Abstract
Gestational Diabetes Mellitus (GDM) is characterised by insulin resistance accompanied by reduced beta-cell compensation to increased insulin demand, typically observed in the second and third trimester and associated with adverse pregnancy outcomes. There is a need for a biomarker that can accurately monitor status and predict outcome in GDM, reducing foetal-maternal morbidity and mortality risks. To this end, circulating microRNAs (miRNAs) present themselves as promising candidates, stably expressed in serum and known to play crucial roles in regulation of glucose metabolism. We analysed circulating miRNA profiles in a cohort of GDM patients (n = 31) and nondiabetic controls (n = 29) during the third trimester for miRNA associated with insulin-secretory defects and glucose homeostasis. We identified miR-330-3p as being significantly upregulated in lean women with GDM compared to nondiabetic controls. Furthermore, increased levels of miR-330-3p were associated with better response to treatment (diet vs. insulin), with lower levels associated with exogenous insulin requirement. We observed miR-330-3p to be significantly related to the percentage of caesarean deliveries, with miR-330-3p expression significantly higher in spontaneously delivered GDM patients. We report this strong novel association of circulating miR-330-3p with risk of primary caesarean delivery as a pregnancy outcome linked with poor maternal glycaemic control, strengthening the growing body of evidence for roles of diabetes-associated miRNAs in glucose homeostasis and adaptation to the complex changes related to pregnancy.
Highlights
The pathophysiology of Gestational Diabetes Mellitus (GDM) manifests as a result of the progressive insulin resistance (IR) and subsequent increased insulin secretion requirement that occurs during normal pregnancy[4]
Altered circulating miRNAs associated with the development and pathogenesis of insulin secretory defects and impaired glucose processing in such a clinically heterogeneous and often asymptomatic cohort would be invaluable in monitoring glycaemic management, treatment response and progression, allowing for tighter control impacting on associated complications
Weight gain was higher in nondiabetic controls (11.8 ± 4.1) compared to the GDM cohort (9.3 ± 4.1) with no significant differences observed in other variables
Summary
The pathophysiology of GDM manifests as a result of the progressive insulin resistance (IR) and subsequent increased insulin secretion requirement that occurs during normal pregnancy[4]. We have demonstrated significant increases in extracellular novel diabetes-linked miRNAs miR-224 and miR-103-3p in biofluids of patients with HNF1A-MODY primary beta-cell dysfunction, capable of differentiating these patients from T2DM23,24. Such ease of access and a minimally invasive approach places circulating miRNA profiling as a promising novel clinical approach in the progression and management of GDM and associated outcomes. Elevated expression of miR-224 in HNF1A-MODY and patients with T1DM, first reported by us as a novel miRNA in the field of diabetes, presents a potential role for miR-224 in beta-cell failure, distinct from relative insulin deficiency.
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