Some microRNA species increase odds for glycemic failure in youth-onset type 2 diabetes
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Key takeaways:
- Increased levels of some microRNA species increased the likelihood for treatment failure among youths in the TODAY study.
- MicroRNA abundance was also tied to lower C-peptide oral disposition index.
Circulating levels of some microRNA species may predict response to diabetes treatment and changes in beta-cell function among children and adolescents with type 2 diabetes, according to findings from the TODAY study.
“We have identified some novel biomarkers for treatment failure and beta-cell decline in youths with type 2 diabetes,” Jeanie B. Tryggestad, MD, associate professor of pediatrics in the section of diabetes/endocrinology, department of pediatrics and the Children’s Hospital Foundation (CHF) Paul and Ruth Jonas Chair in Pediatric Diabetes/Endocrinology at University of Oklahoma Health Sciences Center, told Healio. “While microRNA analysis is not clinically available at this time, this is a promising area moving forward. Also, to understand what is altering the microRNA expression as well as the potential targets of the microRNAs may have therapeutic implications in the future.”
The TODAY study enrolled 699 children and adolescents aged 10 to 17 years with type 2 diabetes for a duration of 2 years or less at baseline and a BMI in the 85th percentile or higher for age and sex. From 2004 to 2011, participants were randomly assigned to metformin alone, metformin with rosiglitazone or metformin plus lifestyle intervention for 2 to 6 years. In a new analysis published in The Journal of Clinical Endocrinology & Metabolism, Tryggestad and colleagues conducted a broad-based screening of microRNAs that were potentially differently expressed among TODAY participants who had treatment failure during the study. Treatment failure was defined as an HbA1c of 8% or more over 6 months or inability to wean from insulin after metabolic decompensation. Researchers selected 17 microRNA species for further analysis among 365 TODAY participants who had a baseline plasma sample available. Additional plasma samples were collected at 24, 48, 60, 96 and 120 months to assess changes in circulating microRNA over time.
MicroRNAs tied to treatment failure
Of participants with plasma samples available, 46% had treatment failure. In a multivariable logistic regression model using a backward selection approach, each 1 U increase in log2 microRNA-194-5p (OR = 1.5; 95% CI, 1.2-1.9) and log2 microRNA-15b-5p (OR = 1.2; 95% CI, 1.1-1.3) was associated with a greater likelihood for treatment failure. Each 1 U increase in log2 microRNA-let 7g-5p (OR = 0.7; 95% CI, 0.5-0.8) and log2 microRNA-431-5p (OR = 0.9; 95% CI, 0.8-1) was associated with lower odds for treatment failure.
Researchers also assessed whether microRNA abundance was associated with beta-cell function indices. Of the study group, 43% had a 20% or greater reduction in C-peptide oral disposition index, which is the product of insulin sensitivity multiplied by C-peptide index. Each 1 U increase in log2 microRNA-155-5p (OR = 1.2; 95% CI, 1.1-1.4) and log2 microRNA-130b-3p (OR = 1.3; 95% CI, 1-1.7) was associated with higher odds of a C-peptide oral disposition index reduction at 6 months, whereas each 1 U increase in log2 microRNA-126-3p was associated with a lower likelihood of C-peptide oral disposition index decline at 6 months (OR = 0.6; 95% CI, 0.4-0.8).
“It was interesting that the combination of microRNAs that predicted treatment failure was not identical to those that predicted a decline in beta-cell function,” Tryggestad said. “While it is clear that beta-cell function is a key player in treatment failure, other mechanisms are also involved.”
More research needed
In an analysis of other markers of beta-cell function, microRNA-122-5p was negatively correlated with C-peptide oral disposition index at baseline (P < .001) and 24 months (P = .001) and was positively correlated with circulating proinsulin levels at baseline (P < .001), 24 months (P < .001) and 60 months (P = .004).
Tryggestad said future studies are needed to look at the targets of microRNAs and how they affect beta-cell function.
“Additionally, work is needed to understand the physiology that drives changes in the microRNA abundance,” Tryggestad said.
For more information:
Jeanie B. Tryggestad, MD, can be reached at jeanie-tryggestad@ouhsc.edu.
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