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Insulin Resistant Pathways are associated with Disease Activity in Rheumatoid Arthritis and are Subject to Disease Modification through Metabolic Reprogramming; A Potential Novel Therapeutic Approach

Author

Gallagher L1,2, Cregan S1, Biniecka M3, Cunningham C2, Veale DJ3, Kane DJ1, Fearon U2, Mullan RH1. Arthritis Rheumatol. 2019 Dec 16. doi: 10.1002/art.41190. [Epub ahead of print]

Author Information

1 Dept. of Rheumatology, Trinity Centre for Health Science, Tallaght Hospital, Dublin.

2 Molecular Rheumatology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin.

3 Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital, University College Dublin, Dublin.

Abstract

OBJECTIVE: 

To investigate a role for insulin-resistant pathways in inflammation and therapeutic targeting for disease modification in Rheumatoid Arthritis.

METHODS: 

RA disease activity and cardiovascular risk factors, including insulin-resistance and body mass index (BMI) were assessed in an Irish RA cohort. GLUT1 and GLUT4 activity in RA and OA synovial tissue were assessed by Immunohistochemistry. Spontaneous release of pro-inflammatory mediators from ex-vivo RA synovial explants and primary synovial fibroblast (RA SFC) cell culture supernatants were quantified by ELISA. Activated AMPK (P-AMPK) and GLUT1 protein expression were analysed by Western Blot. Cellular glycolytic and oxidative phosphorylation were assessed using extracellular-flux analysis.

RESULTS: 

Insulin-resistance was independently associated (Parameter Estimate; 95%CI) with both BMI (0.113,0.059-0.167,p<0.001,n=61) and SJC28 (0.114,0.032-0.197,p=0.008,n=61). Increased GLUT1 expression in RA versus OA synovium was demonstrated (p=0.0003, n=26 &16), with increased expression in the lining, sub-lining and vascular regions. In contrast, decreased GLUT4 expression in RA versus OA lining layer was observed (p=0.0358, n=21 & 8). Decreased GLUT1 protein expression was observed in parallel with increased P-AMPK protein expression in SFC in the presence of metformin (n=4). Metformin increased glycolytic activity (p<0.05), and decreased OxPhos (p<0.05) in RA SFCs (n=7). Metformin or AICAR presence decreased spontaneous production of IL-6, IL-8 and MCP-1 in RA synovial explants and SFCs (n=5-7).

CONCLUSION: 

Insulin Resistance is significantly associated with BMI and synovitis in RA, suggesting distinct interplay between glucose availability and inflammation in RA. Furthermore the effect of metformin on pro-inflammatory mechanisms suggests a role for AMPK modifying compounds for treatment of RA.