Increased expression of microRNA-15a and microRNA-15b in skeletal muscle from adult offspring of women with diabetes in pregnancy

Abstract

Offspring of women with diabetes in pregnancy exhibit skeletal muscle insulin resistance and are at increased risk of developing type 2 diabetes, potentially mediated by epigenetic mechanisms or changes in the expression of small non-coding microRNAs. Members of the miR-15 family can alter the expression or function of important proteins in the insulin signalling pathway, affecting insulin sensitivity and secretion. We hypothesized that exposure to maternal diabetes may cause altered expression of these microRNAs in offspring skeletal muscle, representing a potential underlying mechanism by which exposure to maternal diabetes leads to increased risk of cardiometabolic disease in offspring. We measured microRNA expression in skeletal muscle biopsies of 26- to 35-year-old offspring of women with either gestational diabetes (O-GDM, n = 82) or type 1 diabetes (O-T1DM, n = 67) in pregnancy, compared with a control group of offspring from the background population (O-BP, n = 57) from an observational follow-up study. Expression of both miR-15a and miR-15b was increased in skeletal muscle obtained from O-GDM (both P < 0.001) and O-T1DM (P = 0.024, P = 0.005, respectively) compared with O-BP. Maternal 2 h post OGTT glucose levels were positively associated with miR-15a expression (P = 0.041) in O-GDM after adjustment for confounders and mediators. In all groups collectively, miRNA expression was significantly positively associated with fasting plasma glucose, 2 h plasma glucose and HbA1c. We conclude that fetal exposure to maternal diabetes is associated with increased skeletal muscle expression of miR-15a and miR-15b and that this may contribute to development of metabolic disease in these subjects.

Short Report: Circulating microRNAs are associated with incident diabetes over 10 years in Japanese Americans

“…In a community-based sample, miR-106b, miR-144, miR-15b, miR-451, and miR-93 were upregulated and miR-15a downregulated in skeletal muscle of individuals with type 2 diabetes compared to individuals with normal glucose tolerance 17 . In another study, higher levels of both skeletal muscle miR-15a and miR-15b were associated with higher fasting and 2-hour glucose in adults with and without diabetes 18 . Inconsistency of identified miRNAs in previous as well as the current study could be due to racial and ethnic differences in the study populations, heterogeneous mechanisms contributing to diabetes pathogenesis across the populations studied,or differences in methods (sample source, processing, and profiling).…”

MicroRNA single‐nucleotide polymorphisms and diabetes mellitus: A comprehensive review

“…Houshmand et al found that miR‐15a and miR‐15b were increased in expression in the adult offspring of women diagnosed with GDM during pregnancy. Furthermore, the offspring had significantly higher 2 hours plasma glucose values and borderline higher HbA1C levels …”

“…Furthermore, the offspring had significantly higher 2 hours plasma glucose values and borderline higher HbA1C levels. 60 Recently, the relationship between circulating levels of miRNAs and HbA1C levels has become another focus of current research.…”

Inhibition of miR-383 suppresses oxidative stress and improves endothelial function by increasing sirtuin 1

“…The function of miRNAs is modulated by binding to the 3 0 -UTR of target mRNAs, resulting in degeneration of mRNA and prohibition of translation (11). Previous studies have revealed that various miRNAs regulate the development of diabetes (12,13). Downregulation of miR-15a in the retina of patients with diabetes was found to counteract inflammation and generation of vessels (14).…”