Pancreatic β cell interleukin-22 receptor subunit alpha 1 deficiency impairs β cell function in type 2 diabetes via cytochrome b5 reductase 3

Fan Yu; Shuting Xie; Tongyu Wang; Yeping Huang; Hong Zhang; Danfeng Peng; Yifan Feng; Yumei Yang; Zheyu Zhang; Yunxia Zhu; Zhuoxian Meng; Rong Zhang; Xiaomu Li; Hao Yin; Jie Xu; Cheng Hu

Cell Reports (Dec 2024)

Pancreatic β cell interleukin-22 receptor subunit alpha 1 deficiency impairs β cell function in type 2 diabetes via cytochrome b5 reductase 3

Fan Yu,
Shuting Xie,
Tongyu Wang,
Yeping Huang,
Hong Zhang,
Danfeng Peng,
Yifan Feng,
Yumei Yang,
Zheyu Zhang,
Yunxia Zhu,
Zhuoxian Meng,
Rong Zhang,
Xiaomu Li,
Hao Yin,
Jie Xu,
Cheng Hu

Affiliations

Fan Yu: Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
Shuting Xie: Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
Tongyu Wang: Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
Yeping Huang: Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
Hong Zhang: Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
Danfeng Peng: Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
Yifan Feng: Organ Transplant Center, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China
Yumei Yang: Department of Endocrinology and Metabolism, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
Zheyu Zhang: Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
Yunxia Zhu: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, China
Zhuoxian Meng: Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
Rong Zhang: Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
Xiaomu Li: Department of Endocrinology and Metabolism, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China; Corresponding author
Hao Yin: Organ Transplant Center, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China; Corresponding author
Jie Xu: Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Corresponding author
Cheng Hu: Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai 201499, China; Corresponding author

Journal volume & issue: Vol. 43, no. 12
p. 115057

Abstract

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Summary: Impaired β cell function is a hallmark of type 2 diabetes (T2D), but the underlying cellular signaling machineries that regulate β cell function remain unknown. Here, we identify that the interleukin-22 receptor subunit alpha 1 (IL-22RA1), known as a co-receptor for IL-22, is downregulated in human and mouse T2D β cells. Mice with β cell Il22ra1 knockout (Il22ra1βKO) exhibit defective insulin secretion and impaired glucose tolerance after being fed a high-fat diet (HFD) or an HFD/low dose of streptozotocin (STZ). Mechanistically, β cell IL-22RA1 deficiency inhibits cytochrome b5 reductase 3 (CYB5R3) expression via the IL-22RA1/signal transducer and activator of the transcription 3 (STAT3)/c-Jun axis, thereby impairing mitochondrial function and reducing β cell identity. Overexpression of CYB5R3 reinstates mitochondrial function, β cell identity, and insulin secretion in Il22ra1βKO mice. Moreover, the pharmacological activation of CYB5R3 with tetrahydroindenoindole restores insulin secretion in Il22ra1βKO mice, IL-22RA1-knockdown human islets, and Min6 cells. In conclusion, these findings suggest an important role of IL-22RA1 in preserving β cell function in T2D, which offers a potential therapeutic target for treating diabetes.

CP: Metabolism

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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