Micro ribonucleic acid-363 regulates the phosphatidylinositol 3-kinase/threonine protein kinase axis by targeting NOTCH1 and forkhead box C2, leading to hepatic glucose and lipids metabolism disorder in type 2 diabetes mellitus.

Aims/introduction: Glucose metabolic disorder is the main cause for type 2 diabetes progression. Exploring the molecular mechanisms of metabolic disorder are crucial for type 2 diabetes treatment.

Materials And Methods: Micro ribonucleic acid (miR)-363, NOTCH1 and forkhead box C2 (FOXC2) expressions in high glucose (HG)-treated HepG2 cells and the livers of type 2 diabetes mellitus rats were assessed using quantitative polymerase chain reaction. Protein levels of NOTCH1, FOXC2 and phosphatidylinositol 3-kinase (PI3K)/serine/threonine protein kinase (Akt)-related proteins were evaluated using western blot. Lipid accumulation was determined using Oil Red O staining. Then glucose consumption, blood glucose level and glycogen content were detected using kits. Finally, dual luciferase reporter assay was used to verify the binding relationship between miR-363 and NOTCH1, and the binding relationship between miR-363 and FOXC2.

Results: MiR-363 was significantly upregulated in the livers of diabetic rats and HG-induced HepG2 cells, whereas NOTCH1 and FOXC2 were downregulated. In HG-induced HepG2 cells, miR-363 inhibitor markedly increased glucose consumption and uptake, and reduced accumulation of lipid droplets. Then NOTCH1 and FOXC2 were identified as downstream targets of miR-363. NOTCH1 overexpression or FOXC2 overexpression could ameliorate glucose and lipids metabolism disorder in type 2 diabetes model cells. In addition, we found that FOXC2 inhibition abolished the effect of NOTCH1 overexpression on HG-induced HepG2 cells. Finally, we proved that the PI3K/Akt pathway was the downstream pathway of FOXC2.

Conclusion: MiR-363 was considered as a key regulator of glucose and lipids metabolism in type 2 diabetes mellitus, which regulated PI3K/Akt axis by targeting NOTCH1 and FOXC2, thus leading to hepatic glucose and lipids metabolism disorder in type 2 diabetes.