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.