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.

Abstract

Aims/IntroductionGlucose 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 MethodsMicro 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.ResultsMiR‐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.ConclusionMiR‐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.