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

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posted on 16.10.2020 by Ada Admin, Charles-Henri Malbert, Alain Chauvin, Michael Horowitz, Karen L Jones
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.

Funding

The study was conducted within the Aniscan Imaging Center (Aniscan, INRA), which is supported by BPIFrance within the Investments for the Future program. KLJ’s salary is supported by The University of Adelaide William T Southcott Research Fellowship.

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