Abstract
Aims/hypothesisIntra-islet and gut–islet crosstalk are critical in orchestrating basal and postprandial metabolism. The aim of this study was to identify regulatory proteins and receptors underlying somatostatin secretion though the use of transcriptomic comparison of purified murine alpha, beta and delta cells.MethodsSst-Cre mice crossed with fluorescent reporters were used to identify delta cells, while Glu-Venus (with Venus reported under the control of the Glu [also known as Gcg] promoter) mice were used to identify alpha and beta cells. Alpha, beta and delta cells were purified using flow cytometry and analysed by RNA sequencing. The role of the ghrelin receptor was validated by imaging delta cell calcium concentrations using islets with delta cell restricted expression of the calcium reporter GCaMP3, and in perfused mouse pancreases.ResultsA database was constructed of all genes expressed in alpha, beta and delta cells. The gene encoding the ghrelin receptor, Ghsr, was highlighted as being highly expressed and enriched in delta cells. Activation of the ghrelin receptor raised cytosolic calcium levels in primary pancreatic delta cells and enhanced somatostatin secretion in perfused pancreases, correlating with a decrease in insulin and glucagon release. The inhibition of insulin secretion by ghrelin was prevented by somatostatin receptor antagonism.Conclusions/interpretationOur transcriptomic database of genes expressed in the principal islet cell populations will facilitate rational drug design to target specific islet cell types. The present study indicates that ghrelin acts specifically on delta cells within pancreatic islets to elicit somatostatin secretion, which in turn inhibits insulin and glucagon release. This highlights a potential role for ghrelin in the control of glucose metabolism.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-4033-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
The pancreatic islets provide a centre where signals indicating the nutritional status of the body, including factors such as enteroendocrine hormones, nutrients, metabolites and neuronal signals, can converge and initiate changes in pancreatic hormone secretion to regulate blood glucose levels
Of the cell surface markers, we found that G-protein coupled receptors (GPCRs), ion channels and 32 membrane transporters were differentially expressed between alpha, beta and delta cells (Fig. 1d)
We identified the transcriptome of pancreatic delta cells and performed a comparative transcriptomic analysis with beta and alpha cells
Summary
The pancreatic islets provide a centre where signals indicating the nutritional status of the body, including factors such as enteroendocrine hormones, nutrients, metabolites and neuronal signals, can converge and initiate changes in pancreatic hormone secretion to regulate blood glucose levels. Nuanced interactions and crosstalk between islet cell types are critical in maintaining tight control over blood glucose equilibrium, and elucidating the ways in which enteric signals and islet cells interact to influence circulating glucose levels could provide insights into the mechanisms underlying altered glycaemic control and diabetes [2, 3]. SST appears to exert tonic suppression of insulin and glucagon release within islets [4]. The importance of this potent paracrine mechanism is illustrated by experiments showing that whole-animal genetic ablation of Sst results in aberrant secretion of both insulin and glucagon from isolated islets in response to glucose [5]. Identifying how delta cells differ from their neighbouring alpha and beta cells is crucial for interpreting transcriptomic and functional data obtained from whole islets [7]
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