Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets
| Autor: | Glyn M. Noguchi, Talitha van der Meulen, Joan Vaughan, Cynthia J. Donaldson, Mark O. Huising, Christopher Cowing-Zitron, Michael R. DiGruccio, Alex M. Mawla |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty endocrine system lcsh:Internal medicine Somatostatin secretion Enteroendocrine cell Biology Ucn3 Urocortin 3 Alpha cell 03 medical and health sciences YFP Yellow fluorescent protein Internal medicine medicine lcsh:RC31-1245 Molecular Biology geography Delta cell geography.geographical_feature_category Pancreatic islets Cell Biology GSSS Glucose-stimulated somatostatin secretion Islet Ghsr Growth hormone secretagogue receptor Ghrelin FISH Fluorescent in situ hybridization Beta cell Crhr2 Corticotropin-releasing hormone receptor type 2 030104 developmental biology Endocrinology medicine.anatomical_structure Somatostatin Original Article Iapp Islet amyloid polypeptide Trpm2 Transient receptor potential melastatin 2 Transcriptome Somatostatin release RPKM Reads per kilobase gene model per million reads sequenced |
| Zdroj: | Molecular Metabolism, Vol 5, Iss 7, Pp 449-458 (2016) DiGruccio, MR; Mawla, AM; Donaldson, CJ; Noguchi, GM; Vaughan, J; Cowing-Zitron, C; et al.(2016). Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets. Molecular Metabolism, 5(7), 449-458. doi: 10.1016/j.molmet.2016.04.007. UC Davis: Retrieved from: http://www.escholarship.org/uc/item/2470m615 Molecular Metabolism |
| ISSN: | 2212-8778 |
| DOI: | 10.1016/j.molmet.2016.04.007. |
| Popis: | Objective Complex local crosstalk amongst endocrine cells within the islet ensures tight coordination of their endocrine output. This is illustrated by the recent demonstration that the negative feedback control by delta cells within pancreatic islets determines the homeostatic set-point for plasma glucose during mouse postnatal development. However, the close association of islet endocrine cells that facilitates paracrine crosstalk also complicates the distinction between effects mediated directly on beta cells from indirect effects mediated via local intermediates, such as somatostatin from delta cells. Methods To resolve this problem, we generated reporter mice that allow collection of pure pancreatic delta cells along with alpha and beta cells from the same islets and generated comprehensive transcriptomes for each islet endocrine cell type. These transcriptomes afford an unparalleled view of the receptors expressed by delta, alpha and beta cells, and allow the prediction of which signal targets which endocrine cell type with great accuracy. Results From these transcriptomes, we discovered that the ghrelin receptor is expressed exclusively by delta cells within the islet, which was confirmed by fluorescent in situ hybridization and qPCR. Indeed, ghrelin increases intracellular calcium in delta cells in intact mouse islets, measured by GCaMP6 and robustly potentiates glucose-stimulated somatostatin secretion on mouse and human islets in both static and perfusion assays. In contrast, des-acyl-ghrelin at the same dose had no effect on somatostatin secretion and did not block the actions of ghrelin. Conclusions These results offer a straightforward explanation for the well-known insulinostatic actions of ghrelin. Rather than engaging beta cells directly, ghrelin engages delta cells to promote local inhibitory feedback that attenuates insulin release. These findings illustrate the power of our approach to resolve some of the long-standing conundrums with regard to the rich feedback that occurs within the islet that is integral to islet physiology and therefore highly relevant to diabetes. Graphical abstract |
| Databáze: | OpenAIRE |
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