Upregulation of
chemokine CX3CL1 and its receptor CX3CR1 occurs in the diabetic human placenta.
Metformin, an
insulin-sensitizing
biguanide, is used in the
therapy of diabetic pregnancy. By preventing the activation of NF-κB,
metformin exhibits anti-inflammatory properties. We examined the influence of
hyperglycemia (25 mmol/
L glucose; HG group; N = 36) on
metformin-mediated effects on CX3CL1 and TNF-α production by placental lobules perfused extracorporeally. Additionally, CX3CR1 expression and contents of CX3CR1, TNF-α receptor 1 (
TNFR1), and NF-κB
proteins in the placental tissue were evaluated. Placentae perfused under normoglycemia (5 mmol/
L glucose; NG group; N = 36) served as the control.
Metformin (2.5 and 5.0 mg/L; subgroups B and C) lowered the production of CX3CL1 and TNF-α in a dose-dependent and time-dependent manner.
Hyperglycemia did not weaken the strength of these
metformin effects. Moreover, CX3CL1 levels after perfusion with 5.0 mg/L
metformin were reduced by 33.28 and 33.83% (at 120 and 150 min, respectively) in the HG-C subgroup versus 24.98 and 23.66% in the NG-C subgroup, which indicated an augmentation of the
metformin action over time in
hyperglycemia. CX3CR1 expression was significantly higher in the HG-B and HG-C subgroups compared to that in the NG-B and NG-C subgroups. Increased CX3CR1
protein content in the placental lysates was observed in subgroups B and C. The two higher
metformin concentrations significantly decreased the levels of NF-κBp65
protein content in both groups. However, the decrease was significantly stronger in
hyperglycemia.
TNFR1 upregulation in the HG group was not affected by
metformin. Further studies on
metformin therapy during pregnancy are needed, including safety issues.