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ResearchIn-Press PreviewEndocrinologyMetabolism Open Access | 10.1172/JCI179845

Trapα deficiency impairs the early events of insulin biosynthesis and glucose homeostasis

Xin Li,1 Jingxin Hu,1 Yumeng Huang,1 Hai Zhang,2 Ning Xu,1 Yang Liu,1 Xuan Liu,1 Yuanyuan Ye,1 Xinxin Zhang,1 Xiaoxi Xu,1 Yuxin Fan,1 Ziyue Zhang,1 Weiping J. Zhang,2 Shusen Wang,3 Wenli Feng,1 Peter Arvan,4 and Ming Liu1

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Li, X. in: PubMed | Google Scholar

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Hu, J. in: PubMed | Google Scholar

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Huang, Y. in: PubMed | Google Scholar

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Zhang, H. in: PubMed | Google Scholar

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Xu, N. in: PubMed | Google Scholar

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Liu, Y. in: PubMed | Google Scholar

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Liu, X. in: PubMed | Google Scholar

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Ye, Y. in: PubMed | Google Scholar

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Zhang, X. in: PubMed | Google Scholar

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Xu, X. in: PubMed | Google Scholar

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Fan, Y. in: PubMed | Google Scholar

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Zhang, Z. in: PubMed | Google Scholar

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Zhang, W. in: PubMed | Google Scholar |

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Wang, S. in: PubMed | Google Scholar

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Feng, W. in: PubMed | Google Scholar

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Arvan, P. in: PubMed | Google Scholar |

1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

2National Key Laboratory of Immunity and Inflammation, Department of Pathoph, Naval Medical University, Shanghai, China

3Human Islet Resource Center, Tianjin First Central Hospital, Tianjin, China

4Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Liu, M. in: PubMed | Google Scholar |

Published May 20, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI179845.
Copyright © 2025, Li et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 20, 2025 - Version history
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Abstract

Defects in the early events of insulin biosynthesis, including inefficient preproinsulin (PPI) translocation across the membrane of the endoplasmic reticulum (ER) and proinsulin (PI) misfolding in the ER, can cause diabetes. Cellular machineries involved in these events remain poorly defined. Gene encoding TRanslocon-Associated Protein alpha (TRAPα) shows linkage to glycemic control in humans, although their pathophysiological role remains unknown. Here we found that β-cell specific TRAPα knockout (TRAPα-βKO) mice fed with chow diet or high fat diet (HFD) exhibit decreased circulating insulin, with age- and diet-related glucose intolerance. Multiple independent approaches revealed that TRAPα-βKO not only causes inefficient PPI translocation, but also leads to PI misfolding and ER stress, selectively limiting PI ER export and β-cell compensatory potential. Importantly, decreased TRAPα expression was evident in islets of wild-type mice fed with high fat diet and in patients with type 2 diabetes (T2D). Furthermore, TRAPα expression was positively correlated with insulin content in human islet β cells, and decreased TRAPα was associated with PI maturation defects in T2D islets. Together, these data demonstrate that TRAPα deficiency in pancreatic β-cells impairs PPI translocation, PI folding, insulin production, and glucose homeostasis, contributing to its genetic linkage to T2D.

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