Background: Insulin resistance, a characteristic of Diabetes Mellitus (DM), is caused by the inactivation of the insulin signaling pathway: IRS- PI3K -PKC -AKT2, and GLUT4. Conditions such as oxidative stress, glycated proteins, hyperglycemia, endoplasmic stress, fatty acid accumulation are major factors that cause inactivation of the insulin signaling pathway. Palmatine, an alkaloid, has been previously reported to possess antidiabetic, antioxidant, antiglycation properties and inhibition of endoplasmic stress.
Objective: The current study evaluated the rejuvenation of insulin signaling pathway by Palmatine in insulin-resistant L6 skeletal muscle cells, extracted soleus muscle tissue and streptozotocin (STZ)-induced diabetic rats.
Method: Differentiated L6 skeletal muscle cells and extracted soleus muscle tissue was induced insulin resistance using high insulin and glucose levels media. While STZ was used to induce type 2 DM in Sprague Dawley rats. The cells/tissue/animal was treated with palmatine, while glimepiride and metformin were used as standard drug. The differential gene expression of IRS-1, PI3K, PKC-α, AKT2, and GLUT4 was evaluated using qPCR. In silico docking of palmatine, tyrosine phosphatase SHP-2 (SHP-2) domains protein and Protein tyrosine phosphatase-1B (PTP1B) was done using CDOCKER program available in DS V2.0 software. Result: The results showed that IRS-1, PI3K, AKT2, and GLUT4 were down-regulated, while PKC-α was upregulated in insulin resistant cells, muscle tissue and STZ-induced diabetic rats. In contrast to the insulin-resistant cells of the afore mentioned genes were up-regulated in Palmatine treated cells/tissue/animals, while PKC-α was down-regulated. In silico docking of Palmatine showed a good affinity for tyrosine phosphatase SHP-2 (SHP-2) domains protein and Protein tyrosine phosphatase-1B (PTP1B) proteins suggesting the modulation of these proteins.
Conclusion: Palmatine seem to have rejuvenate the impaired insulin signaling pathway through upregulation of the gene expression of IRS-1, PI3K, AKT2, and GLUT4 and downregulation of PKC-α expression. In silico docking shows a reduced modulation of PTP1B and increase affinity to SHP-2. Reduced expression of PKC-α and modulation of PTP1B maybe the reason for the observed increased expression of IRS-1, PI3K, AKT2, and GLUT4.
The authors acknowledge UCSI University for providing the internal funding for this project grant code: CERVIE REIG grant number REIG-FAS-2020-031
