High Glucose Promotes Inflammation and Weakens Placental Defenses against E. coli and S. agalactiae Infection: Protective Role of Insulin and Metformin

• Published in: International journal of molecular sciences Vol. 24; no. 6; p. 5243
• Main Authors: Jiménez-Escutia, Rodrigo, Vargas-Alcantar, Donovan, Flores-Espinosa, Pilar, Helguera-Repetto, Addy Cecilia, Villavicencio-Carrisoza, Oscar, Mancilla-Herrera, Ismael, Irles, Claudine, Torres-Ramos, Yessica Dorin, Valdespino-Vazquez, María Yolotzin, Velázquez-Sánchez, Pilar, Zamora-Escudero, Rodrigo, Islas-López, Marcela, Carranco-Salinas, Caridad, Díaz, Lorenza, Zaga-Clavellina, Verónica, Olmos-Ortiz, Andrea
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.03.2023; MDPI
• Subjects: Adaptation; Antidiabetics; Antimicrobial agents; Bacteria; bacterial count; Bacterial infections; bacterial invasiveness; beta-Defensins - metabolism; cytokine tolerization; Cytokines; Defensins; Diabetes; Diabetes mellitus; Diabetes, Gestational - metabolism; E coli; Escherichia coli - metabolism; Explants; Female; Glucose; Glucose - metabolism; Humans; Hyperglycemia; Hyperglycemia - metabolism; Hypoglycemia; hypoglycemics; Immunomodulation; Immunosuppressive agents; Inflammation; Inflammation - metabolism; inflammatory cytokines; Inflammatory response; Insulin; Insulin - metabolism; Insulin resistance; Insulin, Regular, Human - pharmacology; Interleukin 6; Invasiveness; Metabolism; Metformin; Metformin - metabolism; Metformin - pharmacology; Metformin - therapeutic use; Mothers; Pathogens; Placenta; Placenta - metabolism; Pregnancy; Pregnancy complications; Streptococcus agalactiae; Streptococcus agalactiae - metabolism; Streptococcus infections; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Urinary tract diseases; Urinary tract infections; Urogenital system; Vagina; Viral infections; hyperglycemia; hypoglycemics; inflammatory cytokines; cytokine tolerization; bacterial count; bacterial invasiveness; human term placenta
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24065243

Placentas from gestational diabetes mellitus (GDM) patients undergo significant metabolic and immunologic adaptations due to hyperglycemia, which results in an exacerbated synthesis of proinflammatory cytokines and an increased risk for infections. Insulin or metformin are clinically indicated for the treatment of GDM; however, there is limited information about the immunomodulatory activity of these drugs in the human placenta, especially in the context of maternal infections. Our objective was to study the role of insulin and metformin in the placental inflammatory response and innate defense against common etiopathological agents of pregnancy bacterial infections, such as and , in a hyperglycemic environment. Term placental explants were cultivated with glucose (10 and 50 mM), insulin (50-500 nM) or metformin (125-500 µM) for 48 h, and then they were challenged with live bacteria (1 × 10 CFU/mL). We evaluated the inflammatory cytokine secretion, beta defensins production, bacterial count and bacterial tissue invasiveness after 4-8 h of infection. Our results showed that a GDM-associated hyperglycemic environment induced an inflammatory response and a decreased beta defensins synthesis unable to restrain bacterial infection. Notably, both insulin and metformin exerted anti-inflammatory effects under hyperglycemic infectious and non-infectious scenarios. Moreover, both drugs fortified placental barrier defenses, resulting in reduced counts, as well as decreased and invasiveness of placental villous trees. Remarkably, the double challenge of high glucose and infection provoked a pathogen-specific attenuated placental inflammatory response in the hyperglycemic condition, mainly denoted by reduced TNF-α and IL-6 secretion after infection and by IL-1β after infection. Altogether, these results suggest that metabolically uncontrolled GDM mothers develop diverse immune placental alterations, which may help to explain their increased vulnerability to bacterial pathogens.