Table 1.

Effects of glucose-lowering agents on arthritis.

Metformin

• antiproliferative, antifibrotic, and antioxidant potential

• ↓ Th17 cells and ↓ proinflammatory cytokines

• inhibition of mitochondrial respiratory chain complex I and ↓ ROS

• ↓ STAT3 phosphorylation via AMPK/mTOR pathway and ↓ Th17 differentiation

• phosphorylation of AMPK

• in synovial fibroblasts ↑ glycolytic activity and ↓ IL 6, IL 8 and monocyte chemotactic protein 1

• in osteoclasts ↓ osteoclastogenesis by the AMPK-mediated inhibition of mTOR

• in macrophages ↓ of TNFα, IL-6, and MCP-1; ↑ release of IL-10

• ↓ inflammatory cytokines by suppressing NF-κB pathway

Thiazolidinediones

• anti-inflammatory activity, immuno-modulation, antioxidant effect

• in macrophages ↓ proliferation

• in T-cells ↑ immunosuppressive effects

• ↓ production of IL-17; ↓ mRNA expression levels of inflammatory mediators; ↓ levels of MMPs

• in synoviocytes/synovial fibroblast ↓ growth and ↓ IL 1β induced PGE2 synthesis

• maintained expression of aggrecan and type II collagen

• ↓ inflammatory cell infiltration, ↓ pannus formation, ↓ cartilage/bone damage

• ↓ TNFα, IL-1β, MCP-1 and RANKL mRNA, ↓ osteoclasts differentiation

• in chondrocytes ↓ NO synthase expression, ↓ IL-1β and MMP-13

• in chondrocytes/synovial fibroblasts ↓ COX-2 expression and PGE2 production

• ↓ NF-κB pathway

Dipeptidyl peptidase-4 inhibitors

• ↓ proliferation of T cells

• ↓ anti-CCP, RANKL, TNFα and IL-6 by ↓TLR/NF-κB pathway

• action on cytokine secretion, T cell‐dependent antibody production and immunoglobulin isotype switching of B cells

• in chondrocytes ↓ degradation of type II collagen by MMP-1, MMP-3, and MMP-13

• ↓ oxidative stress

• ↓ ADAMTS-4 and ADAMTS-5 leading to ↓ degradation of aggrecan

• ↓ p38 MAPK signaling pathway and ↓ NF-κB

Glucagon-like peptide 1 analogues

• in FLSs ↓ TNFα, IL-6, IL-8, IL‐1β, MMP‐3, MMP‐13, HMGB-1, MCP‐1, p38/MAPK and NF‐κB pathways

• in FLSs improved oxidative stress and prevented cell death

• in chondrocytes ↑ anti-apoptotic marker Bcl-2 and ↓ apoptotic proteins active caspase 3 and Bax

• in chondrocytes ↑ deterioration of type II collagen and aggrecan