To test the hypothesis that dapagliflozin, a sodium‐glucose cotransporter‐2 inhibitor, improves β‐cell responses to incretin hormones (or β‐cell incretin sensitivity) by alleviating glucose toxicity in people with type 2 diabetes mellitus (T2DM).

A total of 19 people with T2DM underwent a 3‐hour hyperglycaemic clamp study with incretin infusion before and after 8‐week treatment with dapagliflozin added to the background treatment. In addition, 10 people with normal glucose tolerance (NGT) underwent a single hyperglycaemic clamp study. The hyperglycaemic clamp was targeted at 15.5 mmol/L for 3 hours, with synthetic glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) infusion over a 60‐ to 180‐minute and a 120‐ to 180‐minute period, respectively.

Compared with baseline, the C‐peptide response to GLP‐1 (incremental area under the curve [iAUC] of C‐peptide_{60‐120 minutes}) significantly increased (83.6 ± 42.1 to 106.6 ± 45.7 nmol/L × min; P = .011), and the C‐peptide response to GIP/GLP‐1 (iAUC of C‐peptide_{120‐180 minutes}) tended to increase after dapagliflozin treatment (82.5 ± 58.4 to 101.9 ± 50.3 nmol/L × min; P = .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 participants with T2DM were far lower than those in the participants with NGT. In addition, the improvement in insulin responses to hyperglycaemia was correlated with the improvement in insulin responses to incretin infusion.

Dapagliflozin improved β‐cell responses to incretin hormones as well as glucose during the hyperglycaemic clamp in patients with inadequately controlled T2DM.