In healthy subjects, the incretin effect ensures that plasma glucose concentrations after oral carbohydrates remain low regardless of the amount of glucose taken in. It is due to proportional increases in GLP-1 and GIP secretion and corresponding insulin responses. We studied this phenomenon in obese subjects with T2DM and matched controls and found that incretin release was unimpaired and proportional to the glucose load, but in T2DM the effect on insulin was dramatically reduced regardless of load. We also identified gastric emptying rates of glucose to contribute to both the release of incretin hormones and to regulation of postprandial glycaemia. The incretin effect was also reduced in diabetes secondary to chronic pancreatitis suggesting that the loss is secondary to diabetes. In further studies, we were able to identify that obesity and glucose intolerance are associated with the loss, and a similar loss could be brought about in perfectly healthy subjects during glucocorticoid induced insulin resistance and glucose intolerance. In patients with T2DM, postprandial GLP-1 secretion is generally impaired, and several factors including BMI, insulin resistance and poor metabolic control are associated with this. The insulinotropic actions of physiological amounts of GLP-1 and GIP are lost, but pharmacological amounts of GLP-1 can still normalize glucose induced insulin secretion and glucagon suppression. As a result, pharmacological doses of GLP-1 may greatly improve diabetic metabolism. It can be demonstrated that insulinotropic and glucagonostatic effects of GLP-1 contribute equally to its glucose lowering action. The suppression of glucagon may be one of the most important actions of GLP-1 as indicated from studies of the effects of the antagonist exendin 9-39. Recent studies of GLP-1 secretion in patients with RYGB suggest that hypersecretion of GLP-1 plays a prominent role in the antidiabetic actions of this operation. Convincing clinical results with GLP-1 agonists support this view.