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

## TL;DR

Carica papaya leaf and root extracts help reduce insulin resistance and improve glucose uptake in liver and muscle cells by affecting key signaling pathways.

## Contribution

The study reveals cell-specific mechanisms by which C. papaya extracts modulate insulin resistance in hyperglycemic conditions.

## Key findings

- C. papaya extracts inhibited α-amylase activity, reducing glucose availability.
- In HepG2 cells, MAPK signaling was suppressed, and AMPKα and IRS-1 were upregulated.
- C2C12 myotubes showed enhanced insulin signaling with increased IRS-1 and glycogen synthase expression.

## Abstract

Type 2 diabetes mellitus (T2DM) is characterised by impaired glucose homeostasis arising from insulin resistance and inadequate insulin action in peripheral tissues. Carica papaya 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 C. papaya 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. C. papaya extracts significantly inhibited α-amylase activity (p < 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, C. papaya attenuated MAPK signalling through suppression of Erk1/2 and p38 MAPK, while JNK inhibition was observed exclusively in HepG2 cells (p < 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 (p < 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 (p < 0.05). Collectively, these findings demonstrate that C. papaya 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.

•C. papaya extracts.•Alleviate insulin resistance.•Enhanced glucose uptake.

C. papaya extracts.

Alleviate insulin resistance.

Enhanced glucose uptake.