GLP-1 receptor signaling increases PCSK1 and β cell features in human α cells

• Published in: JCI insight Vol. 6; no. 3
• Main Authors: Saikia, Mridusmita, Holter, Marlena M., Donahue, Leanne R., Lee, Isaac S., Zheng, Qiaonan C., Wise, Journey L., Todero, Jenna E., Phuong, Daryl J., Garibay, Darline, Coch, Reilly, Sloop, Kyle W., Garcia-Ocana, Adolfo, Danko, Charles G., Cummings, Bethany P.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 08.02.2021; American Society for Clinical investigation
• Subjects: Animals; Endocrinology; Female; Gene Knockdown Techniques; Glucagon-Like Peptide-1 Receptor - deficiency; Glucagon-Like Peptide-1 Receptor - genetics; Glucagon-Like Peptide-1 Receptor - metabolism; Glucagon-Like Peptide-1 Receptor Agonists; Glucagon-Secreting Cells - drug effects; Glucagon-Secreting Cells - metabolism; Humans; Hypoglycemic Agents - pharmacology; In Vitro Techniques; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Liraglutide - pharmacology; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Proprotein Convertase 1 - metabolism; RNA-Seq; Signal Transduction; Islet cells; Diabetes; Metabolism; Endocrinology
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.141851

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates glucose-stimulated insulin secretion. GLP-1 is classically produced by gut L cells; however, under certain circumstances α cells can express the prohormone convertase required for proglucagon processing to GLP-1, prohormone convertase 1/3 (PC1/3), and can produce GLP-1. However, the mechanisms through which this occurs are poorly defined. Understanding the mechanisms by which α cell PC1/3 expression can be activated may reveal new targets for diabetes treatment. Here, we demonstrate that the GLP-1 receptor (GLP-1R) agonist, liraglutide, increased α cell GLP-1 expression in a β cell GLP-1R-dependent manner. We demonstrate that this effect of liraglutide was translationally relevant in human islets through application of a new scRNA-seq technology, DART-Seq. We found that the effect of liraglutide to increase α cell PC1/3 mRNA expression occurred in a subcluster of α cells and was associated with increased expression of other β cell-like genes, which we confirmed by IHC. Finally, we found that the effect of liraglutide to increase bihormonal insulin+ glucagon+ cells was mediated by the β cell GLP-1R in mice. Together, our data validate a high-sensitivity method for scRNA-seq in human islets and identify a potentially novel GLP-1-mediated pathway regulating human α cell function.