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 4

TRAPα is important for β cell ER function, and its deficiency causes PI misfolding and ER stress.

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TRAPα is important for β cell ER function, and its deficiency causes PI ...
(A) Transcriptome analyses using islets isolated from 8-week-old control (Con) and TRAPα-βKO male mice (n = 3 in each group). (B) Gene Ontology analyses of RNA-Seq data showed the pathways associated with ER genes that were significantly upregulated in islets of 8-week-old TRAPα-βKO male mice (as in A). (C) mRNA levels of indicated genes were measured by real-time quantitative PCR (qRT-PCR) in islets from 8- to 12-week-old Con and TRAPα-βKO male mice islets (n = 3-6). (D) The protein expression of TRAPα, BiP, and p-eIF2α from 12-week-old Con and TRAPα-βKO male mice was examined by Western blots. (E) Quantification of TRAPα, BiP, and p-eIF2α protein levels in D (n = 3 in each group). (F) The oxidative folding of PI in islets from 8- to 12-week-old Con and TRAPα-βKO male mice was analyzed by Western blots under both nonreducing and reducing conditions. (G) The amounts of PI dimers plus trimers under nonreducing conditions compared with total PI under reducing conditions were quantified and calculated. The ratios of dimers plus trimers to total PI in control islets were set to 100% (n = 4). (H) INS1 control cells (WT) and INS1 with both Ins1 and Ins2 gene-deleted cells (Mut) were transfected with either TRAPα siRNA or scrambled siRNA. At 72 hours after transfection, the cells were lysed, and ER stress responses were analyzed by Western blots, as indicated. (I) Quantification of H from 5–8 independent experiments. (J) Isolated islets were incubated in RPMI 1640 without FBS for 6 hours; the secretion of PI and CPE was analyzed by Western blots. (K) PI and CPE in the islets and media were quantified from J in 3 independent experiments. The secretion efficiency of PI and CPE was calculated, and secretion efficiency of PI and CPE in control islets was set to 100%. Values are reported as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, unpaired Student’s t test and 2-way ANOVA.