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Incretins (GLP-1 and GIP) potentiate insulin secretion through cAMP signaling in pancreatic β-cells in a glucose-dependent manner. We recently proposed a mechanistic model of incretin-induced insulin secretion (IIIS) that requires two critical processes: 1) generation of cytosolic glutamate through the malate-aspartate (MA) shuttle in glucose metabolism and 2) glutamate transport into insulin granules by cAMP signaling to promote insulin granule exocytosis. To directly prove the model, we have established and characterized CRISPR/Cas9-engineered clonal mouse β-cell lines deficient for the genes critical in these two processes: aspartate aminotransferase 1 (AST1, gene symbol  Got1 ), a key enzyme in the MA shuttle, which generates cytosolic glutamate, and the vesicular glutamate transporters (VGLUT1, VGLUT2, and VGLUT3, gene symbol  Slc17a7 ,  Slc17a6 , and  Slc17a8 , respectively), which participate in glutamate transport into secretory vesicles.  Got1  knockout (KO) β-cell lines were defective in cytosolic glutamate production from glucose and showed impaired IIIS. Unexpectedly, different from the previous finding that global  Slc17a7  KO mice exhibited impaired IIIS from pancreatic islets, β-cell specific  Slc17a7  KO mice showed no significant impairment in IIIS, as assessed by pancreas perfusion experiment. Single  Slc17a7  KO β-cell lines also retained IIIS, probably due to compensatory upregulation of  Slc17a6 . Interestingly, triple KO of  Slc17a7 ,  Slc17a6 , and  Slc17a8  diminished IIIS, which was rescued by exogenously introduced wild-type  Slc17a7  or  Slc17a6  genes. The present study provides direct evidence for the essential roles of AST1 and VGLUTs in β-cell glutamate signaling for IIIS and also shows the usefulness of the CRISPR/Cas9 system for studying β-cells by simultaneous disruption of multiple genes.

plos one

Essential roles of aspartate aminotransferase 1 and vesicular glutamate transporters in β-cell glutamate signaling for incretin-induced insulin secretion