Immunoendocrine Dysregulation during Gestational Diabetes Mellitus: The Central Role of the Placenta

Abstract

Gestational Diabetes Mellitus (GDM) is a transitory metabolic condition caused by dysregulation triggered by intolerance to carbohydrates, dysfunction of beta-pancreatic and endothelial cells, and insulin resistance during pregnancy. However, this disease includes not only changes related to metabolic distress but also placental immunoendocrine adaptations, resulting in harmful effects to the mother and fetus. In this review, we focus on the placenta as an immuno-endocrine organ that can recognize and respond to the hyperglycemic environment. It synthesizes diverse chemicals that play a role in inflammation, innate defense, endocrine response, oxidative stress, and angiogenesis, all associated with different perinatal outcomes.

Keywords: IGF-I; adipokines; angiogenesis; antimicrobial peptides; cytokines; inflammation; insulin; lactotroph hormones; metabolic stress; oxidative stress.

Figure 1

Main molecular pathways disturbed in GDM placentae. In this schematic, we highlight in red main molecules reported as overexpressed/overactivated in GDM placentae, whereas downregulation is highlighted in green. High expression of phospho-IR-A and phospho-IR-B has been reported in the GDM placenta. After insulin binding, IR-A phosphorylates IRS-1 and recruits Scheme 2. and Grb2 proteins which induce the GTPase activity of Ras, and then a GDP is exchanged by a GTP. This initiates a subsequent cascade of phosphorylations of Raf, MEK, and Erk 1/2. Finally, overexpressed phospho-Erk proteins translocate to the nucleus and recognize SRE sites favoring active transcription of c-fos and Elk-1. FOS proteins have been implicated as regulators of cell proliferation, survival, differentiation, and transformation. This pathway mediates increased placental weight and increased fetal growth in GDM. Additionally, increased levels of free IGF-I resulting from low IGFBPs serum concentrations also activate IR-A signaling as well as IGF1R and are related to proliferative effects. IGF-I excess has been also implicated in macrosomia and excessive placental growth in GDM women. On the other hand, after insulin binding to IR-B, phospho-IRS-1 activates PI3K and leads the formation of PIP3 from PIP2. Then, PIP3 activates Akt which mediates diverse metabolic effects; one of them includes GLUT4 translocation from endosomes to the cellular membrane through TBC1D4 signaling. High expression of GLUT1 and GLUT9, and probably GLUT4, mediates high glucose uptake in the GDM placenta, which can also participate in fetal and placental growth through an excess of this energetic substrate. Finally, GDM placentae present high expression of leptin and its receptor. High expression of phospho-leptin receptor recruits JaK-2 protein and activates STAT 3 or 5 proteins. Then, STATs dimerize and translocate to the nucleus and recognize GAS sites and provoke transcription of VEGF, MMP-2, MMP-9, TNF-α, IL-1α, IL-1β, IFN-α, IFN-γ, among others, which exacerbate the inflammatory placental milieu and contribute to stimulating the angiogenic process. Additionally, activation of the leptin receptor can also crosstalk with MAPK and Akt pathways. Sustained overactivation of all these pathways finally leads to clinical insulin and leptin resistance. GAS: Gamma-activated sequence. GDM: Gestational diabetes mellitus; GLUTs: Glucose transporters; IGFBPs: IGF-I binding proteins; IGF-I: Insulin-like Growth Factor 1; IGF1R: IGF-I receptor; INS: Insulin; IR-A: Insulin receptor type A; IR-B: Insulin receptor type B; LEP: Leptin; LR: Leptin receptor; SRE: Serum response elements.

Figure 2

Role of placenta in the immunoendocrine dysregulations occurring in gestational diabetes mellitus. Hyperglycemia during pregnancy compromises the correct physiology of diverse organs, and particularly the placenta. Pregestational obesity is characterized by an excessive TG accumulation and changes in IR expression and signaling in adipose tissue, as well as in skeletal muscle cells. These changes in insulin-dependent tissues lead to insulin resistance. Then, adipose tissue secretes high levels of leptin and inhibits those of adiponectin. Leptin activation of JaK-2/STAT 3/5 pathway results in increased cytokine production contributing to peripheral metainflammation. Due to insulin resistance and altered IR signaling, women suffer chronic hyperglycemia. Clinical and biomedical studies indicate there is a positive regulatory loop between hyperglycemia and metainflammation, in which hyperglycemia induces placental and peripheral synthesis of pro-inflammatory cytokines, chemokines, and adipokines. Metainflammation also alters GLUT and IR expression which worsen hyperglycemia status. The synthesis of placental hormones is altered by hyperglycemia. Deficient synthesis of PRL and calcitriol (the active form of vitamin D) has been reported in GDM placentae, whereas hPL synthesis is increased. These placental hormonal changes, and probably estrogens and progestins, compromise pancreatic gene expression of GLUT2, glucokinase, insulin, survivin, cyclin D2, and Bcl6; all these genes are related to b-cells proliferation and survival. Because of reduced b-cells expansion, hyperglycemia worsens. Additionally, deficient synthesis of calcitriol abates placental expression of antimicrobial peptides related to innate defense, increasing mother and fetus vulnerability to infections in the perinatal period. Another endocrine dysregulation is derived from IGF-I overactivation in the placenta, which explains increased placental growth and glucose uptake. The establishment of a chronic inflammatory milieu in the placenta results in: (i) Increased production of pro-inflammatory cytokines, chemokines, and adipokines; (ii) Increased placental infiltration of M1 macrophages, cytotoxic neutrophils, and T cells; (iii) Deregulated production of pro-angiogenic and anti-angiogenic factors; and (iv) Increased lipid peroxidation and synthesis of ROS precursors. Even if angiogenesis is induced, vessels in the placenta are thickened and immature. Overall, altered vessels formation, hyperglycemia, and oxidative stress induce endothelial dysfunction. Furthermore, the serum inflammatory profile is evidenced by high levels of pro-inflammatory cytokines, chemokines, and adipokines as well as a higher presence of cytotoxic monocytes, neutrophils, and T cells. Hyperglycemia and over-activation of IGF-I signaling results in increased fetal growth which may contribute to macrosomia. Finally, hyperglycemia and oxidative stress produce pancreatic overstress in the fetus, causing an increased risk for T2DM development later in life. Experimental and clinical evidence indicates that GDM fetuses present a marked neural pro-oxidative environment which may lead to neural, motor and behavior disturbances. AMPs: antimicrobial peptides; GDM: Gestational diabetes mellitus; GLUT: Glucose transporter; hPL: human placental lactogen; IGF-I: Insulin-like Growth Factor 1; IR: Insulin receptor; N: Neutrophils; PRL: Prolactin; ROS: Reactive oxygen species; T: T lymphocytes; T2DM: type 2 Diabetes mellitus; TG: triglycerides; VD: vitamin D.