Metformin as a Treatment Strategy for Sjögren's Syndrome.

Joa Kim,Yun-Sung Kim,Sung-Hwan Park

doi:10.3390/ijms22137231

Abstract

Sjögren’s syndrome (SS), a chronic inflammatory disease involving the salivary and lacrimal glands, presents symptoms of sicca as well as systemic manifestations such as fatigue and musculoskeletal pain. Only a few treatments have been successful in management of SS; thus treatment of the disease is challenging. Metformin is the first-line agent for type 2 diabetes and has anti-inflammatory potential. Its immunomodulatory capacity is exerted via activation of 5’ adenosine monophosphate-activated protein kinase (AMPK). Metformin inhibits mitochondrial respiratory chain complex I which leads to change in adenosine mono-phosphate (AMP) to adenosine tri-phosphate (ATP) ratio. This results in AMPK activation and causes inhibition of mammalian target of rapamycin (mTOR). mTOR plays an important role in T cell differentiation and mTOR deficient T cells differentiate into regulatory T cells. In this manner, metformin enhances immunoregulatory response in an individual. mTOR is responsible for B cell proliferation and germinal center (GC) differentiation. Thus, reduction of B cell differentiation into antibody-producing plasma cells occurs via downregulation of mTOR. Due to the lack of suggested treatment for SS, metformin has been considered as a treatment strategy and is expected to ameliorate salivary gland function.

Highlights

Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
The aim of this review is to evaluate the pathogenesis of s syndrome (SS) and to enumerate antiinflammatory and immunomodulatory properties of metformin, an old drug with significant potential
We present a new aspect of the drug and suggest it as a strategy for treatment of SS

Summary

Metformin and Its Anti-Inflammatory and Immunomodulatory Effect

A representative drug for treatment of diabetes, is used worldwide. It controls hyperglycemia by reducing hepatic gluconeogenesis via AMPK-dependent and AMPK-independent mechanisms [6,7,8,9,10]. AMPK, monophosphate-activated protein kinase; mTOR, mammalian target of rapamycin; STAT3, signal transducer and activator of transcription 3; Ad-MSC, adipose-derived mesenchymal stem cell; Mt DNA, mitochondrial DNA; NETs, neutrophil extracellular traps; PDC, plasmacytoid dendritic cells; IFNα, interferon alpha; SLE, systemic lupus erythematosus; CD4, cluster of differentiation 4; Th. 17 cell, T helper 17 cell; CAIA, collagen antibody-induced arthritis; IL-17, interleukin-17; Treg cell, regulator T cell; CIA, collagen-induced arthritis; CoQ10, coenzyme Q 10; FGF21, fibroblast growth factor 21; BAT, brown adipose tissue; IGF-IR, insulin-like growth factor 1 receptor; PI3K, phosphoinositide kinase 3; RA-FLS, rheumatoid arthritis fibroblasts-like synoviocytes; BMI, body mass index; GLUT-1, glucose transporter 1; COX-2, cyclooxygenase-2; T2DM, type 2 diabetes mellitus; IL-6, interleukin-6; MTX, methotrexate; HAPLN1, hyaluronan and proteoglycan link protein 1; SIRT1, sirtuin 1; OA, osteroarthritis; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IL-1β, interleukin 1 beta; DMM, destabilization of the medial meniscus; Ad-hMSC, adipose tissue-derived human mesenchymal stem cell; MSU, monosodium urate. Further research on metformin and its immunomodulatory effect via change in gut flora and its metabolites is necessary

Pathophysiology of Sjögren’s Syndrome

Treatment of Sjögren’s Syndrome

Conclusions