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Circulating protein disulfide isomerase family member 4 is associated with type 2 diabetes mellitus, insulin sensitivity, and obesity

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Abstract

Aims

Endoplasmic reticulum (ER) stress is associated with obesity and type 2 diabetes mellitus (T2DM) and increasing evidence demonstrates that some ER stress markers can represent the severity of metabolic dysfunction in either cellular or animal models. However, no appropriate molecule has been identified to demonstrate these relationships in clinical practice.

Methods

To determine whether the serum level of the ER chaperone, protein disulfide isomerase family A, member 4 (PDIA4), is associated with type 2 diabetes mellitus, obesity, and insulin sensitivity, we conducted a cross-sectional study for which a total of 553 adults, including 159 with normal glucose tolerance (NGT), 169 with prediabetes (Pre-DM), and 225 with newly diagnosed T2DM, were recruited.

Results

Serum PDIA4 levels were significantly higher in patients with T2DM than in those with NGT (P < 0.001), even after adjustment for potential confounders. These levels correlated positively with fasting plasma glucose, BMI, waist circumference as well as high-sensitivity C-reactive protein levels, and negatively and strongly correlated with insulin sensitivity. In a multivariate logistic regression analysis, higher serum PDIA4 concentration was observed to be significantly associated with an increased risk of T2DM.

Conclusions

Our findings provide new mechanistic insights linking ER stress, T2DM, insulin sensitivity, and obesity, which may, in part, account for the ER chaperone properties associated with PDIA4. The results suggest that PDIA4 may serve as a potential instigator of and a putative therapeutic target for T2DM.

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Acknowledgements

We sincerely thank the research staff of our hospital for their technical assistance, particularly Miss Su-Zhen Wang for the laboratory measurements, and all the patients who participated in this study.

Funding

This work was supported by research grants from the Ministry of Science and Technology, ROC. (MOST 105-2314-B-016-040-MY3, MOST 108-2314-B-016-033-MY2 and MOST 108-2314-B-016-019-MY3) and Tri‐Service General Hospital (TSGH-C106-006-S02, TSGH-C107-006-006-S02, TSGH-C108-005-006-006-S02, MAB-105-084, MAB-108-046, TSGH-D-110058, TSGH-D-111115), Taiwan.

Author information

Authors and Affiliations

  1. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC

    Sheng-Chiang Su, Chu-Yen Chien & Chien-Hsing Lee

  2. Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Chenggong Rd, Neihu District, Taipei City, 114, Taiwan, ROC

    Sheng-Chiang Su, Yi-Jen Hung, Chang-Hsun Hsieh, Chieh-Hua Lu, Ying-Chen Chen, Peng-Fei Li, Feng-Chih Kuo, Jhih-Syuan Liu, Nain-Feng Chu & Chien-Hsing Lee

  3. School of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC

    Fu-Huang Lin

  4. Department and Graduate Institute of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC

    Yi-Jen Hung & Chien-Hsing Lee

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  1. Sheng-Chiang Su
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Contributions

All authors actively participated in the study and met the requirements for authorship. S-CS designed the experiments, analyzed the data, and wrote the manuscript. P-FL, C-HH, C-HL, J-SL and F-CK analyzed the data, participated in discussions, and reviewed and edited the manuscript. F-HL and N-FC contributed to the discussions and statistical analyses and reviewed and edited the manuscript. C-YC and Y-CC prepared the figures and tables and performed basic laboratory analysis and studies. C-HL and Y-JH supervised the project, are the guarantors of this work, had full access to all the data in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding author

Correspondence to Chien-Hsing Lee.

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Conflict of interest

The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this research. No potential conflict of interest relevant to this article are reported.

Ethical approval

This study was approved by the Internal Review Board of the Ethics Committee of the Tri-Service General Hospital (institutional review board Approval Number: 098-05-182). The study conformed to the ethical guidelines of the Declaration of Helsinki.

Informed consent

Informed consent was obtained from all subjects, and all samples were anonymized for analysis. All authors have read and approved the final version of the manuscript and all authors read the journal’s authorship agreement.

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Su, SC., Hung, YJ., Lin, FH. et al. Circulating protein disulfide isomerase family member 4 is associated with type 2 diabetes mellitus, insulin sensitivity, and obesity. Acta Diabetol 59, 1001–1009 (2022). https://doi.org/10.1007/s00592-022-01892-1

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