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| Status |
Public on Dec 24, 2020 |
| Title |
GLP-1 receptor signaling increases PCSK1 and beta-cell features in human alpha-cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 alpha-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 alpha-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, increases alpha-cell GLP-1 expression in a beta cell GLP-1R-dependent manner. We demonstrate that this effect of liraglutide is translationally relevant in human islets through application of a new scRNA-sequencing technology, DART-seq. We find that the effect of liraglutide to increase alpha-cell PC1/3 mRNA expression occurs in a sub-cluster of alpha-cells and is associated with increased expression of other beta-cell-like genes, which we confirm by IHC. Finally, we find that the effect of liraglutide to increase bi-hormonal insulin+ glucagon+ cells is mediated by the beta-cell GLP-1R in mice. Together, our data validate a new high-sensitivity method for scRNA-sequencing in human islets and identify a novel GLP-1 mediated pathway regulating human alpha-cell function.
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| Overall design |
Single cell RNA-sequencing was performed on human islet samples obtained from three healthy male donors. Each sample was treated with either Saline (Ctrl) or Liraglutude (Lira). For data analysis all three data sets in each category i.e. Ctrl and Lira, were combined and then compared to obtain differentially expressed genes in response to liraglutide treatment.
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| Contributor(s) |
Saikia M, Holter MM, Donahue LR, Lee IS, Zheng QC, Wise JL, Todero JE, Phuong DJ, Coch R, Sloop KW, Garcia-Ocana A, Danko CG, Cummings BP |
| Citation(s) |
33554958 |
| Submission date |
Dec 23, 2020 |
| Last update date |
Mar 25, 2021 |
| Contact name |
Mridusmita Saikia |
| Organization name |
Cornell University
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| Street address |
111 Weill Hall, 237 Tower Road
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| City |
Ithaca |
| State/province |
NY |
| ZIP/Postal code |
14853 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (7)
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| Relations |
| BioProject |
PRJNA687419 |
| SRA |
SRP299053 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE163744_Ctrl_combineddata_gene_exon_tagged.dge.txt.gz |
25.1 Mb |
(ftp)(http) |
TXT |
| GSE163744_Donor-3-DART-seq_gene_exon_tagged.dge.txt.gz |
17.9 Mb |
(ftp)(http) |
TXT |
| GSE163744_Donor-3-Drop-seq_gene_exon_tagged.dge.txt.gz |
15.6 Mb |
(ftp)(http) |
TXT |
| GSE163744_Lira_combineddata_gene_exon_tagged.dge.txt.gz |
36.6 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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