Figure legend
Figure 1. GLP-1 and GLP-1 based drugs. (A) The structure of proglucagon and proglucagon-derived polypeptides (PGDPs). GRPP, glicentin-related pancreatic polypeptide. IP-1 and IP-2, intervening peptides 1 and 2; MPGF, major proglucagon fragment. GLP-1 and GLP-2, glucagon-like peptide 1 and 2. (B) The primary amino acid sequences of human GLP-17-37. GLP-17-37and GLP-17-36amide (not shown) are functional active hormones. The ubiquitously expressed peptidase DPP-4 will cleave X-alanine dipeptides from the N-terminus of GLP-17-37 or GLP-17-36amide to form GLP-19-37 or GLP-19-36amide, respectively. (C) Chemical structures of the six GLP-1R agonists (GLP-1RAs). Due to amino acid substitution or non-covalent binding to albumin or immunoglobulin, these GLP-1RAs are protected from DPP-4 mediated degradation, thus having a much longer half-life.
Figure 2. Illustration of intra-pancreatic and extra-pancreatic functions of GLP-1RAs. In pancreatic islets, GLP-1 stimulates insulin secretion and represses glucagon secretion by pancreatic β- and α-cells, respectively, events that are mediated by GLP-1R. GLP-1RAs were shown to exert their regulatory functions in both macrophages and T lymphocytes in human subjects and in animal models. It remains controversial whether GLP-1R is expressed in majority of immune cells. GLP-1RAs were shown to inhibit the differentiation of M1 macrophage and the production of its markers, such as CCR7, IL-6 and TNF-α. Conversely, the differentiation of M2 macrophage and the production of its markers, such as CD163, Arg-1 and IL-10 could be stimulated by GLP-1RA treatment. Meanwhile, GLP-1RAs were shown to inhibit the differentiation of pro-inflammatory T helper cells, including Th1 and Th17, leading to less pro-inflammatory cytokines, such as IFN-γ, TNF-α, IL-17 and IL-22. The differentiation of the anti-inflammatory Th2 and Treg, as well as the production of IL-4, IL-5, TGFβ and IL-10, however, could be promoted by GLP-1RA treatment.
Figure 3. The effect of GLP-1-based drugs on lung injury.GLP-1R is highly expressed in lung epithelia. Intratracheal LPS delivery induces overexpression of thioredoxin-interacting protein (TxNIP), a member of the NLRP3 inflammasome through Toll-like Receptor (TLR). This is followed by activation of Caspase 1 and production of active IL-1β, which initiates the apoptosis of alveolar epithelial cells and adhesion of immune cells (including monocyte-macrophages and neutrophils) to the capillary. Interaction between GLP-1RA and lung GLP-1R lead to elevated intracellular cAMP level and activation of PKA, which inhibits the expression of TxNIP. Meanwhile, GLP-1 based drugs have potent immuno-regulatory functions on reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines produced by immune cells in both the lung and in the circulation.
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Table 1. FDA approved GLP-1 receptor agonists (GLP-1RA) and DPP-4 inhibitors (DPP-4i)