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

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posted on 21.08.2020, 16:38 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.

Funding

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.

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