Table 1.

Experimental and clinical effects of metformin in rheumatologic autoimmune and inflammatory conditions.

Rheumatoid arthritis (RA)	Lower increase in Th17 cells with reduction of proinflammatory cytokines and improved arthritis score in a CAIA mouse model [20,21]
	Suppression of Th17 cells and enhancement of Treg cells in a CIA murine model [22]
	Suppression of osteoclast differentiation [23]
	Impaired autophagy correction with suppression of inflammatory cytokines and clinical arthritis in a murine model of immune arthritis [24]
	Higher reduction of Th17 cells, induction of Treg cells, and inhibition of osteoclastogenesis with higher arthritis improvement by metformin combined with CoQ10 vs. metformin or CoQ10 alone in a CIA murine model [25]
	Restoration of reciprocal Th17/Treg balance with dampened CIA development in a murine model of diet-induced obesity [26]
	Modulation of macrophage polarization toward M2 phenotype in a model of high-fat diet-fed obese C57/6J male mice [27]
	Inhibition of RA-FLS proliferation on synovial tissue from patients with RA [28]
	Mitochondrial dysfunction reduction by rapamycin combined with metformin vs. rapamycin alone in a CIA obese mouse model [29]
	Reduction of GLUT-1 expression in synovial tissue from patients with RA [30]
	Inverse association between risk of RA and exposure to metformin inT2DM patients [31]
	Lower admission rate of T2DM patients with RA treated with metformin and Cyclooxygenase (COX)-2 inhibitor vs. COX-2 inhibitors alone [32]
Osteoarthritis (OA)	Osteoarthritis limited development and delayed progression in a DMM murine model, not in an AMPK/α1 knockout DMM mice [33]
	Chondroprotection in a partial medial meniscectomy model of non-human primates [33]
	Reduced knee osteoarthritis progression in obese patients [34]
	Decreased risk of joint replacement surgery by 25% over 10 years [35]
	Improvement of osteoarthritis-related pain on a DMM OA mouse model [36]
	Chondroprotective and antinociceptive effect of intravenous [i.v.] administration of metformin-stimulated Ad-hMSCs [37]
Gout	Reduction in release of cell death and inflammatory mediators from monocytes encountering MSU crystals [38]
	Decrease of incident gout in T2DM patients and of gout attacks in gouty non-diabetic patients [39]
Systemic lupus erythematous	Reduction of NET DNA release in cultured neutrophils and inhibition of Interferon (INF)-α generation from stimulated PDCs [40]
	51% reduction of flares frequency in patients with mild or moderate disease [40]
	Restoration of Cluster of Differentiation (CD)4+ T function and reversion of disease phenotypes in a lupus-prone mouse model [41]
Sjögren syndrome	Suppression of effector T cells and induction of regulatory T cells in a murine model of Sjögren syndrome [42]
Ankylosing spondylitis	Potent antiosteogenic effect on human fibroblasts [43]

Abbreviations: AMPK, 5′ adenosine monophosphate-activated protein kinase; CAIA, collagen antibody-induced arthritis; CIA, collagen-induced arthritis; RA-FLS, rheumatoid arthritis fibroblast-like synoviocytes; GLUT1, glucose transporter 1; T2DM, type 2 diabetes mellitus; DMM, destabilization of medial meniscus; MSU, monosodium urate; NET, neutrophil extracellular trap; Ad-hMSCs, adipose tissue-derived human multipotent mesenchymal stem cells; PDCs, plasmacytoid dendritic cells.