miR‐4431 targets TRIP10/PRKD1 and impairs glucose metabolism

Abstract

Aim/Introduction Obesity is considered an important risk factor for many metabolic disorders, especially type 2 diabetes mellitus, and microRNAs (miRNAs) play a vital role in the development of type 2 diabetes mellitus. Therefore, we conducted this study to investigate the role of miR‐4431 in the obesity‐associated pathobiology of type 2 diabetes mellitus. Materials and methods Subjects were divided into normal control (n = 36), obese (n = 36), and type 2 diabetes mellitus (n = 12) groups, and serum miR‐4431 levels were analyzed. Adenovirus‐vectored miR‐4431 mimic or sponge was intraperitoneally injected into the normal diet group and the high‐fat diet group (HFD) mice to investigate glucose tolerance, insulin sensitivity, and lipid levels. The downstream target genes of miR‐4431 were predicted using bioinformatics, and they were verified in vitro. Results Serum miR‐4431 levels were significantly high in obese and type 2 diabetes mellitus individuals, and positively correlated with the body mass index and fasting plasma glucose levels. In HFD mice, miR‐4431 levels in the serum, white adipose tissue, and liver were significantly increased. Moreover, miR‐4431 impaired glucose tolerance, insulin sensitivity, and lipid metabolism in mice. Bioinformatic prediction suggested that TRIP10 and PRKD1 could be the downstream target genes of miR‐4431. The HFD mice showed a remarkable reduction in the mRNA levels of TRIP10 and PRKD1 in the liver, which were countered by blocking miR‐4431. In HepG2 and L02 cells, miR‐4431 could downregulate TRIP10 and PRKD1 while blocking glucose uptake. The luciferase reporter assay showed that miR‐4431 could bind TRIP10 and PRKD1 3′‐UTR. Conclusion miR‐4431 targets TRIP10/PRKD1 and impairs glucose metabolism.

Biomarkers of obesity-mediated insulin resistance: focus on microRNAs

“…2). In recent years, many studies have extensively explored the role of miRNAs as biomarkers for predicting IR development in populations with obesity [62][63][64][65][66][67][68][69][70][71][72][73]. The downstream miRNA targets have also been investigated [74][75][76][77][78][79][80][81][82][83][84][85].…”

“…In recent clinical studies, some investigators have directly compared miRNAs differentially expressed in the peripheral blood of MAO and MHO individuals [62][63][64][65][66][67]. These studies have substantial implications for mining early biomarkers [62][63][64][65][66][67].…”

“…Other studies have identified differentially expressed miRNAs and explored the possible mechanisms of miRNA involvement in obesity-related IR [65][66][67]. In a clinical cohort of 36 healthy individuals, 36 individuals with obesity, and 12 T2D patients, Pan et al [65] observed a positive correlation between serum miR-4431 levels, body mass index (BMI), and fasting glucose levels. Elevated miR-4431 was mainly distributed in the serum, white adipose tissue, and liver of obese mice [65].…”

“…In a clinical cohort of 36 healthy individuals, 36 individuals with obesity, and 12 T2D patients, Pan et al [65] observed a positive correlation between serum miR-4431 levels, body mass index (BMI), and fasting glucose levels. Elevated miR-4431 was mainly distributed in the serum, white adipose tissue, and liver of obese mice [65]. Bioinformatic predictions suggest that miR-4431 impairs glucose metabolism by targeting the thyroid hormone receptor interactor (TRIP) 10/protein kinase (PRK) D1 [65].…”

Non-coding RNAs in diabetes mellitus and diabetic cardiovascular disease

“…Increasing evidence suggests that miRNAs promote pancreatic β-cell injury in diabetes. MiR-195 promotes pancreatic β-cell dedifferentiation by targeting Mfn2 and impairing Pi3k/Akt signaling in T2MD ( 90 ), miRNA-200c targets transcription factor ETV5 to reduce insulin secretion ( 91 ), and miR-4431 targets TRIP10/PRKD1 and impairs glucose metabolism ( 92 ). There are also some miRNAs that are lost in expression during the progression of DM.…”