Carica papaya leaf and root extracts attenuate hyperglycemia-induced insulin resistance by modulating MAPK and PI3K/AKT signalling in hepatic and skeletal muscle cells

Type 2 diabetes mellitus (T2DM) is characterised by impaired glucose homeostasis arising from insulin resistance and inadequate insulin action in peripheral tissues. <i>Carica papaya</i> has been reported to exert antidiabetic effects; however, its molecular mechanisms in hepatic and skeletal muscle cells under hyperglycemic conditions remain incompletely understood. This study investigated the effects of <i>C. papaya</i> leaf and root extracts on glucose uptake and insulin-related signalling pathways in HepG2 hepatocytes and C2C12 myotubes. Enzyme inhibition assays were used to assess α-amylase and α-glucosidase activity, while protein and gene expression of key components of the MAPK and PI3K/AKT pathways were evaluated using Western blotting and qPCR. <i>C. papaya</i> extracts significantly inhibited α-amylase activity (<i>p</i> < 0.05), with a non-significant inhibitory trend observed for α-glucosidase, suggesting reduced glucose availability under hyperglycemic conditions. In both HepG2 and C2C12 cells, <i>C. papaya</i> attenuated MAPK signalling through suppression of Erk1/2 and p38 MAPK, while JNK inhibition was observed exclusively in HepG2 cells (<i>p</i> < 0.05). In HepG2 cells, AKT and GLUT2 gene expression remained unchanged; however, AMPKα and IRS-1 were significantly upregulated, indicating enhanced glucose uptake potential despite a concomitant reduction in glycogen synthase expression (<i>p</i> < 0.05). In contrast, C2C12 myotubes exhibited enhanced insulin signalling characterised by increased phosphorylated IRS-1, AKT activation, and elevated glycogen synthase expression, supporting improved glucose uptake and storage (<i>p</i> < 0.05). Collectively, these findings demonstrate that <i>C. papaya</i> extracts mitigate hyperglycemia-induced insulin resistance by suppressing MAPK signalling and enhancing glucose uptake through distinct, cell-specific mechanisms in hepatic and skeletal muscle cells.