Washington University in St. Louis

New Publication by the Piston Lab

Congratulations to Troy Hutchens and Dave Piston on their new publication in Diabetes!

Hutchens, T and Piston, DW  (2015)  EphA4 Receptor Forward Signaling Inhibits Glucagon Secretion from α-cells.  Diabetes  [E-published August 6] pii: db150488.

Abstract:  The loss of inhibition of glucagon secretion exacerbates hyperglycemia in types 1 and 2 diabetes. However, the molecular mechanisms that regulate glucagon secretion in unaffected and diabetic states remain relatively unexplained. We present evidence supporting a new model of juxtacrine-mediated regulation of glucagon secretion where neighboring islet cells negatively regulate glucagon secretion through tonic stimulation of α-cell EphA receptors. Primarily through EphA4 receptors, this stimulation correlates with maintenance of a dense F-actin network. In islets, additional stimulation and inhibition of endogenous EphA forward signaling results in inhibition and enhancement, respectively, of glucagon secretion, accompanied by an increase and decrease, respectively, in α-cell F-actin density. Sorted α- cells lack endogenous stimulation of EphA forward signaling from neighboring cells, resulting in enhanced basal glucagon secretion as compared to islets and the elimination of glucose-inhibition of glucagon secretion. Restoration of EphA forward signaling in sorted α-cells recapitulates both normal basal glucagon secretion and glucose-inhibition of glucagon secretion. Additionally, α-cell-specific EphA4-/- mice exhibit abnormal glucagon dynamics, and EphA4-/- α-cells contain less dense F-actin networks than EphA4+/+ α-cells. This juxtacrine-mediated model provides insight into the functional and dysfunctional regulation of glucagon secretion and opens up new therapeutic strategies for the clinical management of diabetes.

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