VMAT2 Safeguards β-Cells Against Dopamine Cytotoxicity Under High-Fat Diet–Induced Stress

Sakano, Daisuke; Uefune, Fumiya; Tokuma, Hiraku; Sonoda, Yuki; Matsuura, Kazuki; Takeda, Nobuo; Nakagata, Naomi; Kume, Kazuhiko; Shiraki, Nobuaki; Kume, Shoen

doi:10.2337/db20-0207

Cited by 13 publications

(9 citation statements)

References 55 publications

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“…Recently, Daisuke et.al. reported that ROS production directly triggers the dedifferentiation of β-cells in the islets of β-cell-specific vesicular monoamine transporter 2 knock-out mice [ 66 ]. However, it is unclear whether ROS induces β-cell dedifferentiation without an intermediate role of inflammatory cytokines.…”

Section: Potential Mechanisms Regulating β-Cell Dedifferentiationmentioning

confidence: 99%

A Brief Review of the Mechanisms of β-Cell Dedifferentiation in Type 2 Diabetes

Khin

Lee

2021

Nutrients

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Diabetes is a metabolic disease characterized by hyperglycemia. Over 90% of patients with diabetes have type 2 diabetes. Pancreatic β-cells are endocrine cells that produce and secrete insulin, an essential endocrine hormone that regulates blood glucose levels. Deficits in β-cell function and mass play key roles in the onset and progression of type 2 diabetes. Apoptosis has been considered as the main contributor of β-cell dysfunction and decrease in β-cell mass for a long time. However, recent studies suggest that β-cell failure occurs mainly due to increased β-cell dedifferentiation rather than limited β-cell proliferation or increased β-cell death. In this review, we summarize the current advances in the understanding of the pancreatic β-cell dedifferentiation process including potential mechanisms. A better understanding of β-cell dedifferentiation process will help to identify novel therapeutic targets to prevent and/or reverse β-cell loss in type 2 diabetes.

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Section: Potential Mechanisms Regulating β-Cell Dedifferentiationmentioning

confidence: 99%

A Brief Review of the Mechanisms of β-Cell Dedifferentiation in Type 2 Diabetes

Khin

Lee

2021

Nutrients

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“…Thus, PLUTO may suppress the dedifferentiation of pancreatic β-cells [ 45 , 46 ]. In pancreatic β-cell-specific vesicular monoamine transporter 2 (VMAT2) knockout mice, mature β-cell markers (Ins1, Ins2, MafA, Nkx6.1, Gck, and Pdx-1) decreased with age, and the expression of MafB, an immature β-cell or a mature α cell marker, was upregulated [ 47 ]. GLP-1 is also involved in the suppression of pancreatic β-cell dedifferentiation.…”

Section: Pancreatic β-Cell Dedifferentiation and Transdifferentiationmentioning

confidence: 99%

“…ROS causes reduction of MafA and Pdx-1 expressions, transcription factors required for the development and maintenance of pancreatic β-cells, thereby promoting the dedifferentiation of pancreatic β-cells and decreasing insulin secretion [ 13 , 14 ]. In recent years, antioxidant administration has been reported to protect pancreatic β-cells in obese type 2 diabetes model mice and pancreatic β-cell lines (HIT-T15) [ 14 , 15 ] and VMAT2, which is expressed in pancreatic β-cells, has been shown to suppress oxidative stress through modulation of dopamine levels in pancreatic β-cells, resulting in inhibition of pancreatic β-cell death and dedifferentiation [ 47 ]. In addition, FoxO1 has also gained attention as an inhibitor of pancreatic β-cell dedifferentiation.…”

Section: Pancreatic β-Cell Dedifferentiation and Transdifferentiationmentioning

confidence: 99%

The Plasticity of Pancreatic β-Cells

Honzawa

Fujimoto

2021

Metabolites

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Type 2 diabetes is caused by impaired insulin secretion and/or insulin resistance. Loss of pancreatic β-cell mass detected in human diabetic patients has been considered to be a major cause of impaired insulin secretion. Additionally, apoptosis is found in pancreatic β-cells; β-cell mass loss is induced when cell death exceeds proliferation. Recently, however, β-cell dedifferentiation to pancreatic endocrine progenitor cells and β-cell transdifferentiation to α-cell was reported in human islets, which led to a new underlying molecular mechanism. Hyperglycemia inhibits nuclear translocation and expression of forkhead box-O1 (FoxO1) and induces the expression of neurogenin-3(Ngn3), which is required for the development and maintenance of pancreatic endocrine progenitor cells. This new hypothesis (Foxology) is attracting attention because it explains molecular mechanism(s) underlying β-cell plasticity. The lineage tracing technique revealed that the contribution of dedifferentiation is higher than that of β-cell apoptosis retaining to β-cell mass loss. In addition, islet cells transdifferentiate each other, such as transdifferentiation of pancreatic β-cell to α-cell and vice versa. Islet cells can exhibit plasticity, and they may have the ability to redifferentiate into any cell type. This review describes recent findings in the dedifferentiation and transdifferentiation of β-cells. We outline novel treatment(s) for diabetes targeting islet cell plasticity.

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“…Finally, VMAT2 is expressed in insulin-secreting beta cells of the pancreas and may safeguard them against dopamine toxicity during stress induced by a high-fat diet. 9 To investigate the consequence of abnormal VMAT2 on embryonic development and adult physiology several lines of Vmat2 mutant mice have been generated. [10][11][12][13] Mice homozygous for loss-of-function alleles of Vmat2 do not grow into adulthood.…”

Section: Introductionmentioning

confidence: 99%