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Abstract
<p class="first" id="d3818447e55">Glucagon-like peptide-1 (GLP-1) released from gut
enteroendocrine cells controls meal-related
glycemic excursions through augmentation of insulin and inhibition of glucagon secretion.
GLP-1 also inhibits gastric emptying and food intake, actions maximizing nutrient
absorption while limiting weight gain. Here I review the circuits engaged by endogenous
versus pharmacological GLP-1 action, highlighting key GLP-1 receptor (GLP-1R)-positive
cell types and pathways transducing metabolic and non-glycemic GLP-1 signals. The
role(s) of GLP-1 in the benefits and side effects associated with bariatric surgery
are discussed and actions of GLP-1 controlling islet function, appetite, inflammation,
and cardiovascular pathophysiology are highlighted. Refinement of the risk-versus-benefit
profile of GLP-1-based therapies for the treatment of diabetes and obesity has stimulated
development of orally bioavailable agonists, allosteric modulators, and unimolecular
multi-agonists, all targeting the GLP-1R. This review highlights established and emerging
concepts, unanswered questions, and future challenges for development and optimization
of GLP-1R agonists in the treatment of metabolic disease.
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