AIMS/HYPOTHESIS: Type 2 diabetes is associated with hypersecretion of glucagon during an OGTT, whereas i.v. glucose suppresses glucagon levels. This suggests that type 2 diabetic hyperglucagonaemia may result from glucose stimulation of the gastrointestinal tract. We evaluated glucagon responses to increasing amounts of glucose given orally and corresponding isoglycaemic i.v. glucose infusions (IIGIs) in patients with type 2 diabetes and in healthy controls. METHODS: Plasma glucagon responses were measured during three 4 h OGTTs with increasing loads of glucose (25 g, 75 g and 125 g) and three corresponding IIGIs in eight patients with type 2 diabetes (age [mean ± SEM] 57 ± 4 years; BMI 29.5 ± 1.0 kg/m(2); HbA1c 7.0 ± 0.3% [53 ± 2 mmol/mol]) and eight healthy individuals (age 57 ± 4 years; BMI 28.9 ± 0.7 kg/m(2); HbA1c 5.4 ± 0.1% [36 ± 1 mmol/mol]). RESULTS: In healthy controls no difference in glucagon suppression during the first 45 min of the 25 g OGTT and the corresponding IIGI (-153 ± 35 vs -133 ± 24 min × pmol/l; p = NS) was observed, whereas patients with type 2 diabetes only exhibited significant glucagon suppression following IIGI (29 ± 27 vs -144 ± 20 min × pmol/l; p = 0.005). At higher oral glucose loads this difference increased and also became evident in healthy controls. CONCLUSIONS/INTERPRETATION: In patients with type 2 diabetes increasing amounts of oral glucose elicit hypersecretion of glucagon, whereas corresponding IIGIs result in significant glucagon suppression; a phenomenon that is also observed in healthy individuals when larger glucose loads are ingested orally. This suggests that the hyperglucagonaemic response to oral glucose in type 2 diabetes may represent a pathological version of a gut-derived physiological phenomenon. Trial registration: ClinicalTrials.gov NCT00529048.