Hyperglycemia and gestational diabetes suppress placental glycolysis and mitochondrial function and alter lipid processing

Abstract

The degree that maternal glycemia affects placental metabolism of trophoblast cell types [cytotrophoblast (CTB) and syncytiotrophoblast (SCT)] in pregnant persons with gestational diabetes mellitus (GDM) is unknown. We tested the hypotheses that (a) hyperglycemia suppresses the metabolic rates of CTB and SCT; and (b) low placental metabolic activity from GDM placentas is due to decreased oxygen consumption of CTB. Trophoblast cells isolated from GDM and non‐GDM term placentas were cultured for 8‐hour (CTB) and following syncytialization at 72‐hour (SCT) in 5 mM of glucose or 25 mM of glucose. Oxygen consumption rates, glycolysis, ATP levels, and lipid droplet morphometries were determined in CTB and SCT. In CTB from GDM placentas compared to control CTB: (a) oxidative phosphorylation was decreased by 44% (41.8 vs 74.2 pmol O2/min/100 ng DNA, P = .002); (b) ATP content was 39% lower (1.1 × 10−7 vs 1.8 × 10−7 nM/ng DNA, P = .046); and (c) lipid droplets were two times larger (31.0 vs 14.4 µm2/cell, P < .001) and 1.7 times more numerous (13.5 vs 7.9 lipid droplets/cell, P < .001). Hyperglycemia suppressed CTB glycolysis by 55%‐60% (mean difference 20.4 [GDM, P = .008] and 15.4 [non‐GDM, P = .029] mpH/min/100 ng DNA). GDM SCT was not metabolically different from non‐GDM SCT. However, GDM SCT had significantly decreased expression of genes associated with differentiation including hCG, GCM1, and syncytin‐1. We conclude that suppressed metabolic activity by the GDM placenta is attributable to metabolic dysfunction of CTB, not SCT. Critical placental hormone expression and secretion are decreased in GDM trophoblasts.

Placental Endocrine Activity: Adaptation and Disruption of Maternal Glucose Metabolism in Pregnancy and the Influence of Fetal Sex

“…Accordingly, hCG and free β-hCG in early pregnancy is negatively associated with GDM risk [ 47 , 48 , 49 , 50 ]. This association has been confirmed in GDM-derived primary trophoblasts, which showed significantly decreased expression of genes associated with differentiation, including impaired synthesis of the hCG-beta subunit [ 51 ]. Moreover, serum β-hCG is negatively correlated with the homeostasis model assessment of insulin resistance index (HOMA-IR) [ 52 ].…”

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

“…There has also been reported increased fibrinoid necrosis, chorangiosis, and ischemia [ 25 , 26 ]. Additionally, GDM syncytiotrophoblasts present an exaggerated mitochondrial dysfunction accompanied by a lower rate of glycolysis, oxidative phosphorylation, and ATP synthesis, which indicates a compromised metabolic supply and therefore placental overstress [ 27 , 28 ]. Lipid metabolism of the placenta is also distorted in GDM with evidence of larger lipid droplets, higher triglyceride accumulation, and fatty acid transporter expression [ 28 , 29 ].…”

“…Additionally, GDM syncytiotrophoblasts present an exaggerated mitochondrial dysfunction accompanied by a lower rate of glycolysis, oxidative phosphorylation, and ATP synthesis, which indicates a compromised metabolic supply and therefore placental overstress [ 27 , 28 ]. Lipid metabolism of the placenta is also distorted in GDM with evidence of larger lipid droplets, higher triglyceride accumulation, and fatty acid transporter expression [ 28 , 29 ]. This is all indicative of modification of the endocrine, immune, angiogenic, and antioxidant functions by placentae in GDM mothers.…”

Vicissitudes in the placental cotyledon number in a singleton pregnancy with gestational diabetes

“…Gestational diabetes mellitus (GDM) is a common glucose metabolic disorder, resulting from alterations in glucose homeostasis that occurs during the second and third trimesters of pregnancy, and is clearly not preexisting or overt diabetes. [ 1 2 3 4 5 ] It is one of the common complications encountered during pregnancy. [ 3 6 ] The precise prevalence of GDM remains vague;[ 2 ] on the other hand, the prevalence of GDM showed a dramatic annual increase that is affected by the diagnostic tests applied and the population included in the research.…”