Trapα deficiency impairs the early events of insulin biosynthesis and glucose homeostasis
Xin Li, … , Peter Arvan, Ming Liu
Xin Li, … , Peter Arvan, Ming Liu
Published May 20, 2025
Citation Information: J Clin Invest. 2025;135(14):e179845. https://doi.org/10.1172/JCI179845.
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Research Article Endocrinology Metabolism

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

Abstract

Defects in the early events of insulin biosynthesis, including inefficient preproinsulin (PPI) translocation across the membrane of the ER and proinsulin (PI) misfolding in the ER, can cause diabetes. Cellular machineries involved in these events remain poorly defined. Genes encoding translocon-associated protein α (TRAPα) show linkage to glycemic control in humans, though their pathophysiological role remains unknown. Here, we found that β cell–specific TRAPα-KO mice fed a chow diet or a high-fat diet (HFD) had decreased levels of circulating insulin, with age- and diet-related glucose intolerance. Multiple independent approaches revealed that TRAPα-KO 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 the HFD 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.

Authors

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

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Figure 3

TRAPα-βKO impairs PPI translocation and decreases INS production but does not affect GSIS or islet size and cell composition.

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TRAPα-βKO impairs PPI translocation and decreases INS production but doe...
(A) mRNA levels of INS genes, including Ins1 and Ins2 from 8- to 12-week-old male control (Con) and TRAPα-βKO mice islets (n = 10). (B) Immunohistochemistry staining was performed using anti-INS in pancreatic sections of 8- to 12-week-old male Con and TRAPα-βKO mice. (C) INS content from 8- to 12-week-old male Con and TRAPα-βKO mouse islets was measured using INS ELISA normalized with either islet total protein (left) or islet DNA content (right) to minimize the effects of interislet heterogeneity. The INS content from Con mouse islets was set as 100% (n = 5–10). (D) GSIS was performed using islets isolated from 8- to 12-week-old male Con and TRAPα-βKO mice (n = 6). Secreted INS from male control islets treated with 2.8 mM glucose was set as 100% (n = 6 in each group). (E) H&E staining was performed of pancreases of 8- to 12-week-old male Con and TRAPα-βKO mice. (F) The quantification of the islets size of E (n = 10 in each group). (G) Pancreatic sections of 8- to 12-week-old male Con and TRAPα-βKO mice were immunostained with anti-INS (red), anti-GCG (green, left panel), or anti-somatostatin (green, right panel) as indicated. (H) Islets isolated from 8- to 12-week-old male Con and TRAPα-βKO mice were treated with or without MG132 (10 μM) for 2 hours before being analyzed by Western blotting using anti-INS or anti-TRAPα, as indicated. (I) Quantification of TRAPα protein levels in islets treated with or without MG132 in H (n = 10). (J) Quantification of PI and INS in TRAPα-βKO islets with and without MG132 treatment shown in H (n = 6–16). Values are reported as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, unpaired Student’s t test and 2-way ANOVA.