FIGURE 6. Hypothesis regarding the possible contribution of the proximal intestine to the alterations of glucose metabolism in type 2 diabetes. The passage of nutrients through the intestinal foregut may trigger, in addition to the known incretin response, a concomitant counter-regulatory signal (“anti-incretin factor”) aimed to prevent hypoglycemia. This signal may interfere with pathways of the incretin system and/or act downstream to inhibit insulin action. In predisposed individuals, chronic stimulation with particular nutrients may create an imbalance between incretin and “anti-incretin” signals, resulting in insulin resistance and type 2 diabetes.