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VMAT2 safeguards beta-cells against dopamine cytotoxicity under high-fat diet induced stress
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posted on 2020-08-21, 16:38 authored by Ada AdminAda Admin, Daisuke Sakano, Fumiya Uefune, Hiraku Tokuma, Yuki Sonoda, Kumi Matsuura, Naoki Takeda, Naomi Nakagata, Kazuhiko Kume, Nobuaki Shiraki, Shoen KumeVesicular
monoamine transporter 2 (VMAT2) uptakes cytoplasmic monoamines into vesicles for
storage. VMAT2 plays a role in modulating insulin release by regulating
dopamine levels in the pancreas, although the exact mechanism remains elusive. We
found that VMAT2 expression in beta-cells specifically increases under high
blood glucose conditions. The islets isolated from beta-cell specific Vmat2 knock-out (βVmat2KO) mice show elevated
insulin secretion levels in response to glucose stimulation. Under prolonged high-fat diet feedings, the βVmat2KO
mice exhibit impaired
glucose and insulin tolerance and progressive beta-cell dysfunction. We
demonstrate here that VMAT2 uptakes dopamine to protect it from degradation by
monoamine oxidase, thereby safeguarding beta-cells from excess reactive oxygen
species (ROS) exposure. When under high demand for insulin secretion, the
absence of VMAT2 leads to elevated ROS in beta-cells, which accelerates beta-cell
dedifferentiation and beta-cell loss. Therefore, VMAT2 controls the amount of
dopamine in beta-cells thereby protecting pancreatic beta-cells from excessive
oxidative stress.