Abstract
Insulin resistance (IR) is a critical factor of the pathophysiology of Gestational diabetes mellitus (GDM). Studies on key organs involved in IR, such as livers and adipose tissues, showed that Toll-like receptor 4 (TLR4) can regulate insulin sensitivity. As a maternal-fetal interface with multi-functions, placentae could contribute to the development of IR for GDM. Thus, we investigated the expressions of TLR4/Myeloid Differentiation factor 88 (MyD88)/Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB) in term placentae from 33 GDM women and 36 healthy pregnant women with normal glucose tolerance, evaluated local and systemic IR and furthermore identified the association between placental TLR4 and IR. TLR4 protein was expressed in various cells of term placenta, particularly in syncytiotrophoblast of villi. Compared with normal pregnancy, the expression of TLR4/MyD88/NF-kB pathway increased in the placenta of GDM (p<0.05), and these differences were more pronounced in the maternal section of the placenta and the syncytiotrophoblast of villi. In addition, more severe IR was observed in the placenta of GDM patients than the control group, evidenced with higher pIRS-1(ser312) (p<0.001) and lower IRS-1 (p<0.05) as well as pAkt proteins (p<0.01). The expression of TLR4 in placentae is positively correlated with local IR (pIRS-1: r = 0.76, p <0.001 and pAkt: r = -0.47, p <0.001) and maternal fasting (r = 0.42, p <0.01), one-hour (r = 0.52, p <0.01) and two-hour glucose (r = 0.54, p <0.01) at OGTT. We found an that enhanced expression of the TLR4-MyD88-NF-kB pathway occurs in GDM placentae, which positively correlates with heightened local IR in placentae and higher maternal hyperglycemia. The TLR4/MyD88/NF-kB pathway may play a potential role in the development of IR in placentae of GDM.
Highlights
Gestational diabetes mellitus (GDM) is presented with systemic and local insulin resistance (IR)
Our data identified the enhanced expression of Toll-like receptor 4 (TLR4) and its well-recognized downward molecules, Myeloid Differentiation factor 88 (MyD88) and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB), in the placentae of GDM compared with the control group
The findings of this study showed that TLR4 was expressed by various cells of term placentae, in syncytiotrophoblast of villi
Summary
Gestational diabetes mellitus (GDM) is presented with systemic and local insulin resistance (IR). Maternal IR is a normal part of human pregnancy, during the second trimester and third trimester of human pregnancy. In women diagnosed with GDM, IR is more pronounced. The underlying mechanism of IR has being investigated. Several possible candidates have been identified, including metabolic factors [1,2,3], mitochondrial function [4], oxidative stress [5, 6] and adipocytokines [7]. Systemic and local inflammation is thought to play an important role in the development of IR [8, 9]
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