Abstract
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.
Highlights
Islet dysfunction is the defining step in the development of type 2 diabetes mellitus (T2DM); it consists of impaired β cell insulin production and increased α cell glucagon production [1,2,3]
We report that pharmacologic activation of the β cell GLP-1 receptor (GLP-1R) induced α cell prohormone convertase 1/3 (PC1/3) and GLP1 expression in mice. We demonstrate that this effect of a GLP-1R agonist was translationally relevant in human islets through application of a single-cell RNA-Seq technology, droplet-assisted RNA targeting by single-cell sequencing (DART-Seq) [23], a high-sensitivity scRNA-Seq approach. scRNASeq platforms often suffer from limitations in achieving adequate depth of sequencing to accurately measure lowly expressed transcripts
Following 6 weeks of high-fat diet (HFD), all mice were switched to HFD supplemented with tamoxifen to induce β cell GLP-1R knockdown and were maintained on this diet throughout study, resulting in a total duration of 8 weeks of HFD feeding before intervention, which results in impaired glucose tolerance, insulin secretion, and islet function, as previously established [26,27,28]
Summary
Islet dysfunction is the defining step in the development of type 2 diabetes mellitus (T2DM); it consists of impaired β cell insulin production and increased α cell glucagon production [1,2,3]. The proglucagon-derived peptides, glucagon and glucagon-like peptide-1 (GLP-1), are key regulators of glucose-stimulated insulin secretion (GSIS) [4,5,6,7,8,9]. GLP-1, in addition to various GLP-1R agonists, is a 300-fold stronger inducer of GSIS [4, 9] and does not produce the effects of glucagon to increase hepatic glucose production, which is thought to be a key pathogenic driver of T2DM [3]. Α cells can express PCSK1 and produce active GLP-1, but the mechanisms regulating α cell PCSK1 expression are poorly defined
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