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Cell Rep. 2014 Apr 24;7(2):366-75. doi: 10.1016/j.celrep.2014.03.023. Epub 2014 Apr 13.

MANF is indispensable for the proliferation and survival of pancreatic β cells.

Author information

1
Institute of Biotechnology, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland. Electronic address: maria.lindahl@helsinki.fi.
2
Institute of Biotechnology, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland.
3
Neuroscience Center, University of Helsinki, Viikinkaari 4, 00014 Helsinki, Finland.
4
Research Program for Molecular Neurology and Biomedicum Stem Cell Center, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland.
5
Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
6
Research Program for Molecular Neurology and Biomedicum Stem Cell Center, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, Haartmaninkatu 8, 00014 Helsinki, Finland.
7
Institute of Biomedicine, Anatomy, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland.

Abstract

All forms of diabetes mellitus (DM) are characterized by the loss of functional pancreatic β cell mass, leading to insufficient insulin secretion. Thus, identification of novel approaches to protect and restore β cells is essential for the development of DM therapies. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-stress-inducible protein, but its physiological role in mammals has remained obscure. We generated MANF-deficient mice that strikingly develop severe diabetes due to progressive postnatal reduction of β cell mass, caused by decreased proliferation and increased apoptosis. Additionally, we show that lack of MANF in vivo in mouse leads to chronic unfolded protein response (UPR) activation in pancreatic islets. Importantly, MANF protein enhanced β cell proliferation in vitro and overexpression of MANF in the pancreas of diabetic mice enhanced β cell regeneration. We demonstrate that MANF specifically promotes β cell proliferation and survival, thereby constituting a therapeutic candidate for β cell protection and regeneration.

PMID:
24726366
DOI:
10.1016/j.celrep.2014.03.023
[Indexed for MEDLINE]
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