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Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets
Open accessAbstract
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.
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![Figure 2 Delta cells selectively express Ghsr. A: Normalized browser plots illustrating the expression of a series of GPCRs in delta, beta and alpha cells of the mouse islet. B: Confirmation by qPCR that Ghsr message is selectively expressed by pancreatic delta cells. C: Violin plots of single cell RNA-seq of wild type mouse pancreatic islet cells [25] confirms that Ghsr expression is detectable only in delta cells. D: FISH confirmation of the expression of Ghsr gene (green dots) in pancreatic delta cells of wild type mice, colocalized with Sst message (red dots) and Sst peptide (white). E: mRNA for Ghsr (green dots) and Sst (red dots) co-localizes in a peripheral islet population that does not express Gcg peptide (white). *P < 0.05; **P < 0.01; ***P < 0.001.](/paper-figures/fd91c95c826d4032bf1472059ffe1203/comprehensive-alpha-beta-and-delta-cell-transcriptomes-reveal-that-ghrelin-figure-2.jpg)
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“We estimate (Equation 3.2. in ref. 26) the gap junctional conductance between β-cells and δ-cells to be 23 pS.”
From Loss of electrical β-cell to δ-cell coupling underlies impaired hypoglycaemia-induced glucagon secretion in type-1 diabetes (2024) · cites this paper as [16]
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In the citing paper
“Both mouse (3, 146) and human (68, 475) β-cells express Hcn/HCN2-4.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [146]
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“which is expressed in mouse β-cells(3, 146).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [146]
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“However, these are only expressed at low levels in mouse and human β-cells alike (3, 68, 146, 475).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [146]
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“Both human and mouse β-cells also express Slc6a17/SLC6a17 (3, 68, 146, 475) that encodes a synaptic vesicle glycine transporter (502).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [146]
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“These are both expressed at low levels in mouse and human β-cells (3, 68, 146, 475).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [146]
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“Mouse and human β-cells express CAPS1 (Cadps/CADPS) and low amounts of CAPS2 (Cadps2/CADPS2) (3, 68, 146, 475).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [146]
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“In human β-cells, only SYN1 is expressed, whereas mouse β-cells express both Syn1 and Syn2 (3, 68, 146, 475).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [146]
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Metadata
- Authors
- DiGruccio, M. R., Mawla, A. M., Donaldson, C. J., Noguchi, G. M., Vaughan, J., Cowing-Zitron, C., van der Meulen, T., & Huising, M. O.
- Affiliations
- University of California, Davis (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Huising, Mark O.
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 5
- Issue
- 7
- Pages
- 449-458
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC4921781
- OpenAlex
- W2346764160
- Cited by
- 353
- References
- 50
- Citations by year
- 2026: 25 · 2025: 23 · 2024: 41 · 2023: 45 · 2022: 41 · 2021: 47 · 2020: 40 · 2019: 29 · 2018: 27 · 2017: 23 · 2016: 12
- FWCI
- 33.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- Juvenile Diabetes Research Foundation (2-2013-54)
- Hartwell Foundation (201500731)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- ghrelin, pancreatic delta cells, somatostatin secretion, growth hormone secretagogue receptor, pancreatic islets, islet endocrine cells, alpha cells, pancreatic beta cells, intracellular calcium, des-acyl ghrelin, paracrine signaling, glucose-stimulated insulin secretion, islet transcriptome, reporter mice, diabetes mellitus
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