Cell-specific resetting of mouse islet cellular clocks by glucagon, glucagon-like peptide 1 and somatostatin.
Acta Physiol (Oxf)
; 222(4): e13021, 2018 04.
Article
en En
| MEDLINE
| ID: mdl-29271578
AIM: Molecular clocks, operative in pancreatic islet cells, represent an intrinsic mechanism regulating intracellular metabolism and hormone secretion. Glucagon, somatostatin and glucagon-like peptide 1 (GLP-1) are essential coordinators of islet physiology. Here, we assess the synchronizing capacity of glucagon, somatostatin and GLP-1 on pancreatic α- and ß-cell circadian clocks. METHODS: Triple transgenic mice, expressing a circadian PER2::luciferase (luc) reporter combined with α- and ß-cell-specific fluorescent reporters, were employed. Isolated pancreatic islets and fluorescence-activated cell sorting-separated α- and ß-cells were synchronized with glucagon, somatostatin analogue or GLP-1 mimetics, with subsequent real-time PER2::luc bioluminescence recording. Gene expression of Gcgr, Sstr2, Sstr3 and Glp1r in islet cells was assessed by RNA sequencing and RT-qPCR. RESULTS: Glucagon and GLP-1 mimetics (liraglutide and exenatide) induced high-amplitude rhythmic expression of the PER2::luc reporter in ß-cells, but not in α-cells, while the somatostatin analogue octreotide generated a significant phase shift between α- and ß-cells. Enrichment of Gcgr and Glp1r transcripts was detected in ß-cells compared to their α-cell counterparts. The synchronizing effect of glucagon was dose-dependent and mediated by the adenylate cyclase signalling cascade, as it was diminished by adenylate cyclase inhibitor. CONCLUSION: We conclude that proglucagon-derived peptides and somatostatin exhibit receptor-mediated cell-specific synchronizing effects for mouse α- and ß-cell oscillators. Differential islet cell clock modulation by glucagon and somatostatin may represent a physiological mechanism underlying paracrine regulation of rhythmic glucagon and insulin secretion. The reported here strong synchronizing properties of GLP-1 mimetics, widely used for treatment of type 2 diabetes, are of high clinical relevance.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Glucagón
/
Somatostatina
/
Islotes Pancreáticos
/
Péptido 1 Similar al Glucagón
/
Relojes Circadianos
Límite:
Animals
Idioma:
En
Revista:
Acta Physiol (Oxf)
Asunto de la revista:
FISIOLOGIA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Suiza
Pais de publicación:
Reino Unido