Npas4 Is a Novel Activity-Regulated Cytoprotective Factor in Pancreatic β-Cells

  1. Francis C. Lynn1,2
  1. 1Diabetes Research Group, Child and Family Research Institute, Vancouver, British Columbia, Canada
  2. 2Department of Surgery and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada
  3. 3Montreal Diabetes Research Center, CRCHUM, and Department of Medicine, Université de Montréal, Montréal, Quebec, Canada
  4. 4Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  5. 5Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
  1. Corresponding author: Francis Lynn, francis.lynn{at}ubc.ca

Abstract

Cellular homeostasis requires intrinsic sensing mechanisms to temper function in the face of prolonged activity. In the pancreatic β-cell, glucose is likely a physiological trigger that activates an adaptive response to stimulation, thereby maintaining cellular homeostasis. Immediate early genes (IEGs) are activated as a first line of defense in cellular homeostasis and are largely responsible for transmitting an environmental cue to a cellular response. Here we examine the regulation and function of the novel β-cell IEG, neuronal PAS domain protein 4 (Npas4). Using MIN6 cells, mouse and human islets, as well as in vivo infusions, we demonstrate that Npas4 is expressed within pancreatic islets and is upregulated by β-cell depolarizing agents. Npas4 tempers β-cell function through a direct inhibitory interaction with the insulin promoter and by blocking the potentiating effects of GLP-1 without significantly reducing glucose-stimulated secretion. Finally, Npas4 expression is induced by classical endoplasmic reticulum (ER) stressors and can prevent thapsigargin- and palmitate-induced dysfunction and cell death. These results suggest that Npas4 is a key activity-dependent regulator that improves β-cell efficiency in the face of stress. We posit that Npas4 could be a novel therapeutic target in type 2 diabetes that could both reduce ER stress and cell death and maintain basal cell function.

  • Received November 5, 2012.
  • Accepted March 28, 2013.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

This Article

  1. Diabetes
  1. Supplementary Data
  2. All Versions of this Article:
    1. db12-1527v1
    2. 62/8/2808 most recent