MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice

Global lack of mesencephalic astrocyte-derived neurotropic factor (MANF) leads to progressive postnatal loss of b-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 beta-cell mass and for adult b-cell maintenance in mice. Detailed analysis of Pdx-1Cre(+/-) :: Manf(fl/fl) mice revealed mosaic MANF expression in postnatal pancreata and a significant correlation between the number of MANF-positive beta-cells and beta-cell mass in individual mice. In vitro, recombinant MANF induced beta-cell proliferation in islets from aged mice and protected from hyperglycemia-induced endoplasmic reticulum (ER) stress. Consequently, excision of MANF from beta-cells of adult MIP-1Cre(ERT)::Manf(fl/fl) mice resulted in reduced b-cell mass and diabetes caused largely by beta-cell ER stress and apoptosis, possibly accompanied by beta-cell dedifferentiation and reduced rates of beta-cell proliferation. Thus, MANF expression in adult mouse beta-cells is needed for their maintenance in vivo. We also revealed a mechanistic link between ER stress and inflammatory signaling pathways leading to beta-cell death in the absence of MANF. Hence, MANF might be a potential target for regenerative therapy in diabetes.