159-LB: Circulating MicroRNAs as Predictors of ß-Cell Function in Youth Onset Type 2 Diabetes—The TODAY Study

In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, half the participants reached the primary outcome (HbA1c≥8% for at least 6 months) within 4 years which was associated with a decrease in C-peptide oral disposition index (oDI). We aimed to identify circulating miRNA species associated with β cell function decline. Following a preliminary survey of select participants using nCounter Human v3 miRNA Panel (NanoString Technologies), polymerase chain reaction validations were carried out for 17 miRNAs from 365 participants with samples at baseline, 24, 60, 96, and 120 months. During the first 6 months in TODAY, 150 (43%) of the participants (mean age 14 years at baseline and diabetes duration <2 years) had a ≥20% decrease in C-peptide oDI. Using backward elimination modeling and adjusting for demographic characteristics, three baseline miRNA log2 fold changes remained significant predictors of this C-peptide oDI decline ≥20% (p<0.05). Increased levels of miR-155 (OR:1.21, 95%CI:1.07-1.38) and miR-130b (OR:1.32, 95%CI: 1.02-1.70) were associated with oDI decline, while decreased levels of miRNA-126 (OR:0.60, 95%CI: 0.44-0.81) were associated with oDI decline. miR-122 was negatively correlated with C-peptide oDI at baseline and 24-months (R=0.22, p<0.01 and R=0.19, p<0.01, respectively), and positively correlated with proinsulin, at baseline, 24-, and 60-months (R=0.26, p<0.01, R=0.26, p<0.01, R=0.18, p<0.01, respectively). These miRNA species are associated with alterations in β cell insulin secretion and apoptosis targeting pyruvate dehydrogenase, glucokinase, and GLI-similar zinc finger proteins, suggesting that differences in baseline abundance may serve as circulating markers of β cell dysfunction, providing potential mechanistic insights into the aggressive nature of youth-onset type 2 diabetes.