Carica papaya leaf and root extracts present a promising therapeutic alternative for managing type 2 diabetes mellitus by reducing oxidative stress-related inflammation associated with insulin resistance in cultured HepG2 liver and C2C12 muscle cells

Insulin resistance (IR) significantly contributes to developing type 2 diabetes mellitus (T2DM), affecting the liver, muscle, and adipose tissues. Hyperglycaemia leads to oxidative stress and inflammation, key factors in the development of IR. Carica papaya is known for its anti-inflammatory and antioxidant properties; however, the mechanisms underlying these properties remain unclear. This study investigated the effects of C. papaya leaf and root extracts on hyperglycaemia, oxidative stress, and IR in HepG2 liver and C2C12 muscle cells. The research measured oxidative stress markers, including H 2 O 2 , MDA, LDH, SOD2, NRF2 and DPPH scavenging capacity. Inflammatory markers were evaluated using Western blot analysis, focusing on proteins such as JNK, NF-κB, CRP, and AMPKα. The findings revealed that C . papaya leaf extracts exhibited significant antioxidant properties, demonstrated by a reduction in H 2 O 2 concentrations in both cell lines; however, the reduction associated with the root extract was not statistically significant. In HepG2 cells, while MDA production increased, C . papaya extracts enhanced the antioxidants SOD2 and NRF2 levels, contributing to cellular protection as indicated by decreased LDH release. In C2C12 cells, MDA and SOD2 levels remained relatively unchanged, yet NRF2 expression was significantly reduced alongside LDH externalisation. Both extracts mitigated inflammation by downregulating JNK and inhibiting NF-κB in C2C12 cells, with both extracts at 500 μg/mL producing similar effects in HepG2 cells. Moreover, the extracts elevated AMPKα levels in both cell lines, suggesting glucose uptake-promoting and reduced cytokine production. Overall, C. papaya leaf and root extracts may serve as promising candidates for further research as therapeutic agents for managing T2DM by alleviating oxidative stress and inflammation related to insulin resistance.