MANF is indispensable for the proliferation and survival of pancreatic beta-cells

Research output: Contribution to journalArticleScientificpeer-review

Abstract

All forms of diabetes mellitus (DM) are characterized by the loss of functional pancreatic β cell mass, leading to insufficient insulin secretion. Thus, identification of novel approaches to protect and restore β cells is essential for the development of DM therapies. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-stress-inducible protein, but its physiological role in mammals has remained obscure. We generated MANF-deficient mice that strikingly develop severe diabetes due to progressive postnatal reduction of β cell mass, caused by decreased proliferation and increased apoptosis. Additionally, we show that lack of MANF in vivo in mouse leads to chronic unfolded protein response (UPR) activation in pancreatic islets. Importantly, MANF protein enhanced β cell proliferation in vitro and overexpression of MANF in the pancreas of diabetic mice enhanced β cell regeneration. We demonstrate that MANF specifically promotes β cell proliferation and survival, thereby constituting a therapeutic candidate for β cell protection and regeneration.
Original languageEnglish
JournalCell Reports
Volume7
Issue number2
Pages (from-to)366-375
Number of pages10
ISSN2211-1247
DOIs
Publication statusPublished - Apr 2014
MoE publication typeA1 Journal article-refereed

Fields of Science

  • ENDOPLASMIC-RETICULUM STRESS
  • UNFOLDED PROTEIN RESPONSE
  • NEUROTROPHIC FACTOR
  • DOPAMINERGIC-NEURONS
  • GENE-EXPRESSION
  • ER STRESS
  • MECHANISM
  • APOPTOSIS
  • BRAIN
  • ARMET
  • 3111 Biomedicine

Cite this

@article{263e526bd4c04169a0db9845f7ce061a,
title = "MANF is indispensable for the proliferation and survival of pancreatic beta-cells",
abstract = "All forms of diabetes mellitus (DM) are characterized by the loss of functional pancreatic β cell mass, leading to insufficient insulin secretion. Thus, identification of novel approaches to protect and restore β cells is essential for the development of DM therapies. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-stress-inducible protein, but its physiological role in mammals has remained obscure. We generated MANF-deficient mice that strikingly develop severe diabetes due to progressive postnatal reduction of β cell mass, caused by decreased proliferation and increased apoptosis. Additionally, we show that lack of MANF in vivo in mouse leads to chronic unfolded protein response (UPR) activation in pancreatic islets. Importantly, MANF protein enhanced β cell proliferation in vitro and overexpression of MANF in the pancreas of diabetic mice enhanced β cell regeneration. We demonstrate that MANF specifically promotes β cell proliferation and survival, thereby constituting a therapeutic candidate for β cell protection and regeneration.",
keywords = "ENDOPLASMIC-RETICULUM STRESS, UNFOLDED PROTEIN RESPONSE, NEUROTROPHIC FACTOR, DOPAMINERGIC-NEURONS, GENE-EXPRESSION, ER STRESS, MECHANISM, APOPTOSIS, BRAIN, ARMET, 3111 Biomedicine",
author = "Maria Lindahl and Tatiana Danilova and Erik Palm and Paivi Lindholm and Vootele Voikar and Elina Hakonen and Jarkko Ustinov and Jaan-Olle Andressoo and Harvey, {Brandon K.} and Timo Otonkoski and Jari Rossi and Mart Saarma",
year = "2014",
month = "4",
doi = "10.1016/j.celrep.2014.03.023",
language = "English",
volume = "7",
pages = "366--375",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "2",

}

TY - JOUR

T1 - MANF is indispensable for the proliferation and survival of pancreatic beta-cells

AU - Lindahl, Maria

AU - Danilova, Tatiana

AU - Palm, Erik

AU - Lindholm, Paivi

AU - Voikar, Vootele

AU - Hakonen, Elina

AU - Ustinov, Jarkko

AU - Andressoo, Jaan-Olle

AU - Harvey, Brandon K.

AU - Otonkoski, Timo

AU - Rossi, Jari

AU - Saarma, Mart

PY - 2014/4

Y1 - 2014/4

N2 - All forms of diabetes mellitus (DM) are characterized by the loss of functional pancreatic β cell mass, leading to insufficient insulin secretion. Thus, identification of novel approaches to protect and restore β cells is essential for the development of DM therapies. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-stress-inducible protein, but its physiological role in mammals has remained obscure. We generated MANF-deficient mice that strikingly develop severe diabetes due to progressive postnatal reduction of β cell mass, caused by decreased proliferation and increased apoptosis. Additionally, we show that lack of MANF in vivo in mouse leads to chronic unfolded protein response (UPR) activation in pancreatic islets. Importantly, MANF protein enhanced β cell proliferation in vitro and overexpression of MANF in the pancreas of diabetic mice enhanced β cell regeneration. We demonstrate that MANF specifically promotes β cell proliferation and survival, thereby constituting a therapeutic candidate for β cell protection and regeneration.

AB - All forms of diabetes mellitus (DM) are characterized by the loss of functional pancreatic β cell mass, leading to insufficient insulin secretion. Thus, identification of novel approaches to protect and restore β cells is essential for the development of DM therapies. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-stress-inducible protein, but its physiological role in mammals has remained obscure. We generated MANF-deficient mice that strikingly develop severe diabetes due to progressive postnatal reduction of β cell mass, caused by decreased proliferation and increased apoptosis. Additionally, we show that lack of MANF in vivo in mouse leads to chronic unfolded protein response (UPR) activation in pancreatic islets. Importantly, MANF protein enhanced β cell proliferation in vitro and overexpression of MANF in the pancreas of diabetic mice enhanced β cell regeneration. We demonstrate that MANF specifically promotes β cell proliferation and survival, thereby constituting a therapeutic candidate for β cell protection and regeneration.

KW - ENDOPLASMIC-RETICULUM STRESS

KW - UNFOLDED PROTEIN RESPONSE

KW - NEUROTROPHIC FACTOR

KW - DOPAMINERGIC-NEURONS

KW - GENE-EXPRESSION

KW - ER STRESS

KW - MECHANISM

KW - APOPTOSIS

KW - BRAIN

KW - ARMET

KW - 3111 Biomedicine

U2 - 10.1016/j.celrep.2014.03.023

DO - 10.1016/j.celrep.2014.03.023

M3 - Article

VL - 7

SP - 366

EP - 375

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 2

ER -