Lack or dysfunction of insulin producing beta 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 beta 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 beta cells suggesting that loss of Mao contributes to beta cell dysfunction. MaoB expression was also reduced in beta cells of MafA-deficient mice, a mouse model for beta 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 beta cells. These findings demonstrate that regulation of monoamine levels by Mao activity in beta cells is pivotal for physiological insulin secretion and that loss of MaoB expression may contribute to the beta cell dysfunction in type 2 diabetes. (C) 2015 Elsevier Inc. All rights reserved.