Gene Expression Pattern of PI3K/AKT Pathway Based on Insulin Resistance and Vitamin D Toward the Understanding of T2DM Pathogenesis

Background: Insulin-stimulated glucose transport occurs via PI3K/AKT -dependent pathway which results in GLUT4 translocation from intracellular vesicles to plasma membrane and glucose uptake. PTEN , as a phosphatase, is the main antagonist of the PI3K/AKT pathway’s kinases. Present study was performed to investigate underlying mechanism responsible for defects in insulin signaling and the plausible role of vitamin D in pathogenesis of T2DM through the comparison of serum vitamin D and expression of genes involved in insulin signaling in diabetics and non-diabetics. Results: RT-PCR was employed to investigate mRNA expression level of IRS1/PI3K/PDK1/AKT2/GLUT4/PTEN in diabetic and non-diabetic participants and serum vitamin D was measured by HPLC. Findings provide evidence that IRS1 expression was preserved while PI3K /AKT2/GLUT4 were expressed significantly lower and PDK1 was expressed significantly higher in diabetics compared to non-diabetics. Albeit there was no significant difference in PTEN expression between groups, it was up-regulated by the years of having diabetes. No significant correlation between serum vitamin D and gene expression of GOIs was observed in either group. Conclusion: Since PTEN has been identified as a negative regulator of insulin signaling, it has generated great interest in new therapeutic approaches. This study reveals that insulin resistance is not caused through an alteration in PTEN expression as a primary defect but may be caused by decreased PI3K/AKT2/GLUT4 signalling and dysregulation of feedback loops. Particularly, PTEN expression showed a significant relation with duration of diabetes, suggesting that PTEN may not be the cause of the reduced expression of PI3K/AKT pathway in diabetics while it can be the effect of that. Therefore, the future investigations should be focused on regulators of pathway instead of PTEN . No significant correlation between serum vitamin D and gene expression of GOIs could be due to the non-linearity relationships as insulin signaling is a cascade with amplifying properties.