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Title page for ETD etd-08132015-130825


Type of Document Dissertation
Author Hutchens, Troy John
URN etd-08132015-130825
Title Novel Regulators of Glucagon Secretion from α-Cells
Degree PhD
Department Chemical and Physical Biology
Advisory Committee
Advisor Name Title
Anne K. Kenworthy, Ph.D. Committee Chair
David A. Jacobson, Ph.D. Committee Member
David W. Piston, Ph.D. Committee Member
Jin Chen, MD, Ph.D. Committee Member
Kevin D. Niswender, M.D., Ph.D. Committee Member
Keywords
  • α-cell
  • glucagon
  • EphA receptors
  • ephrin-A ligands
  • brown adipose tissue
Date of Defense 2015-08-07
Availability unrestricted
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. The work discussed here presents evidence for two novel regulators of glucagon secretion; EphA/ephrin-A juxtacrine signaling and an unknown factor secreted by brown adipose tissue (BAT). This work supports a new juxtacrine-mediated model of glucagon secretion in which 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. Further, α-cell-specific EphA4-/- mice exhibit abnormal glucagon dynamics, and EphA4-/- α-cells contain less dense F-actin networks than EphA4+/+ α-cells. In a separate project, an unidentified factor secreted by BAT was found to act directly on islets to inhibit glucagon secretion. Buffer conditioned in the presence of BAT or a brown adipocyte cell line greatly inhibited glucagon secretion from mouse islets. Size fractionation of this conditioned buffer further revealed the active factor to be less than 3 kDa. These new regulators of glucagon secretion (EphA-ephrin-A signaling and a BAT secreted factor) provide insight into the functional and dysfunctional regulation of glucagon secretion and open up new therapeutic strategies for the clinical management of diabetes through the inhibition of glucagon secretion and the correction of hyperglucagonemia.
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