title: Islet-specific monoamine oxidase A and B expression depends on MafA transcriptional activity and is compromised in type 2 diabetes.
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.
authors.affiliation: Stem Cell Center, Lund University, Klinikgatan 26, Lund 22184, Sweden.
authors.forename: Elvira
authors.initials: E
authors.lastname: Ganic
authors.affiliation: Stem Cell Center, Lund University, Klinikgatan 26, Lund 22184, Sweden.
authors.forename: Jenny K
authors.initials: JK
authors.lastname: Johansson
authors.affiliation: Stem Cell Center, Lund University, Klinikgatan 26, Lund 22184, Sweden.
authors.forename: Hedvig
authors.initials: H
authors.lastname: Bennet
authors.affiliation: Stem Cell Center, Lund University, Klinikgatan 26, Lund 22184, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Fex
authors.affiliation: Stem Cell Center, Lund University, Klinikgatan 26, Lund 22184, Sweden. Electronic address: Isabella.Artner@med.lu.se.
authors.forename: Isabella
authors.initials: I
authors.lastname: Artner
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D051473:Maf Transcription Factors, Large / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008995:Monoamine Oxidase / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D007328:Insulin; C485159:MAFA protein, human; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D008995:Monoamine Oxidase
keywords: Insulin secretion; MafA; MaoA; MaoB; Monoamine oxidase; Transcription; Type 2 diabetes; β cell