Aims: People with type 2 diabetes mellitus (T2DM) are characterized by reduced incretin effect and inappropriate glucagon levels. We evaluated a and ß-cell responses to oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion (IIGI) in lean and obese persons with T2DM or normal glucose tolerance (NGT) to elucidate the impact of obesity on the incretin effect and incretin hormone and glucagon responses. Methods: Four hour 50-g OGTT and IIGI were performed in (i) Eight obese patients with T2DM [mean body mass index (BMI): 37 (range: 35-41) kg/m(2) ]; (ii) Eight obese subjects with NGT [BMI: 33 (35-38) kg/m(2) ]; (iii) Eight lean patients with T2DM [BMI: 24 (22-25) kg/m(2) ]; and (iv) Eight lean healthy subjects [BMI: 23 (20-25) kg/m(2) ]. Results: The incretin effect was significantly (p <0.05) reduced in patients with T2DM {obese: 7 ± 7% [mean ± standard error of the mean (SEM)]; lean: 29 ± 8%; p = 0.06)} and was lower in obese subjects (41 ± 4%) than in lean subjects with NGT (53 ± 4%; p <0.05). Obese subjects with NGT were also characterized by elevated fasting plasma glucagon levels, but the inappropriate glucagon responses to OGTT found in the T2DM patients were not evident in these subjects. Conclusions: Our findings suggest that reduced incretin effect and fasting hyperglucagonaemia constitute very early steps in the pathophysiology of T2DM detectable even in obese people who despite their insulin-resistant state have NGT.