Discrepancy in Insulin Regulation between Gestational Diabetes Mellitus (GDM) Platelets and Placenta

Abstract

Earlier findings have identified the requirement of insulin signaling on maturation and the translocation of serotonin (5-HT) transporter, SERT to the plasma membrane of the trophoblast in placenta. Because of the defect on insulin receptor (IR) in the trophoblast of the gestational diabetes mellitus (GDM)-associated placenta, SERT is found entrapped in the cytoplasm of the GDM-trophoblast. SERT is encoded by the same gene expressed in trophoblast and platelets. Additionally, alteration in plasma 5-HT levels and the 5-HT uptake rates are associated with the aggregation rates of platelets. Therefore, here, we investigated a novel hypothesis that GDM-associated defects in platelet IR should change their 5-HT uptake rates, and this should be a leading factor for thrombosis in GDM maternal blood. The maternal blood and the placentas were obtained at the time of cesarean section from the GDM and non-diabetic subjects (n ‫؍‬ 6 for each group), and the platelets and trophoblasts were isolated to determine the IR activity, surface level of SERT, and their 5-HT uptake rates.Interestingly, no significant differences were evident in IR tyrosine phosphorylation or the downstream elements, AKT and S6K in platelets and their aggregation rates in both groups. Furthermore, insulin stimulation up-regulated 5-HT uptake rates of GDM-platelets as it does in the control group. However, the phosphorylation of IR and the downstream elements were significantly lower in GDM-trophoblast and showed no response to the insulin stimulation while they showed 4-fold increase to insulin stimulation in control group. Similarly, the 5-HT uptake rates of GDM-trophoblast and the SERT expression on their surface were severalfold lower compared with control subjects. IR is expressed in all tissues, but it is not known if diabetes affects IR in all tissues equally. Here, for the first time, our findings with clinical samples show that in GDM-associated defect on IR is tissue type-dependent. While IR is impaired in GDM-placenta, it is unaffected in GDM-platelet. Gestational diabetes mellitus (GDM)2 is the most common metabolic complication of pregnancy, affecting up to 10 -15% of all pregnancies (1-7), depending on the diagnostic criteria. GDM carries risks to both mother and fetus including the development of obesity, diabetes, and cardiovascular disease in later life. GDM is defined as carbohydrate intolerance due to the impaired insulin signaling with onset or first recognition during pregnancy (1-5). In GDM, the pancreatic ␤ cells fail to produce enough insulin to overcome insulin resistance, which leads to carbohydrate intolerance (5, 6), and a great potential of developing type II diabetes mellitus (1).Recently, it has been shown that the placenta develops insulin resistance in GDM (8 -10), for reasons that are not well understood. The placenta not only transports nutrients to the growing fetus, but importantly, serotonin (5-HT), 5-hydroxytryptamine, is transported across the placenta and is as an essential molecule for embryogenesis (11,12). Stu...

Sex-Specific Neurodevelopmental Programming by Placental Insulin Receptors on Stress Reactivity and Sensorimotor Gating

“…The current study aimed to delineate the specific role of InsR in placental trophoblasts, the cell population known to exhibit insulin resistance in human diabetic placental tissue (21). Effects on InsR outside of trophoblast cells were not detected at E12.5, at E17.5, or in the adult brain; however, the potential impact at additional time points has not been examined.…”

Molecular pathways disrupted by gestational diabetes mellitus

“…Although the insulin receptor is not implicated in placental glucose transport, placental insulin signalling may instead contribute to lipid metabolism (Ruiz-Palacios et al 2017). Examination of GDM placenta displayed reduced expression of insulin receptor together with reduced phosphorylation of its downstream molecule, Akt (Li et al 2016). However, limited data are available on the consequences of altered placental insulin signalling on fetal outcome.…”

Frontiers of Serotonin Beyond the Brain

“…Post-translational modifications regulate the uptake kinetics and membrane trafficking of SERT, in part by regulating the proper folding and assembly of SERT in a host-dependent manner [80]. As a result, these modifications have important effects on 5-HT roles in the central nervous system and in the periphery [44,59,81,82]. Thus, identification of the pathways and factors associated with post-translational modification of SERT is important to understand SERT function in various biological processes.…”