Over the past years tremendous amounts of clinical and fundamental data have been generated about GLP-1 and related therapeutic strategies for the treatment of type 2 diabetes. However, the cellular and physiological mechanisms through which GLP-1 is secreted, controls glycemia, and behaves as a therapeutic agent are certainly unclear. This is due to the dogma that proposes that upon glucose absorption GLP-1 is secreted into the hepatoportal blood flow, binds to its receptor at the surface of the insulin secreting beta cells, and triggers the secretion of insulin to control glycemia. However, these events have never been demonstrated sequentially for the control of glycemia. This conclusion is supported by a growing number of evidences that point out that the enteric and the central nervous systems are main actors in the control of GLP-1 action. This involves the triggering of the gut-to-brain and to periphery axis where nutrients regulate the release of GLP-1 and activate the tightly regulated enteric and cerebral neuronal circuits. These integrate and redistribute the GLP-1-dependent signals toward numerous targeted tissues. We will review some of them.