Maf transcription factors in beta cell function
Author
Summary, in English
Diabetes mellitus is metabolic disorder caused by a defect or lack of beta cell-produced insulin that
controls blood glucose homeostasis. In addition to glucose, insulin secretion is regulated by the
autonomic nervous system (ANS); the neurotransmitter acetylcholine as well as monoamines, such
as dopamine, serotonin, melatonin and norepinephrine. Using a MafA mutant mouse model, we
show that MafA is essential for ANS-mediated insulin secretion. We show that the monoamine
oxidase genes (MaoA, MaoB) and nicotinic receptor genes (ChrnB2, ChrnB4) are expressed in the
islets and that MafA directly activates their transcription. These genes comprise integral parts of the
neurotransmitter signaling pathways. Chrns encode subunits forming the nicotinic acetylcholine
receptors, while Maos metabolize monoamines and thereby control the balance of monoamine
levels that modulate insulin secretion. We show that acetylcholine-mediated insulin secretion is
dependent on nicotinic and muscarinic acetylcholine receptor activity. We also show that nicotinic
receptor expression is positively correlated with insulin secretion and glycemic control in human
donor islets. Moreover, single nucleotide polymorphisms (SNPs) in the MAFA binding regions of the
nicotinic receptor gene CHRNB4 are associated with type II diabetes in human subjects. Our data
show that the activity of the MafA transcription factor is crucial for the establishment of beta cell
sensitivity to monoamine signaling. We also identify nicotinic signaling as a novel regulator of insulin
secretion that is associated with type II diabetes.
Furthermore, we identify the Microphthalmia-associated transcription factor (Mitf) as a novel
transcriptional repressor in adult beta cells. Mitf deletion in mice leads to an enhanced insulin
secretory response and the expression of genes central for regulation of blood glucose levels,
insulin and Glut2, and beta cell development and function, Pax4 and Pax6, is significantly higher in
Mitf mutant mice than in their wild type littermates which indicates that Mitf is important for beta cell
function.
controls blood glucose homeostasis. In addition to glucose, insulin secretion is regulated by the
autonomic nervous system (ANS); the neurotransmitter acetylcholine as well as monoamines, such
as dopamine, serotonin, melatonin and norepinephrine. Using a MafA mutant mouse model, we
show that MafA is essential for ANS-mediated insulin secretion. We show that the monoamine
oxidase genes (MaoA, MaoB) and nicotinic receptor genes (ChrnB2, ChrnB4) are expressed in the
islets and that MafA directly activates their transcription. These genes comprise integral parts of the
neurotransmitter signaling pathways. Chrns encode subunits forming the nicotinic acetylcholine
receptors, while Maos metabolize monoamines and thereby control the balance of monoamine
levels that modulate insulin secretion. We show that acetylcholine-mediated insulin secretion is
dependent on nicotinic and muscarinic acetylcholine receptor activity. We also show that nicotinic
receptor expression is positively correlated with insulin secretion and glycemic control in human
donor islets. Moreover, single nucleotide polymorphisms (SNPs) in the MAFA binding regions of the
nicotinic receptor gene CHRNB4 are associated with type II diabetes in human subjects. Our data
show that the activity of the MafA transcription factor is crucial for the establishment of beta cell
sensitivity to monoamine signaling. We also identify nicotinic signaling as a novel regulator of insulin
secretion that is associated with type II diabetes.
Furthermore, we identify the Microphthalmia-associated transcription factor (Mitf) as a novel
transcriptional repressor in adult beta cells. Mitf deletion in mice leads to an enhanced insulin
secretory response and the expression of genes central for regulation of blood glucose levels,
insulin and Glut2, and beta cell development and function, Pax4 and Pax6, is significantly higher in
Mitf mutant mice than in their wild type littermates which indicates that Mitf is important for beta cell
function.
Department/s
Publishing year
2015
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2016:10
Full text
- Available as PDF - 10 MB
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Document type
Dissertation
Publisher
Stem Cell Center, Lund University
Topic
- Cell and Molecular Biology
Keywords
- Beta cell
- MafA
- type 2 diabetes
- insulin secretion
- transcription
- monoamine oxidase
- MaoA
- MaoB
- nicotinic receptor subunits
- nAChRs
Status
Published
Supervisor
- Isabella Artner
- Henrik Semb
- Edgar Pera
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-7619-235-1
Defence date
25 January 2016
Defence time
09:30
Defence place
Segerfalkssalen, Wallenberg Neurocentrum, BMC A10, Lund University
Opponent
- Palle Serup (Professor)