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The glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) is a key target for type 2 diabetes (T2D) treatment. Because endocytic trafficking of agonist-bound receptors is one of the most important routes for regulation of receptor signaling, a better understanding of this process may facilitate the development of new T2D therapeutic strategies. Here, we screened 29 proteins with known functions in G protein-coupled receptor trafficking for their role in GLP-1R potentiation of insulin secretion in pancreatic β-cells. We identify five (clathrin, dynamin1, AP2, sorting nexins [SNX] SNX27, and SNX1) that increase and four (huntingtin-interacting protein 1 [HIP1], HIP14, GASP-1, and Nedd4) that decrease insulin secretion from murine insulinoma MIN6B1 cells in response to the GLP-1 analog exendin-4. The roles of HIP1 and the endosomal SNX1 and SNX27 were further characterized in mouse and human β-cell lines and human islets. While HIP1 was required for the coupling of cell surface GLP-1R activation with clathrin-dependent endocytosis, the SNXs were found to control the balance between GLP-1R plasma membrane recycling and lysosomal degradation and, in doing so, determine the overall β-cell incretin responses. We thus identify key modulators of GLP-1R trafficking and signaling that might provide novel targets to enhance insulin secretion in T2D.

Original publication

DOI

10.2337/db17-0639

Type

Journal article

Journal

Diabetes

Publication Date

03/2018

Volume

67

Pages

385 - 399

Keywords

Animals, Calcium Signaling, Cell Line, Cyclic AMP, DNA-Binding Proteins, Endocytosis, Glucagon-Like Peptide-1 Receptor, Humans, Incretins, Insulin, Insulin-Secreting Cells, Lysosomes, Mice, Microscopy, Electron, Transmission, Peptides, RNA Interference, Recombinant Fusion Proteins, Second Messenger Systems, Sorting Nexins, Tissue Culture Techniques, Venoms