Abstract
From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, 60% of the participants demonstrated diabetes-related complications by 10 years. We aimed to identify circulating microRNA (miRNA) species associated with microvascular disease in TODAY participants with youth-onset type 2 diabetes. Using nCounter Human v3 miRNA Panel (NanoString Technologies) to identify relevant miRNAs in two groups of participants who lost glycemic control and either developed microvascular complications during follow-up (n=6) or not (n=11), 53 miRNA species were differentially expressed at baseline (p<0.05) and 2 at the end of study visit (p<0.05). Polymerase chain reaction validations were carried out for 17 miRNAs from 365 participants with samples obtained at baseline, 24, 60, 96, and 120 months. During follow-up, 250 (68%) of the participants (mean 14 years old and diabetes duration <2 years at entry) developed at least one microvascular complication. Using backward elimination modeling and adjusting for demographic characteristics, a set of four baseline miRNA log2 fold changes remained significant predictors of microvascular complications (p<0.05). Increased levels of miR-122 (OR:1.17, 95%CI:1.03-1.32) and miR-221 (OR:1.51, 95%CI: 1.51-1.98) were associated with higher risk of complication, while increased levels of miRNA-let 7g (OR:0.75, 95%CI: 0.60-0.94) and miRNA-130a (OR:0.82, 95%CI: 0.68-0.99) were associated with lower risk of complication. miR-122 abundance was also positively correlated with urine albumin/creatinine ratio at baseline and 24-months (R=0.11, p=0.041 and R=0.16, p=0.005, respectively). The alterations in miR-122, 221, 130a, and let 7g in circulation are all consistent with in vitro alterations that promote endothelial dysfunction suggesting that these early alterations in circulation may predict those at highest risk of microvascular disease in the future. Disclosure D. Redling: None. S. Bialek: None. S. Chernausek: Advisory Panel; Ascendis Pharma A/S. L. El ghormli: None. J. B. Tryggestad: None. Funding National Institutes of Health (5U01DK061230-16)
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