Format

Send to

Choose Destination
Cell Metab. 2016 Jan 12;23(1):179-93. doi: 10.1016/j.cmet.2015.10.016. Epub 2015 Nov 25.

Reduced Insulin Production Relieves Endoplasmic Reticulum Stress and Induces β Cell Proliferation.

Author information

1
Department of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, BC V6T1Z3, Canada.
2
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
3
Child and Family Research Institute, University of British Columbia, BC V5Z 4H4, Canada.
4
Centre for High-Throughput Biology, University of British Columbia, BC V6T 1Z3, Canada.
5
Faculty of Pharmaceutical Sciences, University of British Columbia, BC V6T 1Z3, Canada.
6
UVic-Genome BC Proteomics Centre, University of Victoria, BC V8Z 7X8, Canada.
7
Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA 15212-4772, USA.
8
Department of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, BC V6T1Z3, Canada. Electronic address: James.D.Johnson@ubc.ca.

Abstract

Pancreatic β cells are mostly post-mitotic, but it is unclear what locks them in this state. Perturbations including uncontrolled hyperglycemia can drive β cells into more pliable states with reduced cellular insulin levels, increased β cell proliferation, and hormone mis-expression, but it is unknown whether reduced insulin production itself plays a role. Here, we define the effects of ∼50% reduced insulin production in Ins1(-/-):Ins2(f/f):Pdx1Cre(ERT):mTmG mice prior to robust hyperglycemia. Transcriptome, proteome, and network analysis revealed alleviation of chronic endoplasmic reticulum (ER) stress, indicated by reduced Ddit3, Trib3, and Atf4 expression; reduced Xbp1 splicing; and reduced phospho-eIF2α. This state was associated with hyper-phosphorylation of Akt, which is negatively regulated by Trib3, and with cyclinD1 upregulation. Remarkably, β cell proliferation was increased 2-fold after reduced insulin production independently of hyperglycemia. Eventually, recombined cells mis-expressed glucagon in the hyperglycemic state. We conclude that the normally high rate of insulin production suppresses β cell proliferation in a cell-autonomous manner.

KEYWORDS:

ER stress; beta cells; dedifferentiation; diabetes; insulin; islets; metabolomic; proliferation; protein synthesis; proteomic; transcriptomic

PMID:
26626461
DOI:
10.1016/j.cmet.2015.10.016
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center