9 ± 50.3 nmol/L×min, P = 0.087), whereas both the insulin responses to GLP-1 and GIP/GLP-1 increased significantly. First-phase C-peptide response, which reflects β-cell function, significantly increased after dapagliflozin treatment. However, all these improved values in the T2DM subjects were far lower than those of the NGT subjects. In addition, the improvement of insulin responses to hyperglycemia was correlated with the improvement of insulin responses on incretin infusion. Conclusions Dapagliflozin improved β-cell responses to incretin hormones as well as glucose during the hyperglycemic clamp in patients with inadequately controlled T2DM.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/dom.13081

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