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

Su, Sheng-Chiang; Hung, Yi‐Jen; Lin, Fu-Huang; Hsieh, Chang‐Hsun; Lu, Chieh-Hua; Chien, Chu-Yen; Chen, Ying‐Chen; Li, Pengfei; Kuo, Feng-Chih; Liu, Jhih‐Syuan; Chu, Nain-Feng; Lee, Chien-Hsing

doi:10.1007/s00592-022-01892-1

Cited by 4 publications

(2 citation statements)

References 33 publications

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“…We found that serum PDIA4 levels were associated with IR and inflammatory cytokines levels in subjects with normal or impaired glucose tolerance. These results were consistent with our recent report (61). Moreover, individuals in the second and third tertile of HOMA-2 IR levels had higher PDIA4 levels than those in the first tertile.…”

Section: Discussionsupporting

confidence: 94%

PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle

et al. 2022

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IntroductionEndoplasmic reticulum (ER) stress has emerged as a key player in insulin resistance (IR) progression in skeletal muscle. Recent reports revealed that ER stress-induced the expression of protein disulfide isomerase family a member 4 (PDIA4), which may be involved in IR-related diseases. A previous study showed that metformin modulated ER stress-induced IR. However, it remained unclear whether metformin alleviated IR by regulating PDIA4 expression in skeletal muscle.MethodsHerein, we used palmitate-induced IR in C2C12 cells and a high-fat diet-induced IR mouse model to document the relations between metformin, IR, and PDIA4.ResultsIn C2C12 cells, palmitate-induced IR increased inflammatory cytokines and PDIA4 expression. Besides, knocking down PDIA4 decreased palmitate-induced IR and inflammation in C2C12 cells. Furthermore, metformin modulated PDIA4 expression and alleviated IR both in vitro and in vivo. In addition, serum PDIA4 concentrations are associated with IR and inflammatory cytokines levels in human subjects.DiscussionThus, this study is the first to demonstrate that PDIA4 participates in the metformin-induced effects on skeletal muscle IR and indicates that PDIA4 is a potential novel therapeutic target for directly alleviating IR.

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Section: Discussionsupporting

confidence: 94%

PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle

et al. 2022

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“…One report stated that Pdia4 regulated adipocytes by down-regulating adiponectin [ 27 ]. Consistently, serum Pdia4 was shown to be related to obesity, insulin sensitivity, and diabetes [ 28 ]. The adiponectin/leptin ratio was proposed as a functional marker of fat inflammation in human patients of diabetes [ 29 ].…”

Section: Discussionmentioning

confidence: 88%

Pharmacological and mechanistic study of PS1, a Pdia4 inhibitor, in β-cell pathogenesis and diabetes in db/db mice

Tseng

Chen

Kuo

et al. 2023

Cell. Mol. Life Sci.

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Pdia4 has been characterized as a key protein that positively regulates β-cell failure and diabetes via ROS regulation. Here, we investigated the function and mechanism of PS1, a Pdia4 inhibitor, in β-cells and diabetes. We found that PS1 had an IC50 of 4 μM for Pdia4. Furthermore, PS1 alone and in combination with metformin significantly reversed diabetes in db/db mice, 6 to 7 mice per group, as evidenced by blood glucose, glycosylated hemoglobin A1c (HbA1c), glucose tolerance test, diabetic incidence, survival and longevity (P < 0.05 or less). Accordingly, PS1 reduced cell death and dysfunction in the pancreatic β-islets of db/db mice as exemplified by serum insulin, serum c-peptide, reactive oxygen species (ROS), islet atrophy, and homeostatic model assessment (HOMA) indices (P < 0.05 or less). Moreover, PS1 decreased cell death in the β-islets of db/db mice. Mechanistic studies showed that PS1 significantly increased cell survival and insulin secretion in Min6 cells in response to high glucose (P < 0.05 or less). This increase could be attributed to a reduction in ROS production and the activity of electron transport chain complex 1 (ETC C1) and Nox in Min6 cells by PS1. Further, we found that PS1 inhibited the enzymatic activity of Pdia4 and mitigated the interaction between Pdia4 and Ndufs3 or p22 in Min6 cells (P < 0.01 or less). Taken together, this work demonstrates that PS1 negatively regulated β-cell pathogenesis and diabetes via reduction of ROS production involving the Pdia4/Ndufs3 and Pdia4/p22 cascades.

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Association of protein disulfide isomerase family A, member 4, and inflammation in people living with HIV

Wang¹,

Chen²,

Lin³

2023

International Journal of Infectious Diseases

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

Cited by 4 publications

References 33 publications

PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle

PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle

Pharmacological and mechanistic study of PS1, a Pdia4 inhibitor, in β-cell pathogenesis and diabetes in db/db mice

Association of protein disulfide isomerase family A, member 4, and inflammation in people living with HIV

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