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Structural basis for delta cell paracrine regulation in pancreatic islets.

ABSTRACT: Little is known about the role of islet delta cells in regulating blood glucose homeostasis in vivo. Delta cells are important paracrine regulators of beta cell and alpha cell secretory activity, however the structural basis underlying this regulation has yet to be determined. Most delta cells are elongated and have a well-defined cell soma and a filopodia-like structure. Using in vivo optogenetics and high-speed Ca²⁺ imaging, we show that these filopodia are dynamic structures that contain a secretory machinery, enabling the delta cell to reach a large number of beta cells within the islet. This provides for efficient regulation of beta cell activity and is modulated by endogenous IGF-1/VEGF-A signaling. In pre-diabetes, delta cells undergo morphological changes that may be a compensation to maintain paracrine regulation of the beta cell. Our data provides an integrated picture of how delta cells can modulate beta cell activity under physiological conditions.

SUBMITTER: Arrojo E Drigo R

PROVIDER: S-EPMC6697679 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Structural basis for delta cell paracrine regulation in pancreatic islets.

Arrojo E Drigo Rafael R Jacob Stefan S García-Prieto Concha F CF Zheng Xiaofeng X Fukuda Masahiro M Nhu Hoa Tran Thi HTT Stelmashenko Olga O Peçanha Flavia Letícia Martins FLM Rodriguez-Diaz Rayner R Bushong Eric E Deerinck Thomas T Phan Sebastien S Ali Yusuf Y Leibiger Ingo I Chua Minni M Boudier Thomas T Song Sang-Ho SH Graf Martin M Augustine George J GJ Ellisman Mark H MH Berggren Per-Olof PO

Nature communications 20190816 1

Little is known about the role of islet delta cells in regulating blood glucose homeostasis in vivo. Delta cells are important paracrine regulators of beta cell and alpha cell secretory activity, however the structural basis underlying this regulation has yet to be determined. Most delta cells are elongated and have a well-defined cell soma and a filopodia-like structure. Using in vivo optogenetics and high-speed Ca<sup>2+</sup> imaging, we show that these filopodia are dynamic structures that c ...[more]

PMID: 31420552

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Project description:ObjectiveComplex 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.MethodsTo 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.ResultsFrom 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.ConclusionsThese 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.

Dataset Information

Structural basis for delta cell paracrine regulation in pancreatic islets.

Publications

Structural basis for delta cell paracrine regulation in pancreatic islets.

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