Kuvaus
| Alkuperäiskieli | englanti |
|---|---|
| Lehti | Diabetes |
| Vuosikerta | 68 |
| Numero | 1 |
| Sivut | 66-80 |
| Sivumäärä | 15 |
| ISSN | 0012-1797 |
| DOI - pysyväislinkit | |
| Tila | Julkaistu - tammikuuta 2019 |
| OKM-julkaisutyyppi | A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu |
Tieteenalat
- 3121 Sisätaudit
Lainaa tätä
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MANF is Required for the Postnatal Expansion and Maintenance of the Pancreatic β-Cell Mass in Mice. / Danilova, Tatiana; Belevich, Ilya; Li, Huini; Palm, Erik; Jokitalo, Eija; Otonkoski, Timo; Lindahl, Maria.
julkaisussa: Diabetes, Vuosikerta 68, Nro 1, 01.2019, s. 66-80.Tutkimustuotos: Artikkelijulkaisu › Artikkeli › Tieteellinen › vertaisarvioitu
TY - JOUR
T1 - MANF is Required for the Postnatal Expansion and Maintenance of the Pancreatic β-Cell Mass in Mice
AU - Danilova, Tatiana
AU - Belevich, Ilya
AU - Li, Huini
AU - Palm, Erik
AU - Jokitalo, Eija
AU - Otonkoski, Timo
AU - Lindahl, Maria
PY - 2019/1
Y1 - 2019/1
N2 - 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.
AB - 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.
KW - ENDOPLASMIC-RETICULUM STRESS
KW - UNFOLDED PROTEIN RESPONSE
KW - NF-KAPPA-B
KW - NEUROTROPHIC FACTOR
KW - INSULIN DEMAND
KW - ER STRESS
KW - GENE
KW - PROLIFERATION
KW - INFLAMMATION
KW - DYSFUNCTION
KW - 3121 Internal medicine
U2 - 10.2337/db17-1149
DO - 10.2337/db17-1149
M3 - Article
VL - 68
SP - 66
EP - 80
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 1
ER -