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AIMS: Within a few years after onset of type 1 diabetes (T1DM), the glucagon response to hypoglycaemia is severely diminished. Inhibitors of the enzyme dipeptidyl peptidase-4 (DPP-4), which under normal circumstances inactivate the incretin hormones (glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)), have been suggested to enhance glucagon secretion during hypoglycaemia in patients with type 2 diabetes. The aim of this study was to assess whether the DPP-4 inhibitor sitagliptin affects glucagon and other counterregulatory hormone responses to hypoglycaemia in patients with T1DM.METHODS: We conducted a single-centre, randomized, double-blind, placebo-controlled, three-period cross-over study. We studied 16 male patients with T1DM aged 18-52 years, with diabetes duration of 5-20 years and intact hypoglycaemia awareness. Participants received sitagliptin (100 mg/day) or placebo for 6 weeks and attended the hospital for three acute hypoglycaemia studies (at baseline, after sitagliptin treatment and after placebo). The primary outcome was differences between the three hypoglycaemia study days with respect to plasma glucagon responses from the initialization phase of the hypoglycaemia intervention to 40 minutes after onset of the autonomic reaction.RESULTS: Sitagliptin treatment significantly increased active levels of GIP and GLP-1. No significant differences were observed for glucagon or adrenergic counterregulatory responses during the three hypoglycaemia studies. Growth hormone concentration at 40 minutes after occurrence of autonomic reaction was significantly lower after sitagliptin treatment [23 (0.2-211.0)mEq/l] compared to placebo [90 (8.8-180)mEq/l](p=0.008).CONCLUSIONS: Sitagliptin does not affect glucagon or adrenergic counterregulatory responses in patients with T1DM, but attenuates the growth hormone response during late hypoglycaemia.