Background and Objectives Rebaudioside A, a steviol glycoside, is deglycosylated by intestinal microflora prior to the absorption of steviol and conjugation to steviol glucuronide. While glucose-lowering properties are observed for rebaudioside A in mice, they have been attributed to the metabolites steviol and steviol glucuronide. We aimed to characterize the pharmacokinetic and pharmacodynamic properties of rebaudioside A and its metabolites in patients with early-onset type 2 diabetes mellitus (T2DM). Methods This randomized, placebo-controlled, open-label, two-way crossover trial was performed in subjects with T2DM on metformin or no therapy at the University Hospitals Leuven, Belgium. Following oral rebaudioside A (3 g), plasma concentrations of rebaudioside A, steviol and steviol glucuronide were determined. The effect on glucose homeostasis was examined by an oral glucose tolerance test (OGTT) performed 19 h following rebaudioside A administration, i.e. the presumed time of maximal steviol and steviol glucuronide concentrations. The primary pharmacodynamic endpoint was the difference in area under the blood glucose concentration–time curve during the first 2 h of the OGTT (AUC Glucose(0–2h) ) for rebaudioside A vs. placebo. Results In total, 30 subjects [63.5 (57.8–69.0) years of age, 86.7% male] completed the trial. Rebaudioside A was detected as early as 1 h after administration in nearly all subjects. As expected, steviol and steviol glucuronide reached their maximal concentrations at 19.5 h following rebaudioside A administration. Rebaudioside A did not lower the AUC Glucose(0–2h) compared to placebo (− 0.7 (95% CI − 22.3; 20.9) h·mg/dL, P = 0.95). Insulin and C-peptide concentrations were also comparable between both conditions ( P > 0.05). Conclusion Rebaudioside A is readily absorbed after oral administration and metabolized to steviol and steviol glucuronide. However, no effect on glucose nor insulin or C-peptide excursion was observed during the OGTT at the time of maximal metabolite concentrations. Thus, no antidiabetic properties of rebaudioside A could be observed in patients with T2DM after single oral use. Clinical Trial Registration Registered on ClinicalTrials.gov (NCT03510624). Supplementary Information The online version contains supplementary material available at 10.1007/s13318-022-00792-7.

During pregnancy, metabolic adaptations occur to maintain the balance between maternal and foetal growth, including increased insulin secretion and decreased insulin sensitivity. When the body fails to adjust, gestational diabetes mellitus develops. To gain insight in the pregnancy-induced adaptations, we applied continuous glucose monitoring via telemetric transmitters. We show that continuous glucose monitoring in conscious, non-stressed, freely moving mice throughout the full pregnancy is feasible, accurate and safe. We show that healthy mice during a full pregnancy develop adaptations in glucose homeostasis reminiscent of those in pregnant women. Furthermore, continuous glucose monitoring allows the complete analysis of all aspects of glucose excursions associated with spontaneous feeding episodes, and the thorough analysis of glycaemic variability. In conclusion, continuous glucose monitoring allows a detailed description of the glycaemic status during pregnancy, which will help to unravel specific mechanisms for gestational diabetes mellitus.

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.