Mechanisms of metabolic surgery effectiveness in obesity and type 2 diabetes: a puzzle with some known pieces.

Metabolic surgery is currently the most effective available treatment for obesity and diabetes. However, it cannot be practiced widely, as some potential candidate patients do not have access to this procedure, primarily because it is expensive, necessitates experience on the part of operators, and requires adequate hospital facilities. Furthermore, side effects, although rare, remain a problem. Consequently, an ideal approach would be to reproduce the mechanisms of action of metabolic surgery through a noninvasive pharmacological treatment. To accomplish this, it is necessary to determine the exact mechanisms involved. Despite numerous studies in this field, a definitive conclusion has not yet been reached. Some of the known effects of metabolic surgery on organisms are described herein. Upon in-depth examination, all can be traced back to a functional modification of the autonomic GI-brain axis, mediated by afferent vagal fibers, establishing a constant relationship with brain centers to control food intake. These mechanisms act through the postsynaptic receptors of certain neurotransmitters. A viable path for implementing a pharmacological therapy for obesity may therefore be to identify drugs that act on these receptors to achieve adequate therapeutic responses. Possible candidates include substances that modulate various subtypes of NMDA glutamate receptors or gamma-aminobutyric acid (GABA) receptors. In conclusion, autonomic modifications which have so far been shown to be activated by metabolic surgery represent the pieces of a puzzle which, when put together, allow us to identify the functional modification of the GI-brain vagal axis as the primary cause of this treatment's positive effects. These findings suggest the plausibility of an alternative pharmacological mechanism.