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- Ganic, Elvira, et al.
(author)
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Islet-specific monoamine oxidase A and B expression depends on MafA transcriptional activity and is compromised in type 2 diabetes.
- 2015
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In: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 468:4, s. 629-635
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Journal article (peer-reviewed)abstract
- Lack or dysfunction of insulin producing β cells results in the development of type 1 and type 2 diabetes mellitus, respectively. Insulin secretion is controlled by metabolic stimuli (glucose, fatty acids), but also by monoamine neurotransmitters, like dopamine, serotonin, and norepinephrine. Intracellular monoamine levels are controlled by monoamine oxidases (Mao) A and B. Here we show that MaoA and MaoB are expressed in mouse islet β cells and that inhibition of Mao activity reduces insulin secretion in response to metabolic stimuli. Moreover, analysis of MaoA and MaoB protein expression in mouse and human type 2 diabetic islets shows a significant reduction of MaoB in type 2 diabetic β cells suggesting that loss of Mao contributes to β cell dysfunction. MaoB expression was also reduced in β cells of MafA-deficient mice, a mouse model for β cell dysfunction, and biochemical studies showed that MafA directly binds to and activates MaoA and MaoB transcriptional control sequences. Taken together, our results show that MaoA and MaoB expression in pancreatic islets is required for physiological insulin secretion and lost in type 2 diabetic mouse and human β cells. These findings demonstrate that regulation of monoamine levels by Mao activity in β cells is pivotal for physiological insulin secretion and that loss of MaoB expression may contribute to the β cell dysfunction in type 2 diabetes.
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| 2. |
- Ganic, Elvira
(author)
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Maf transcription factors in beta cell function
- 2015
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Doctoral thesis (other academic/artistic)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.
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