fig1

Figure 1. A simplified graphic demonstrating the differences between endogenous and exogenous GLP-1. (A) Taking sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (RYGB) as the archetypal examples of metabolic bariatric operations, both procedures lead to a net increase of endogenous GLP-1 with different mechanisms: LSG via rapid gastric emptying and RYGB due to the presence of undigested nutrients in the intestinal lumen in segments rich in L-cells, such as the ileum^[45,46]. This has also been demonstrated clinically^[47,48]. Consequently, GLP-1 that is secreted by intestinal L-cells is rapidly degraded by dipeptylpeptidase-4 (DPP-4) in the endothelium of the portal circulation and in the liver, as well as by a soluble circulating moiety of DPP-4. Simultaneously, GLP-1 interacts with afferent vagal fibers that transmit the signal to the brainstem and the hypothalamus. The net effect is that after MBS, endogenous GLP-1 primarily acts on the brain to inhibit appetite, while only 10% of the secreted GLP-1 reaches the pancreas; (B) Exogenously administered GLP-1, as the one contained in NAOMs, is readily available in systemic circulation, bypassing portal circulation and the deleterious effects of DPP-4. Additionally, these pharmaceutical molecules have undergone lipidation, which facilitates binding with albumin and prolongs their presence in the bloodstream. Consequently, they achieve robust glycemic control via direct action on the pancreas, where they increase insulin synthesis and secretion and enhance beta-cell function^[49]. In the meantime, exogenous GLP-1 maintains its ability to act on the brainstem and hypothalamus by direct action. Although these molecules do not cross the blood-brain barrier (BBB), they exert their action through the circumventricular organs and several select sites adjacent to the ventricles^[50]. Beyond the pancreas and the brain, GLP-1 has pleiotropic effects on several other tissues, the role of which has only recently started being elucidated. Among these effects, increased insulin sensitivity, either by direct action on target organs or secondary to weight loss, might act synergistically with enhanced beta-cell function and insulin upregulation in the pancreas, collectively improving metabolic control.