Reduced insulin production relieves endoplasmic reticulum stress and induces-beta cell proliferation.
(2016) Cell Metabolism — Vol. 23, p. 179-193 (2016)
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- et. al.
- 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.
- Affiliations
University of British Columbia, Canada Dept. Cellular and Physiological Science
Citations
Szabat M., Page, M., Panzhinskiy, E., Skovso, S., Mojibian, M., Fernandez-Tajes, J., Bruin, JE., Bround, MJ., Lee, JT., Xu, EE., Taghizadeh, F., O’Dwyer, S., van de Bunt, M., Moon, KM., Sinha, S., Han, J., Fan, Y., Lynn, FC., Trucco, M., et al. (2016). Reduced insulin production relieves endoplasmic reticulum stress and induces-beta cell proliferation. Cell Metabolism, 23, 179-193. https://doi.org/10.1016/j.cmet.2015.10.016 (Original work published 2016)