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VMAT2 safeguards beta-cells against dopamine cytotoxicity under high-fat diet induced stress

posted on 21.08.2020 by Ada Admin, Daisuke Sakano, Fumiya Uefune, Hiraku Tokuma, Yuki Sonoda, Kumi Matsuura, Naoki Takeda, Naomi Nakagata, Kazuhiko Kume, Nobuaki Shiraki, Shoen Kume
Vesicular 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.


This work was supported by a grant from the Project for Realization of Regenerative Medicine from Japan Agency for Medical Research and Development (AMED) under Grant Number (17bm0704004h0101). Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (#18H02861 to SK and #17K09455 to DS). This work was also supported in part by the Takeda Science Foundation, Japan Insulin Dependent Diabetes Mellitus (IDDM) Network.