Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets.
Adriaenssens, Alice E
Holst, Jens J
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Adriaenssens, A. E., Svendsen, B., Lam, B., Yeo, G., Holst, J. J., Reimann, F., & Gribble, F. (2016). Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets.. Diabetologia, 59 (10), 2156-2165. https://doi.org/10.1007/s00125-016-4033-1
Aims/hypothesis: Intra-islet and gut-islet crosstalk are critical in orchestrating basal and post-prandial metabolism. The aim of this study was to identify regulatory proteins and receptors underlying somatostatin secretion, by transcriptomic comparison of purified murine alpha, beta and delta cells. Methods: SST (somatostatin)-Cre mice crossed with fluorescent reporters were used to identify delta cells, and Glu-Venus mice were used to identify alpha and beta cells. Alpha, beta and delta cells were purified by flow cytometry and analysed by RNA-sequencing. Validation of the role of the ghrelin receptor was performed by imaging delta cell calcium concentrations using islets with delta-cell restricted expression of the calcium reporter GCaMP3, and in perfused mouse pancreas. Results. A database was constructed of all genes expressed in alpha, beta and delta cells. The ghrelin receptor, Ghsr, was highlighted as being highly expressed and enriched in delta cells. GHSR activation raised cytosolic calcium levels in primary pancreatic delta cells, and in the perfused pancreas enhanced somatostatin secretion, correlating with a decrease in insulin and glucagon release. The inhibition of insulin secretion by ghrelin was prevented by somatostatin receptor (SSTR) antagonism. Conclusions: Our transcriptomic database of genes expressed in the principal islet cell populations will facilitate rational drug design to target specific islet cell types. Arising from this analysis, we conclude that ghrelin acts specifically on delta cells within pancreatic islets to elicit somatostatin secretion, which in turn inhibits insulin and glucagon release. This highlights the potential role of ghrelin in the control of glucose metabolism.
Alpha cells, Beta cells, Delta cells, Ghrelin, Glucagon, Insulin, RNA sequencing, Somatostatin, Animals, Calcium, Ghrelin, Glucagon, Glucagon-Secreting Cells, Insulin, Insulin-Secreting Cells, Islets of Langerhans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Reverse Transcriptase Polymerase Chain Reaction, Somatostatin-Secreting Cells, Transcriptome
Wellcome Trust (100574/Z/12/Z)
External DOI: https://doi.org/10.1007/s00125-016-4033-1
This record's URL: https://www.repository.cam.ac.uk/handle/1810/256533
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/