| Autor: |
Jason Fan, Wen Du, Ja Young Kim-Muller, Jinsook Son, Taiyi Kuo, Delfina Larrea, Christian Garcia, Takumi Kitamoto, Michael J. Kraakman, Edward Owusu-Ansah, Vincenzo Cirulli, Domenico Accili |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
Molecular Metabolism, Vol 34, Iss , Pp 97-111 (2020) |
| Druh dokumentu: |
article |
| ISSN: |
2212-8778 |
| DOI: |
10.1016/j.molmet.2019.12.008 |
| Popis: |
Objective: Diabetes is characterized by pancreatic β-cell dedifferentiation. Dedifferentiating β cells inappropriately metabolize lipids over carbohydrates and exhibit impaired mitochondrial oxidative phosphorylation. However, the mechanism linking the β-cell's response to an adverse metabolic environment with impaired mitochondrial function remains unclear. Methods: Here we report that the oxidoreductase cytochrome b5 reductase 3 (Cyb5r3) links FoxO1 signaling to β-cell stimulus/secretion coupling by regulating mitochondrial function, reactive oxygen species generation, and nicotinamide actin dysfunction (NAD)/reduced nicotinamide actin dysfunction (NADH) ratios. Results: The expression of Cyb5r3 is decreased in FoxO1-deficient β cells. Mice with β-cell-specific deletion of Cyb5r3 have impaired insulin secretion, resulting in glucose intolerance and diet-induced hyperglycemia. Cyb5r3-deficient β cells have a blunted respiratory response to glucose and display extensive mitochondrial and secretory granule abnormalities, consistent with altered differentiation. Moreover, FoxO1 is unable to maintain expression of key differentiation markers in Cyb5r3-deficient β cells, suggesting that Cyb5r3 is required for FoxO1-dependent lineage stability. Conclusions: The findings highlight a pathway linking FoxO1 to mitochondrial dysfunction that can mediate β-cell failure. Keywords: Beta cell dedifferentiation, Mitochondrial complex III failure, Type 2 diabetes, Diabetes genetics, Endocrine pancreas, Transcription factor in beta cell function, Hyperglycemia, Glucose clamp, Diabetes therapy |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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