Fig. 4.

The role of insulin resistance in the OA degenerative process. During IR, the insulin receptors in chondrocytes and synovium become less responsive to insulin’s beneficial effects leading to the overproduction of cytokines. There is also an increase in FFA which leads to mitochondrial dysfunction which ultimately leads to cytokines release and apoptosis. Furthermore, hyperinsulinemia hinders the formation of mature chondrocytes by increasing the proliferation of chondrocytes, preventing their differentiation, and reducing the circulating levels of thyroid hormones. Red arrows with pointed ends imply the processes which are ultimately induced because of IR, while those with blunt ends imply processes which are ultimately inhibited as a consequence of IR. Cyt C: cytochrome C, FFA: free fatty acids, IL-1β: interleukin-1β, MMP: matrix metalloproteinases, mtROS: mitochondrial-reactive oxygen species, T3 and T4: thyroid hormones, and TNF-α: tumor necrosis factor α. Created by Biorender.com.