Essential Role of Syntaxin-Binding Protein-1 in the Regulation of Glucagon-Like Peptide-1 Secretion

Abstract

Circadian secretion of the incretin, glucagon-like peptide-1 (GLP-1), correlates with expression of the core clock gene, Bmal1, in the intestinal L-cell. Several SNARE proteins known to be circadian in pancreatic α- and β-cells are also necessary for GLP-1 secretion. However, the role of the accessory SNARE, Syntaxin binding protein-1 (Stxbp1; also known as Munc18-1) in the L-cell is unknown. The aim of this study was to determine whether Stxbp1 is under circadian regulation in the L-cell and its role in the control of GLP-1 secretion. Stxbp1 was highly-enriched in L-cells, and STXBP1 was expressed in a subpopulation of L-cells in mouse and human intestinal sections. Stxbp1 transcripts and protein displayed circadian patterns in mGLUTag L-cells line, while chromatin-immunoprecipitation revealed increased interaction between BMAL1 and Stxbp1 at the peak time-point of the circadian pattern. STXBP1 recruitment to the cytosol and plasma membrane within 30 minutes of L-cell stimulation was also observed at this time-point. Loss of Stxbp1 in vitro and in vivo led to reduced stimulated GLP-1 secretion at the peak time-point of circadian release, and impaired GLP-1 secretion ex vivo. In conclusion, Stxbp1 is a circadian regulated exocytotic protein in the intestinal L-cell that is an essential regulatory component of GLP-1 secretion.

Internalization-Dependent Free Fatty Acid Receptor 2 Signaling Is Essential for Propionate-Induced Anorectic Gut Hormone Release

“…More recently, propionate-induced GLP-1 release was also found to be regulated by p38 in chicken intestinal epithelial cells ( Zhang et al., 2019 ), suggesting a conserved role of this kinase in anorectic gut hormone secretion induced by distinct metabolites. How p38 may regulate gut hormone secretion is unknown, although this kinase pathway may phosphorylate components of the SNARE complex such as syntaxin1a, shown recently to be essential for GLP-1 secretion in intestinal L-cells ( Wheeler et al., 2017 ; Campbell et al., 2020 ).…”

Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice

“…Transgenic Glu CreERT2 ; Rosa26-eYFP and Ins1 Cre/+ ; Rosa26-eYFP C57BL/6 mice were bred in-house at the Biomedical and Behavioural Research Unit (BBRU) at Ulster University, Coleraine. Full details of the generation and characterization of mouse models are provided by Campbell et al., 2020 ( 22 ) and Tanday et al., 2020a ( 23 ), respectively. It is important to note that Glu CreERT2 and Ins1 Cre/+ are not equivalent lineage tracers.…”

“…As such, Ins1 Cre/+ will come on as soon as a cell makes Ins1 , whereas Glu CreERT2 will only label cells producing glucagon when concomitantly exposed to tamoxifen. PCR genotyping for each colony was employed as previously described ( 12 , 22 ). Glu CreERT2 ; Rosa26-eYFP animals were administered tamoxifen (7 mg/mouse bw, i.p.…”

“…Fully characterized Glu CreERT2 ; ROSA26-eYFP and Ins1 Cre/+ ; Rosa26-eYFP transgenic mouse models ( 22 , 23 ) were used to directly investigate the impact of sustained NPY1R signaling on both alpha- to beta-, as well as beta- to alpha-cell, transdifferentiation, respectively. It is generally considered that islet cell transdifferentiation only occurs following severe pancreatic insult, as experienced in diabetes ( 11 ).…”

Antidiabetic drug therapy alleviates type 1 diabetes in mice by promoting pancreatic α-cell transdifferentiation

“…Nine-week old Glu CreERT2 ;ROSA26-eYFP transgenic mice were used to perform all studies. An original colony, developed on the C57Bl/6 background at the University of Cambridge [27], was subsequently transferred to the animal facility at Ulster University and genotyped to assess Cre-ERT2 and ROSA26eYFP gene expression (Table 1).…”