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Gestational Diabetes Mellitus Alters Cytokine Profiles and Macrophage Polarization in Human Placenta

Martalice Ribeiro Barbosa,Gabriela Feres de Marchi,Kênia Maria Rezende Silva,D. C. H. França,Marcondes Alves Barbosa da Silva,Jakeline Ribeiro Barbosa,Laura Valdiane Luz Melo,E. L. França,A. Honório-França

Published 2025 in International Journal of Molecular Sciences

ABSTRACT

Gestational Diabetes Mellitus (GDM) is a metabolic condition characterized by glucose intolerance, which manifests or is diagnosed for the first time during pregnancy. Hyperglycemia associated with GDM can induce a systemic and local inflammatory environment, directly affecting the maternal–fetal interface, particularly the placenta. The placenta, in turn, plays a central role in immune modulation and can alter cytokine and immune cell expression in response to metabolic stress. This study aimed to evaluate levels of inflammatory cytokines and the profiles of type 1 (M1) and type 2 (M2) macrophages in placentas from pregnant women with GDM. Forty placental samples were analyzed and divided into two groups: pregnant women with GDM (n = 20) and normoglycemic pregnant women (n = 20). The villous and extravillous portions were separated and analyzed for cytokine levels by flow cytometry and for macrophage immunophenotyping. The results showed a significant increase in IL-6, IL-8, IL-10, and IL-12P70 levels in the placentas of mothers with GDM, whereas IL-1β and TNF-α were reduced in the extravillous portion of this group. In addition, a higher percentage of CD14+ cells and M2 macrophages was observed, especially in the villous portion of the placentas of pregnant women with GDM. These findings suggest that gestational hyperglycemia modulates the placental immune response, altering cytokine levels and macrophage polarization patterns. GDM influences the placental immunological microenvironment, which can contribute to alterations in placental function and increased risks to fetal development. The data underscore the placenta’s role as an immunoregulatory organ and highlight the need for greater attention to inflammation associated with GDM in maternal and child health.

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