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?-cells and ?-cells are electrically coupled and regulate ?-cell activity via somatostatin.
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ABSTRACT: Key points
We used a mouse expressing a light-sensitive ion channel in ?-cells to understand how ?-cell activity is regulated by ?-cells. Light activation of ?-cells triggered a suppression of ?-cell activity via gap junction-dependent activation of ?-cells. Mathematical modelling of human islets suggests that 23% of the inhibitory effect of glucose on glucagon secretion is mediated by ?-cells via gap junction-dependent activation of ?-cells/somatostatin secretion.Abstract
Glucagon, the body's principal hyperglycaemic hormone, is released from ?-cells of the pancreatic islet. Secretion of this hormone is dysregulated in type 2 diabetes mellitus but the mechanisms controlling secretion are not well understood. Regulation of glucagon secretion by factors secreted by neighbouring ?- and ?-cells (paracrine regulation) have been proposed to be important. In this study, we explored the importance of paracrine regulation by using an optogenetic strategy. Specific light-induced activation of ?-cells in mouse islets expressing the light-gated channelrhodopsin-2 resulted in stimulation of electrical activity in ?-cells but suppression of ?-cell activity. Activation of the ?-cells was rapid and sensitive to the gap junction inhibitor carbenoxolone, whereas the effect on electrical activity in ?-cells was blocked by CYN 154806, an antagonist of the somatostatin-2 receptor. These observations indicate that optogenetic activation of the ?-cells propagates to the ?-cells via gap junctions, and the consequential stimulation of somatostatin secretion inhibits ?-cell electrical activity by a paracrine mechanism. To explore whether this pathway is important for regulating ?-cell activity and glucagon secretion in human islets, we constructed computational models of human islets. These models had detailed architectures based on human islets and consisted of a collection of >500 ?-, ?- and ?-cells. Simulations of these models revealed that this gap junctional/paracrine mechanism accounts for up to 23% of the suppression of glucagon secretion by high glucose.
SUBMITTER: Briant LJB
PROVIDER: S-EPMC5767697 | biostudies-literature | 2018 Jan
REPOSITORIES: biostudies-literature
Publications
δ-cells and β-cells are electrically coupled and regulate α-cell activity via somatostatin.
The Journal of physiology 20171102 2
<h4>Key points</h4>We used a mouse expressing a light-sensitive ion channel in β-cells to understand how α-cell activity is regulated by β-cells. Light activation of β-cells triggered a suppression of α-cell activity via gap junction-dependent activation of δ-cells. Mathematical modelling of human islets suggests that 23% of the inhibitory effect of glucose on glucagon secretion is mediated by β-cells via gap junction-dependent activation of δ-cells/somatostatin secretion.<h4>Abstract</h4>Glucag ...[more]