PT  - JOURNAL ARTICLE
AU  - Danilova, Tatiana
AU  - Belevich, Ilya
AU  - Li, Huini
AU  - Palm, Erik
AU  - Jokitalo, Eija
AU  - Otonkoski, Timo
AU  - Lindahl, Maria
TI  - MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice
AID  - 10.2337/db17-1149
DP  - 2019 Jan 01
TA  - Diabetes
PG  - 66--80
VI  - 68
IP  - 1
4099  - http://diabetes.diabetesjournals.org/content/68/1/66.short
4100  - http://diabetes.diabetesjournals.org/content/68/1/66.full
SO  - Diabetes2019 Jan 01; 68
AB  - Global lack of mesencephalic astrocyte-derived neurotropic factor (MANF) leads to progressive postnatal loss of β-cell mass and insulin-dependent diabetes in mice. Similar to Manf−/− mice, embryonic ablation of MANF specifically from the pancreas results in diabetes. In this study, we assessed the importance of MANF for the postnatal expansion of pancreatic β-cell mass and for adult β-cell maintenance in mice. Detailed analysis of Pdx-1Cre+/−::Manffl/fl mice revealed mosaic MANF expression in postnatal pancreata and a significant correlation between the number of MANF-positive β-cells and β-cell mass in individual mice. In vitro, recombinant MANF induced β-cell proliferation in islets from aged mice and protected from hyperglycemia-induced endoplasmic reticulum (ER) stress. Consequently, excision of MANF from β-cells of adult MIP-1CreERT::Manffl/fl mice resulted in reduced β-cell mass and diabetes caused largely by β-cell ER stress and apoptosis, possibly accompanied by β-cell dedifferentiation and reduced rates of β-cell proliferation. Thus, MANF expression in adult mouse β-cells is needed for their maintenance in vivo. We also revealed a mechanistic link between ER stress and inflammatory signaling pathways leading to β-cell death in the absence of MANF. Hence, MANF might be a potential target for regenerative therapy in diabetes.