Plasma exosome microRNA profiling unravels a new potential modulator of adiponectin pathway in diabetes: effect of glycemic control

Context: type 2 diabetes is a chronic disease characterized by inadequate beta-cell response to the progressive insulin resistance. MicroRNAs (miRNAs) are short, endogenous, non-coding, RNAs representing a class of powerful gene expression modulators. Previous population studies observed a modulation of circulating miRNAs in diabetic patients; however, little data are presently available on miRNA modulation in diabetic patients naϊve to pharmacological treatment, as well as the effect of glycemic control on this. Objective: we aimed at studying circulating miRNAs expression in diabetic patients naϊve to treatment, and at investigating the influence on this of glycemic control. Design: case-control study. Participants: eighteen treatment naϊve diabetic patients with poor-metabolic control and 12 control patients. Main outcome measures: wide miRNA expression profiling was performed, and the expression of miRNAs found to be dysregulated was then validated by qRT-PCR. Finally, algorithm-identified putative miRNA targets were evaluated by qRT-PCR and ELISA. Results: in diabetic patients, microarray analysis showed that 4 miRNAs are increased, whereas 21 miRNAs are decreased. qRT-PCR validation confirmed the significant up-regulation of miR-326 (p=0.004) and down-regulation of let-7a (p<0.001) and let-7f (p=0.003). Notably, an inverse negative correlation was found between circulating miR-326 and its putative target adiponectin (Δ=-0.479, p=0.009). After 12-months of anti-diabetic treatment, qRT-PCR data analysis showed that miR-326 levels were unaffected, whereas the levels of let-7a and let-7f were significantly increased. Conclusions: treatment naϊve, poorly controlled diabetic patients show a significant dysregulation of miRNAs involved in regulation of the adiponectin pathway, a phenomenon that may be reversed, at least in part, by improved glycemic control.