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Mechanistic and therapeutic links between rheumatoid arthritis and diabetes mellitus

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Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and irreversible cartilage and bone damage. Despite its predominant osteoarticular and periarticular manifestations, RA is also a systematic disease associated with organ-specific extra-articular manifestation. Increasing evidence indicates that RA patients are susceptible to diabetes mellitus (DM), and RA aggravates metabolic disordered in DM, indicating the close association between RA and DM. Many factors involved in RA stimulate insulin resistance and DM development. These factors include proinflammatory cytokines (such as TNF-α, IL-6, IL-1β), RA autoantibodies (such as rheumatoid factor, cyclic citrullinated peptide antibodies), excess RA related adipokines (such as leptin, resistin, ANGPTL4), C-creative protein, and other protein (such as TXNDC5, NLRP3, RBP4). Furthermore, commonly used RA drugs, such as conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biological disease-modifying antirheumatic drugs (bDMARDs), and glucocorticoids, provide potential benefits in improving insulin resistance and inhibiting DM development. This review discusses the mechanistic and therapeutic links between RA and DM, aiming to provide valuable information for the prevention and treatment of DM in RA patients.

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Abbreviations

ACPA:

Cyclic citrullinated peptide antibodies

AGEs:

Advanced glycation end products

AKT:

Protein kinase B

ANGPTL4:

Angiopoientin-like protein 4

bDMARDs:

Biological disease-modifying antirheumatic drugs

CPRD:

Clinical Practice Research Datalink

CRP:

C-creative protein

csDMARDs:

Conventional synthetic disease-modifying antirheumatic drugs

CTLA-4:

Cytotoxic T-lymphocyte-associated antigen 4

DAS:

Disease activity score

DKD:

Diabetic kidney disease

DM:

Diabetes mellitus

Fas:

Factor associated suicide

FasL:

Factor associated suicide ligand

FLS:

Fibroblast-like synoviocyte

GLUT4:

Glucose transporter 4

GSK-3:

Glycogen synthase kinase-3

HbA1c:

Glycated hemoglobin

HCQ:

Hydroxychloroquine

HDL-C:

High-density lipoprotein cholesterol

HOMA-IR:

Homeostatic Model Assessment of Insulin Resistance

HR:

Harzard ratio

hs-CRP:

High-sensitivity CRP

IGF-1:

Insulin-like growth factors-1

IGFBP1:

Insulin-like growth factor binding protein

IGF-IR:

Insulin-like growth factor 1 receptor

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

IRS-1:

Insulin receptor substrate-1

IRS-2:

Insulin receptor substrate-2

PI3K:

Phosphatidylinositol 3 kinase

JAK2:

Janus Kinases 2

JAKi:

Inhibitors of JAKs

JNK:

C-Jun N-terminal kinase

LDL-C:

Low-density lipoprotein cholesterol

LepRb:

Leptin receptor

MMP:

Matrix metalloproteinases

MTX:

Methotrexate

NDB:

National Data Bank

NF-κB:

Nuclear factor kappa-B

NLRP3:

NOD-like receptor protein 3

NOS:

Nitric oxide synthase

PGE2:

Prostaglandin E2

PPARγ:

Peroxisome proliferator-activated receptor γ

PTP-1B:

Protein tyrosine phosphatase 1B

RA:

Rheumatoid arthritis

RF:

Rheumatoid factor

RANKL:

Receptor Activator of Nuclear Factor-κ B Ligand

RBP4:

Retinol-binding protein 4

SOCS3:

Suppressor of cytokine signaling-3

STAT3:

Signal transducer and activator of transcription 3

TG:

Triglycerides

TLR4:

Toll-like receptor 4

TNF-α:

Tumor necrosis factor α antagonists

TNFR:

TNF receptors

TXNDC5:

Thioredoxin domain-containing protein 5

VEGF:

Vascular endothelial growth factor

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Funding

This work was supported by the National Natural Science Foundation of China (No. 81972133, 82172482, 81670806), the Fundamental Research Funds for the Central Universities (No. xzy012019094), and the Natural Science Basic Research Program of Shaanxi (No. 2020JM-365).

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  1. Jing Li and Yazhuo Chen authors have contributed equally to this work.

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  1. Center for Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China

    Jing Li, Yazhuo Chen, Qingyun Liu & Yan Zhang

  2. Xi’an Central Hospital, Xi’an, People’s Republic of China

    Zhufang Tian

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Li, J., Chen, Y., Liu, Q. et al. Mechanistic and therapeutic links between rheumatoid arthritis and diabetes mellitus. Clin Exp Med 23, 287–299 (2023). https://doi.org/10.1007/s10238-022-00816-1

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