Circulating miR-191 and miR-375 are associated with markers of insulin resistance in overweight /obese children: results of the I.Family Study

Background: The promising emergence of circulating miRNAs as stable, reproducible, and consistent among individuals has opened a promising research avenue for non-invasive biomarker detection. A solid connection between circulating miRNAs and glycaemic as well as metabolic homeostasis has been established, demonstrating that levels of specific miRNAs vary under different physio-pathological conditions. Objective: In this study, we explored the expression of candidate miRNAs, in relation to biomarkers of insulin sensitivity (insulin levels, HOMA index) in a subgroup (n=58) of subjects participating in the European I.Family Study, a project aimed at assessing the determinants of eating behavior in children and adolescents and related health outcomes (Trial registration: ISRCTN62310987). The sample included children/adolescents with overweight/obesity, as overweight/obesity is a known risk factor for impaired glucose homeostasis and metabolic disorders. Besides, dysregulation in insulin signaling is among the typical and earliest metabolic signs predisposing to the development of type 2 diabetes. Of note, no one of the study-subject suffered from metabolic syndrome or TD2, no alterations in blood levels of glucose and HbA1c were recognized. Results: The differential expression of miR-191-3p and miR-375 was statistically confirmed to be associated with early changes in insulin level and HOMA index in both girls and boys. The analyses were adjusted for confounding factors, including puberty since puberty is characteristically associated with a decrease in insulin sensitivity. Covariates also included the country of origin, age, BMI z-score, total energy intake, energy from fats, energy from carbohydrates, energy from proteins, and the highest educational level of parents since several studies indicated that parental influences have a marked effect on nutritional habits, dietary intakes, and food preferences of young children. To gain a mechanistic understanding of how the miRNAs could be associated with glycaemic impairment, molecular interactions of confirmed miRNAs were also predicted by bioinformatics. Conclusion: In recent years, numerous efforts have been made to identify early, reliable and predictive biomarkers of altered insulin sensitivity; nevertheless, risk-screening methods are nearly limited. Identification of circulating miRNAs associated with insulin impairment may offer novel approaches to assessing early variations in insulin sensitivity to timely detect insulin impairment and prediabetes. Furthermore, the results provide new evidence about the underlying molecular mechanisms connected to early changes in glycaemic homeostasis.