Maf transcription factors in beta cell function

• 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.

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

Beta cell

MafA

type 2 diabetes

insulin secretion

transcription

monoamine oxidase

MaoA

MaoB

nicotinic receptor subunits

nAChRs

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