Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
VIB Center for Brain & Disease Research, Leuven, Belgium.
Eur J Drug Metab Pharmacokinet. 2022 Nov;47(6):827-839. doi: 10.1007/s13318-022-00792-7. Epub 2022 Sep 3.
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).
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) for rebaudioside A vs. placebo.
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 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).
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.
Registered on ClinicalTrials.gov (NCT03510624).
甜菊糖苷 A 是一种甜菊醇糖苷，在被人体吸收并与甜菊醇葡萄糖苷结合之前，会被肠道微生物群去糖基化。虽然在小鼠中观察到甜菊糖苷 A 具有降血糖作用，但这些作用归因于代谢产物甜菊醇和甜菊醇葡萄糖苷。我们旨在描述早期 2 型糖尿病（T2DM）患者中甜菊糖苷 A 及其代谢物的药代动力学和药效学特性。
这项随机、安慰剂对照、开放标签、双向交叉试验在比利时鲁汶大学医院的 T2DM 患者中进行，这些患者正在接受二甲双胍或无治疗。给予口服甜菊糖苷 A（3 克）后，测定甜菊糖苷 A、甜菊醇和甜菊醇葡萄糖苷的血浆浓度。通过口服葡萄糖耐量试验（OGTT）在给予甜菊糖苷 A 19 小时后（即推测的甜菊醇和甜菊醇葡萄糖苷浓度达到最大值的时间）检查对葡萄糖稳态的影响。主要药效学终点是 OGTT 前 2 小时内血葡萄糖浓度-时间曲线下面积（AUC）的差异，即与安慰剂相比，甜菊糖苷 A 的 AUC。
共有 30 名受试者（[63.5（57.8-69.0）岁，86.7%为男性]完成了试验。几乎所有受试者在给药后 1 小时即可检测到甜菊糖苷 A。如预期的那样，在给予甜菊糖苷 A 19.5 小时后，甜菊醇和甜菊醇葡萄糖苷达到最大浓度。与安慰剂相比，甜菊糖苷 A 并未降低 AUC（-0.7（95%CI-22.3；20.9）h·mg/dL，P=0.95）。两种情况下的胰岛素和 C 肽浓度也相似（P>0.05）。
口服给予后，甜菊糖苷 A 易于吸收并代谢为甜菊醇和甜菊醇葡萄糖苷。然而，在 OGTT 期间，在代谢物浓度达到最大值时，未观察到葡萄糖以及胰岛素或 C 肽的变化。因此，在 T2DM 患者单次口服后，无法观察到甜菊糖苷 A 的抗糖尿病特性。
在 ClinicalTrials.gov 上注册（NCT03510624）。
