Misregulated hormone secretion from the islet of Langerhans is central to the pathophysiology of diabetes. While insulin plays a key role in glucose regulation, the importance of glucagon is increasingly acknowledged. However, the mechanisms that regulate glucagon secretion from α-cells are still unclear. We utilized pseudo-islets reconstituted from dispersed islet cells to study α-cells with and without various indirect effects from other islet cells. Dispersed islet cells secrete aberrant levels of glucagon and insulin at basal and elevated glucose levels. When cultured, murine islet cells reassociate to form pseudo-islets, which recover normal glucose-regulated hormone secretion, and human islet cells follow a similar pattern. We created small (∼40 µm) pseudo-islets using all of the islet cells, or only some of the cell types, which allowed us to characterize novel aspects of regulated hormone secretion. The recovery of regulated glucagon secretion from α-cells in small pseudo-islets depends upon the combined action of paracrine factors, like insulin and somatostatin, and juxtacrine signals between EphA4/7 on α-cells and ephrins on β-cells. While these signals modulate different pathways, both appear to be required for proper inhibition of glucagon secretion in response to glucose. This improved understanding of the modulation of glucagon secretion can provide novel therapeutic routes for the treatment of some diabetic individuals.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-1291/-/DC1.
- Received October 24, 2016.
- Accepted January 23, 2017.
- © 2017 by the American Diabetes Association.