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ResearchIn-Press PreviewEndocrinologyMetabolism
Open Access | 10.1172/JCI179845
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:
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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.
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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:
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Published May 20, 2025 - More info
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.