Maf transcription factors in beta cell function

Abstract

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.

Abstract (Swedish)

Popular Abstract in English

According to the International Diabetes Federation (IDF), 415 million people suffer

from diabetes worldwide. Diabetes occurs when the pancreatic beta cells are no longer

able to produce or properly use insulin. Insulin regulates blood glucose levels by

enabling glucose uptake into cells, providing the body with energy. Elevated glucose

levels cause damages to highly vascularized organs such as heart, kidney and eyes.

Other complications include nerve damage and metabolic difficulties. There is

currently no cure for diabetes and diabetic individuals depend on regular insulin

injections to control blood glucose levels. In order to treat and finally cure diabetes, it

is important to understand the underlying causes of the disease and broaden our

understanding of the complex function of the insulin producing beta cells. Our

research focuses on the development and function these cells. In addition to glucose,

insulin release can be controlled through communication between beta cells and the

central nervous system (CNS). This communication is critical for both acute and long

term blood glucose control. However, very little is known about how beta cells

communicate with the nervous system. Combining genetic and physiological studies

in cells, mice and to some extent human subjects, I have investigated how different

factors affect glucose metabolism and what happens when these factors are impaired

or removed. My results have shown that a specific protein, MafA, is crucial for the

CNS-beta cell interaction. MafA can regulate this process by directly controlling

distinct genes. Genes regulated by MafA are essential for neurotransmitter-mediated

regulation of blood glucose levels. These genes include nicotinic acetylcholine

receptors, proteins essential for neurotransmitter signaling, and monoamine oxidases

(A and B), proteins that metabolize specific neurotransmitters and thereby maintain a

balance of the signals regulating blood glucose levels. Additionally, my results show

that MafA controls the expression of genes involved in different aspects of beta cell

function, ranging from the level of neurotransmitters and their receptors to the

expression, release and storage of insulin. Furthermore, our studies on adult beta cells

identified a novel protein important for blood glucose control, Mitf. Deletion of the

Mitf gene in mice resulted in increased insulin release and faster blood glucose

clearance. Researchers have found links between long term increases in blood glucose

levels and depression, a condition originating in the brain. Understanding how the

brain and the pancreas communicate in order to influence the production and release

of insulin and thus maintain normal glucose control could open up new possibilities

in improving the function of beta cells and treating diabetes.

• author: Ganic, Elvira
• supervisor: Isabella Artner; Henrik Semb; Edgar Pera
• opponent: Professor Serup, Palle, Developmental Biology, DanStem, Copenhagen University
• organization: Stem Cell Center; EXODIAB: Excellence of Diabetes Research in Sweden; StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
• publishing date: 2015
• type: Thesis
• publication status: published
• subject: Cell and Molecular Biology
• keywords: Beta cell, MafA, type 2 diabetes, insulin secretion, transcription, monoamine oxidase, MaoA, MaoB, nicotinic receptor subunits, nAChRs
• in: Lund University Faculty of Medicine Doctoral Dissertation Series
• volume: 2016:10
• pages: 134 pages
• defense location: Segerfalkssalen, Wallenberg Neurocentrum, BMC A10, Lund University
• defense date: 2016-01-25 09:30:00
• ISSN: 1652-8220
• ISBN: 978-91-7619-235-1
• language: English
• LU publication?: yes
• id: 26f97e2b-d22e-45f1-928f-798f1b155089 (old id 8518961)
• date added to LUP: 2016-04-01 14:31:38
• date last changed: 2020-09-28 10:50:45