High‐mobility group box 1 at the time of parturition in women with gestational diabetes mellitus

Abstract

ProblemHigh‐mobility group box 1 (HMGB1), a danger‐associated molecular pattern marker, may indicate sterile inflammation through innate immune pathways. HMGB1 is implicated in hyperglycemia and excess glucose in trophoblast. Metabolic dysfunction and dyslipidemia are associated with gestational diabetes mellitus (GDM), but few studies examined associations between HMGB1 and GDM. We determined HMGB1 levels, and the ratio of HMGB1 to innate immune markers, in women with GDM at parturition.Method of studyThis case‐control study of 50 GDM pregnancies and 100 healthy controls utilized data and plasma samples from PeriBank. HMGB1, pentraxin‐3, and interleukin (IL)‐6 were measured by ELISA. Logistic regression calculated odds ratios (OR) and 95% confidence intervals (CI) adjusting for age, pre‐pregnancy body mass index, and type of labor.ResultsThere were no significant associations between HMGB1 and GDM. The ratio of HMGB1 to pentraxin‐3 and IL‐6 did not alter the odds of GDM. There was a significant statistical interaction between HMGB1 and maternal age (P = .02). When associations were examined by age groups, HMGB1 was associated with reduced odds of HMGB1 among women ≤25 (AOR = 0.007 CI 95% <0.001‐0.3). Odds ratios increased as age increased (AOR range 1.2‐3.8) but results were not statistically significant.ConclusionHigh‐mobility group box 1 was not associated with GDM. However, we found evidence that maternal age was a potential effect modifier of the relationship between HMGB1 and GDM. As there is growing evidence that HMGB1 may play important roles in reproduction, future studies should explore maternal factors that may alter HMGB1 levels.

High‐mobility group box 1 is a driver of inflammation throughout pregnancy

“…Thus, in the third trimester of pregnancy, HMGB1 serum levels have been shown to be increased in GDM patients and associated with insulin resistance. 26 However, no difference in HMGB1 maternal plasma or serum level is seen at delivery, in GDM compared to normal patients 27,28 . In addition, the decrease in HMGB1 plasma levels at delivery does not have a significant association between IL‐6 and pentraxin‐3 levels in GDM, but is significantly associated with maternal age 27 .…”

“… 26 However, no difference in HMGB1 maternal plasma or serum level is seen at delivery, in GDM compared to normal patients 27,28 . In addition, the decrease in HMGB1 plasma levels at delivery does not have a significant association between IL‐6 and pentraxin‐3 levels in GDM, but is significantly associated with maternal age 27 . Interestingly, fetal membranes collected from GDM patients are the only tissue that shows increased HMGB1 protein expression 28 .…”

“…However, after the embryo has attached, an anti-inflammatory environment is key for the maintenance of pregnancy up until the initiation of parturition. 12 Thus, it is thought that if HMGB1 levels are elevated during the greater part of gestation, it can promote the inappropriate proinflammatory signaling that is central to many pregnancy morbidities such as preeclampsia, [13][14][15][16][17][18][19][20][21][22][23][24][25] gestational diabetes, [26][27][28] placenta inflammation, 20,[29][30][31][32] and anti-phospholipid syndrome (Table 1). 33,34 Indeed, the severity of these pregnancy complications is thought to be driven by sustained inflammation that may be due to increased secretion and cytoplasmic protein expression of HMGB1 within gestational tissues.…”

Inappropriate activation of invariant natural killer T cells and antigen‐presenting cells with the elevation of HMGB1 in preterm births without acute chorioamnionitis

“…Recent studies have suggested that HMGB1 is implicated in pregnancy complications, PB, [50][51][52][53] pre-eclampsia, 54,55 and gestational diabetes mellitus. 56 The aim of this study was to clarify the mechanism of PL and preterm premature rupture of membrane (PPROM) without aCAM related to microbial infection. To this end, the characteristics of immune cells in the deciduas of patients who underwent early to moderate PB without aCAM were investigated.…”

“…Extracellular HMGB1 binds to TLR2, TLR4, TLR9, RAGE, and CD24, 44 and ligation results in excessive inflammation. Recent studies have suggested that HMGB1 is implicated in pregnancy complications, PB, 50‐53 pre‐eclampsia, 54,55 and gestational diabetes mellitus 56 …”