Glucose-sensing mediated by portal GLP-1 receptor is markedly impaired in insulin-resistant obese animals

The glucose portal sensor informs the brain of changes in glucose inflow via vagal afferents that require an activated GLP-1 receptor (GLP-1r). The GLP-1 system is known to be impaired in insulin-resistant conditions and we sought to understand the consequences of GLP-1 resistance on glucose portal signaling. GLP-1-dependent portal glucose signaling was identified, in vivo, using a novel ⁶⁸Ga labeled GLP-1r positron-emitting probe that supplied a quantitative in situ tridimensional representation of the portal sensor with specific reference to the receptor density expressed in binding potential units. It also served as a map for single-neuron electrophysiology driven by an image-based abdominal navigation. We determined that, in insulin-resistant animals, portal vagal afferents failed to inhibit their spiking activity during glucose infusion, a GLP-1r-dependent function. This reflected a reduction in portal GLP-1r binding potential, particularly between the splenic vein and the entrance of the liver. We propose that insulin-resistance, through a reduction in GLP-1r density, leads to functional portal desensitization with a consequent suppression of vagal sensitivity to portal glucose.