Diabetes Modulates MicroRNAs 29b-3p, 29c-3p, 199a-5p and 532-3p Expression in Muscle: Possible Role in GLUT4 and HK2 Repression

Abstract

The reduced expression of solute carrier family 2, facilitated glucose transporter member 4 (GLUT4) and hexokinase-2 (HK2) in skeletal muscle participates in insulin resistance of diabetes mellitus (DM). MicroRNAs (miRNAs) have emerged as important modulators of mRNA/protein expression, but their role in DM is unclear. We investigated miRNAs hypothetically involved in GLUT4/HK2 expression in soleus muscle of type 1 diabetes-like rats. In silico analysis revealed 651 miRNAs predicted to regulate solute carrier family 2 member 4 (Slc2a4) mRNA, several of them also predicted to regulate Hk2 mRNA, and 16 miRNAs were selected for quantification. Diabetes reduced Slc2a4/GLUT4 and Hk2/HK2 expression (50–77%), upregulated miR-29b-3p and miR-29c-3p (50–100%), and downregulated miR-93-5p, miR-150-5p, miR-199a-5p, miR-345-3p, and miR-532-3p (~30%) expression. Besides, GLUT4 and HK2 proteins correlated (P < 0.05) negatively with miR-29b-3p and miR-29c-3p and positively with miR-199a-5p and miR-532-3p, suggesting that these miRNAs could be markers of alterations in GLUT4 and HK2 expression. Additionally, diabetes increased the nuclear factor kappa B subunit 1 protein (p50) expression, a repressor of Slc2a4, which was also predicted as a target for miR-199a-5p and miR-532-3p. Correlations were also detected between these miRNAs and blood glucose, 24-h glycosuria and plasma fructosamine, and insulin therapy reversed most of the alterations. In sum, we report that diabetes altered miR-29b-3p, miR-29c-3p, miR-199a-5p and miR-532-3p expression in muscle of male rats, where their predicted targets Slc2a4/GLUT4 and Hk2/HK2 are repressed. These data shed light on these miRNAs as a markers of impaired skeletal muscle glucose disposal, and, consequently, glycemic control in diabetes.

Blood Co-Circulating Extracellular microRNAs and Immune Cell Subsets Associate with Type 1 Diabetes Severity

“…Among the miRNAs also associated with serum C-peptide concentration, we identified plasmatic miR-29c-3p, which was univocally up-regulated in children who manifest DKA at T1D diagnosis (Figure 4). Several studies in mice and rats have associated miR-29c-3p dysregulation with impaired glucose transporter expression and glycemic control in skeletal muscle, exacerbated vascular remodeling, and hepatic negative regulation of insulin signaling in diabetes [59][60][61][62]. Less information is available on the involvement of miR-29c-3p in human diabetes.…”

MicroRNA-29b-3p Promotes Human Retinal Microvascular Endothelial Cell Apoptosis via Blocking SIRT1 in Diabetic Retinopathy

“…Recent studies have revealed the decrease of SIRT1 in diabetes patients (Balestrieri et al, 2013) and the increase of miR-29b-3p in diabetes (Esteves et al, 2018). Furthermore, Su et al (2019) have proved the direct regulation of miR-29b-3p to SIRT1 in insulin resistance.…”

LncRNA IMFlnc1 Promotes Porcine Intramuscular Adipocyte Adipogenesis by Sponging Mir-199a-5p to Up-regulate CAV-1

“…It also regulates cardiomyocyte apoptosis by targeting JunB (JunB proto-oncogene) [37]. In diabetic individuals, miR-199a-5p may be involved in skeletal muscle insulin resistance by inhibiting glucose transporter 4 (GLUT4) and hexokinase 2 (HK2) [38]. MiR-199a-5p also participates in lipid metabolism,in Italian Large White pigs, miR-199a-5p showed a higher expressional level in the backfat of the lean groups than that in the fat group [39].…”