Sammanfattning

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.
Originalspråkengelska
TidskriftDiabetes
Volym68
Utgåva1
Sidor (från-till)66-80
Antal sidor15
ISSN0012-1797
DOI
StatusPublicerad - jan 2019
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 3121 Inre medicin

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title = "MANF is Required for the Postnatal Expansion and Maintenance of the Pancreatic β-Cell Mass in Mice",
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.",
keywords = "ENDOPLASMIC-RETICULUM STRESS, UNFOLDED PROTEIN RESPONSE, NF-KAPPA-B, NEUROTROPHIC FACTOR, INSULIN DEMAND, ER STRESS, GENE, PROLIFERATION, INFLAMMATION, DYSFUNCTION, 3121 Internal medicine",
author = "Tatiana Danilova and Ilya Belevich and Huini Li and Erik Palm and Eija Jokitalo and Timo Otonkoski and Maria Lindahl",
year = "2019",
month = "1",
doi = "10.2337/db17-1149",
language = "English",
volume = "68",
pages = "66--80",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association",
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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 -