Volume 27, Issue 4, Pages (April 2018)

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Volume 27, Issue 4, Pages 740-756 (April 2018) Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1 Daniel J. Drucker Cell Metabolism Volume 27, Issue 4, Pages 740-756 (April 2018) DOI: 10.1016/j.cmet.2018.03.001 Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 1 Structure of Mammalian Proglucagon and the Proglucagon-Derived Peptides, and Principal Cell Types that Express the Canonical GLP-1 Receptor GRPP, glicentin-related pancreatic polypeptide; IP-1 and IP-2, intervening peptides 1 and 2; GLP-1R, GLP-1 receptor; IEL, intraepithelial lymphocyte; VSM, vascular smooth muscle cell; SAN, sinoatrial node cell; EC, endothelial cell; EEC, enteroendocrine cell; MPGF, major proglucagon fragment. Cell Metabolism 2018 27, 740-756DOI: (10.1016/j.cmet.2018.03.001) Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 2 Pancreatic Endocrine and Exocrine Actions of GLP-1 on Islet and Acinar Cells GLP-1 acts through the GLP-1 receptor (GLP-1R) expressed on islet β cells and δ cells to control insulin and somatostatin (SMS) secretion, respectively. SMS in turn inhibits glucagon secretion from islet α cells via the somatostatin-2 receptor (SSTR2). Cell Metabolism 2018 27, 740-756DOI: (10.1016/j.cmet.2018.03.001) Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 3 Actions of GLP-1 in the Context of Bariatric Surgery GLP-1 levels rise following Roux-en-Y gastric bypass (RYGB) or after vertical sleeve gastrectomy (VSG). Cell Metabolism 2018 27, 740-756DOI: (10.1016/j.cmet.2018.03.001) Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 4 The Role of Microbial Products and Metabolites in the Control of GLP-1 Secretion TLR, Toll-like receptor; IEL, intraepithelial lymphocyte; EEC, enteroendocrine cell. Cell Metabolism 2018 27, 740-756DOI: (10.1016/j.cmet.2018.03.001) Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 5 Representative Structures of Semaglutide, an Investigational Human GLP-1R Agonist, and an Investigational Tri-agonist Containing Amino Acids and Peptide Epitopes Enabling Activation of the Glucagon, GLP-1, and GIP Receptors Lower panel depicts potential for GLP-1 receptor engagement with a small-molecule allosteric modulator, a biased peptide agonist, or a small molecule orally available GLP-1R agonist. Cell Metabolism 2018 27, 740-756DOI: (10.1016/j.cmet.2018.03.001) Copyright © 2018 Elsevier Inc. Terms and Conditions