In order to maintain glycemic homeostasis during pregnancy, the increase in maternal insulin resistance is compensated by hyperplasia and increased function of maternal pancreatic beta cell. The failure of this compensatory mechanism is associated with GDM (1).
GDM occurs in 10–18% of all pregnancies (2–4) and it confers a higher risk of several pregnancy complications for both mother and newborn, such as cesarean delivery, polyhydramnios, preeclampsia, jaundice, macrosomia, and neonatal hypoglycemia. GDM is also considered a risk factor for type 2 diabetes mellitus (T2D), obesity and cardiovascular disease (5, 6).
Studies conducted in vitro and in rodent models have shown modified expression of many islet genes during pregnancy. Among the most significantly upregulated genes are the ones encoding the two isoforms of tryptophan hydroxylase (Tph1 and Tph2), the rate-limiting enzyme of serotonin (5-hydroxytryptamine, 5-HT) synthesis (7, 8). Βeta cells have the ability to synthesize, store and secrete 5-HT and islet 5-HT content increases during pregnancy (7–9), secondarily to stimulation of TPH1 and TPH2 expression in beta cells. This process is dependent on placental lactogen (PL) acting through prolactin receptors (PRLR) (9); thus, 5-HT acts downstream of PL signaling to drive beta cell expansion (8, 10, 11).
5-HT receptors are classified into seven different families (HTR1–7), some of which contain different subtypes (12). In pregnant mice, the HTR2B expression closely matched the period of increased beta cell proliferation (8, 13) and blocking HTR2B signaling impaired beta cell expansion, causing glucose intolerance (8).
Microarray and RNA sequencing analyses revealed transcripts of almost all 5-HT receptors in human islets (14, 15) and an in vitro study have shown that the activation of HTR2B promoted glucose-stimulated insulin secretion (GSIS) not only in mouse, but also in human beta cells, suggesting that 5-HT also stimulates insulin release through HTR2B (15).
Given the importance of the serotoninergic system for the adaptation of beta cells to the increased insulin demand during pregnancy, we hypothesized that genetic variations SNPs in the HTR2B gene could influence the risk of developing GDM.
Subjects
This was a case-control study that initially recruited 1,130 pregnant women between September 2014 and September 2017; 90 refused to participate and 36 were considered ineligible for not meeting the inclusion criteria. Of the 1,004 pregnant women then recruited, 108 were lost to follow-up, resulting in a final number of 896. After a diagnostic evaluation for GDM, women were classified into two study groups: 453 pregnant women that had GDM diagnosis in a prior pregnancy or in the current pregnancy and 443 pregnant women without the diagnosis of GDM. All pregnant women were followed-up at the Obstetric Clinic of a tertiary university hospital. The study was carried out in compliance with the Declaration of Helsinki, in accordance with institutional ethics committees. After signing informed consent, participants were evaluated for clinical and biochemical characteristics.