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

Show full item record



Permalink

http://hdl.handle.net/10138/297076

Citation

Danilova , T , Belevich , I , Li , H , Palm , E , Jokitalo , E , Otonkoski , T & Lindahl , M 2019 , ' MANF is Required for the Postnatal Expansion and Maintenance of the Pancreatic β-Cell Mass in Mice ' , Diabetes , vol. 68 , no. 1 , pp. 66-80 . https://doi.org/10.2337/db17-1149 , https://doi.org/10.2337/db17-1149

Title: MANF is Required for the Postnatal Expansion and Maintenance of the Pancreatic β-Cell Mass in Mice
Author: Danilova, Tatiana; Belevich, Ilya; Li, Huini; Palm, Erik; Jokitalo, Eija; Otonkoski, Timo; Lindahl, Maria
Contributor: University of Helsinki, Institute of Biotechnology
University of Helsinki, Electron Microscopy
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Centre of Excellence in Stem Cell Metabolism
University of Helsinki, Institute of Biotechnology
Date: 2019-01
Language: eng
Number of pages: 15
Belongs to series: Diabetes
ISSN: 0012-1797
URI: http://hdl.handle.net/10138/297076
Abstract: Global lack of mesencephalic astrocyte-derived neurotropic factor (MANF) leads to progressive postnatal loss of β-cells mass and insulin-dependent diabetes in mice. Similarly 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 the pancreatic β-cell mass and for adult β-cell maintenance in mice. Detailed analysis of Pdx-1Cre +/- ::Manf fl/fl mice revealed mosaic MANF expression in postnatal pancreases and 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-1Cre ERT ::Manf fl/fl mice resulted in reduced β-cell mass and diabetes caused largely by β-cell ER stress and apoptosis, possibly accompanied by β-cell de-differentiation 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.
Subject: ENDOPLASMIC-RETICULUM STRESS
UNFOLDED PROTEIN RESPONSE
NF-KAPPA-B
NEUROTROPHIC FACTOR
INSULIN DEMAND
ER STRESS
GENE
PROLIFERATION
INFLAMMATION
DYSFUNCTION
3121 General medicine, internal medicine and other clinical medicine
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
Danilova_et_al_2018_Diabetes.pdf 10.63Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record