Regulated Glucagon Secretion from Islet and Pseudo-Islet Alpha Cells

Abstract

Misregulated hormone secretion from the islets of Langerhans is central to the pathophysiology of Diabetes. While insulin plays a key role in glucose regulation and the modulation of secretion has immediate clinical implications, the importance of glucagon is increasingly acknowledged. However, the mechanisms that regulate glucagon secretion from alpha cells are still unclear. We utilized pseudo-islets reconstituted from dispersed islet cells to study alpha cells with and without various indirect effects from other islet cells. When cultured, both murine and human islet cells reassociated into pseudo-islets, which recovered normal glucose-regulated hormone secretion. We generated 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. Our data suggest that the recovery of regulated glucagon secretion from alpha cells in small pseudo-islets depends upon the combined action of paracrine factors, like insulin and somatostatin, and juxtacrine signals between EphA4/7 on alpha cells and ephrins on beta cells. While these signals modulate different pathways, both appear to be required for proper inhibition of glucagon secretion in response to glucose. The improved understanding of the modulation of hormone secretion can provide novel therapeutic routes for the treatment of Diabetic individuals.