Fig. 1.: Proposed mechanisms underpinning the beneficial neurological action of glucagon-...

Proposed mechanisms underpinning the beneficial neurological action of glucagon-like peptide-1 (GLP-1) receptor (R) agonists. The GLP-1R, a class B1 G-protein-coupled receptor, is present on numerous cells within the nervous system—including throughout the brain on multiple types of neurons as well as on astrocytes and microglia. GLP-1, chiefly generated by L cells within the gastrointestinal tract, is also produced by select preproglucagon neurons that are primarily localized to the nucleus of the solitary tract within the hind brain 87 —providing projections to extensive brain areas. Notably, GLP-1 appears also be generated by M2 microglia 88 to potentially provide reparative/anti-inflammatory actions. Endogenous GLP-1 and/or long-acting GLP-1 agonists gaining access to the brain can provide neurotrophic/protective actions that are mediated via GLP-1R binding and activation (as such actions are lost in the presence of GLP-1R antagonists and in GLP-1R knockout studies 35 , 89 , 90 ).

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