Placenta tissue-based and circulating markers of cellular senescence in gestational diabetes mellitus

BACKGROUND: Cellular senescence is an important pathophysiological feature in placenta-related pregnancy complications, but its role in gestational diabetes mellitus is not established. Our aim was to examine histomorphological features, as well as immunohistochemical and circulating markers of senescence in placentas and plasma from women with gestational diabetes compared to euglycemic controls. METHODS: Normotensive women (gestational diabetes: n = 20; gestational age-matched euglycemic controls: n = 20) with placenta and third trimester plasma samples were included. Histomorphological placenta assessment was done using the Amsterdam Workshop Consensus Criteria. Immunohistochemical antibodies to p21, p16, interleukin 6, 8-hydroxy-2'-deoxyguanosine, aldehyde oxidase 1 and caspase-3 were analyzed in trophoblast nuclei and cytoplasm. The circulating senescence marker β-Galactosidase and seven markers of the senescence-associated secretory phenotype were analyzed in maternal plasma. Significance was set at p ≤ 0.05. RESULTS: Intervillous fibrin was increased for gestational age in a higher proportion of gestational diabetes placentas compared to controls (50% vs. 5%, p = 0.001). A lower proportion of gestational diabetes placentas had distal villous hypoplasia (10% vs. 40%, p = 0.03) and positive staining in trophoblast nuclei for p21 (p < 0.001) compared to controls. In women with gestational diabetes, seven of the eight circulating senescence markers showed higher median levels compared to controls, of which five were statistically significant. CONCLUSION: We found increased intervillous fibrin, but no immunohistochemical evidence of increased placental cellular senescence in our well-controlled gestational diabetes group compared to euglycemic controls. The elevated levels of circulating senescence biomarkers suggest that extraplacental inflammatory-associated senescence occurs even in well-controlled gestational diabetes.