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Elife. 2018 Nov 9;7. pii: e38519. doi: 10.7554/eLife.38519.

Insulin mutations impair beta-cell development in a patient-derived iPSC model of neonatal diabetes.

Author information

Research Programs Unit, Molecular Neurology and Biomedicum Stem Cell Centre, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Department of Biosciences, University of Helsinki, Helsinki, Finland.
Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Clinical Genetics, HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.


Insulin gene mutations are a leading cause of neonatal diabetes. They can lead to proinsulin misfolding and its retention in endoplasmic reticulum (ER). This results in increased ER-stress suggested to trigger beta-cell apoptosis. In humans, the mechanisms underlying beta-cell failure remain unclear. Here we show that misfolded proinsulin impairs developing beta-cell proliferation without increasing apoptosis. We generated induced pluripotent stem cells (iPSCs) from people carrying insulin (INS) mutations, engineered isogenic CRISPR-Cas9 mutation-corrected lines and differentiated them to beta-like cells. Single-cell RNA-sequencing analysis showed increased ER-stress and reduced proliferation in INS-mutant beta-like cells compared with corrected controls. Upon transplantation into mice, INS-mutant grafts presented reduced insulin secretion and aggravated ER-stress. Cell size, mTORC1 signaling, and respiratory chain subunits expression were all reduced in INS-mutant beta-like cells, yet apoptosis was not increased at any stage. Our results demonstrate that neonatal diabetes-associated INS-mutations lead to defective beta-cell mass expansion, contributing to diabetes development.


CRISPR-Cas9; Insulin gene mutations; beta-cell development; endoplasmic reticulum stress; human; induced pluripotent stem cells; mTORC1; regenerative medicine; stem cells

Conflict of interest statement

DB, JS, DB, MS, PL, EG, SE, JU, HG, HH, JP, KW, TO No competing interests declared

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