TRPM4 Ion Channels in Glycemic Control during Pregnancy.

During pregnancy, the glucose homeostasis of the mother adapts to accommodate the needs of a growing fetus. Decreased insulin sensitivity and increased insulin secretion from the pancreatic beta-cell contribute to this adaptation. Electrophysiological changes in the beta-cell during pregnancy, that could explain the increased insulin secretion, have not yet been identified. The non-selective Transient Receptor Potential Melastatin 4 (TRPM4) cation channel, expressed in beta-cells, may depolarize the beta-cell membrane and promote insulin release. In other organs, TRPM4 ion channel expression fluctuates depending on the relative concentration of estrogen and progesterone, hormones important during pregnancy. These findings suggest a role of TRPM4 in glycemic control, which can be influenced by female reproductive hormones during pregnancy. Using in vivo continuous glucose monitoring throughout the full pregnancy of wildtype (WT) and TRPM4 knockout (KO) mice allows to analyze glycemia during oral glucose tolerance tests (OGTTs) and spontaneous feeding behavior, and to determine glycemic variability. TRPM4 KOmice are hyperglycemic compared to WT mice, mainly before and during the first half of pregnancy. The mean glucose concentration was increased in TRPM4 KO mice in the beginning of pregnancy. In both WT mice and TRPM4 KO mice, the overall glycemia gradually increased during this period, maintaining the difference in glycemia between the two genotypes. Later in pregnancy, the glycemia of both genotypes started gradually decreasing. However, glycemia of TRPM4 KO mice decreased faster, reducing the difference in glycemia between the two genotypes. This indicates a different adaptation to pregnancy. The maximum glucose levels reached during the OGTTs were larger for the TRPM4 KO mice compared to the wildtype mice, which is in line with the general observed hyperglycemia of TRPM4 KOmice. Furthermore, we observed that fasting glucose concentrations, obtained right before the OGTTs, were significantly increased for the TRPM4 KO mice compared to WT mice. Glycemic variability provides information regarding sudden changes and fluctuations in the blood glucose concentration. In general, there were no substantial differences in terms of glycemic variability between both genotypes. To conclude, we could show that TRPM4 plays an active role in glycemic control, before and during pregnancy.