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

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.