1784-P: Liraglutide Treatment Stimulates Alpha Cells to Produce Glucagon-Like Peptide-1 via Expression of Prohormone Convertase 1/3 in Mice and Human

Glucagon-like peptide-1 (GLP-1) regulates islet function by enhancing glucose-stimulated insulin secretion (GSIS). We previously found that the beta cell GLP-1 receptor (GLP-1R) contributes to improvements in glucose regulation and islet function in mice that have undergone bariatric surgery, specifically, vertical sleeve gastrectomy (VSG). Further investigation revealed that VSG increases alpha cell GLP-1 production by turning on the expression of prohormone convertase 1/3 (PC1/3, gene: Pcsk1) in a beta cell GLP-1R-dependent fashion. These findings lead us to hypothesize that beta cell GLP-1R signaling increases alpha cell GLP-1 production to augment GSIS in a paracrine positive feedback loop. In the current study, we tested whether the effects of VSG can be recapitulated by pharmacologic stimulation of the GLP-1R, using a GLP-1 analog, liraglutide. We found that liraglutide treatment increases alpha cell GLP-1 expression in a beta cell GLP-1R dependent fashion (GLP-1 area per islet (µm2): Vehicle WT = 132 ± 3, Vehicle KO = 73 ± 2, Liraglutide WT = 241 ± 15, Liraglutide KO = 67 ± 1; P<0.05 Liraglutide WT vs. all groups). We then used an innovative single-cell RNA-sequencing platform, DART-seq, to determine the translational relevance of this new model of islet function. We validated application of DART-seq in human islets, and using this technology we observed that liraglutide induces a 1.5 log-fold increase in Pcsk1 mRNA expression compared with saline treated controls in a subset of alpha cells (P<0.05 saline vs. liraglutide). Additionally, our DART-seq data suggests that liraglutide-induced increase in alpha cell PC1/3 expression may be part of a broader induction of alpha-cell transdifferentiation to beta cells. Thus, our study demonstrates that the effect of beta cell GLP-1R signaling to increase alpha-cell GLP-1 expression can be stimulated by pharmacological activation of the GLP-1R and has translational relevance in humans.