Hukkanen J, Rysa J, Makela K A, Herzig K-H, Hakkola J, Savolainen M J
Research Unit of Internal Medicine, University of Oulu, Oulu, Finland.
Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.
J Physiol Pharmacol. 2015 Dec;66(6):831-9.
We recently showed that pregnane X receptor (PXR) agonists cause hyperglycaemia during oral glucose tolerance test (OGTT) in rats and healthy volunteers (Rifa-1 study). We now aimed to determine if the secretion of incretin hormones, especially glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), are affected by PXR agonists since these gut-secreted hormones are major regulators of postprandial glucose metabolism. The Rifa-2 study had a one-phase, open-label design. Twelve subjects were given 600 mg of rifampicin a day for a week. OGTT with glucose, insulin, and incretin hormone measurements was performed before and after the rifampicin dosing. Incretins and insulin were analysed in previously collected rat OGTT samples after pregnenolone 16α-carbonitrile (PCN) or control treatment for 4 days. Rifampicin treatment did not affect glucose, insulin, GLP-1, GIP, glucagon, and peptide YY levels statistically significantly. Incremental AUCs (AUCincr) of glucose and insulin tended to increase (41% increase in glucose AUCincr, P = 0.21, 95% confidence interval (CI) of the difference -47, 187; 24% increase in insulin AUCincr, P = 0.084, CI of the difference -110, 1493). Glucagon AUC was increased in women (53% increase, P = 0.028) and decreased in men (19% decrease, P < 0.001) after rifampicin dosing. In combined analysis of human Rifa-1 and Rifa-2 studies, glucose AUCincr was elevated by 63% (P = 0.010) and insulin AUCincr by 37% (P = 0.011). PCN increased rat insulin level at 60 min time point but did not affect incretin and insulin AUCs statistically significantly. In conclusion, PXR agonists do not affect the secretion of incretin hormones. The regulation of glucagon secretion by PXR may be sexually dimorphic in humans. The mechanism of disrupted glucose metabolism induced by PXR activation requires further study.
我们最近发现，孕烷X受体（PXR）激动剂在大鼠和健康志愿者的口服葡萄糖耐量试验（OGTT）期间会导致高血糖（Rifa-1研究）。我们现在旨在确定肠促胰岛素激素的分泌，尤其是胰高血糖素样肽-1（GLP-1）和胃抑制多肽（GIP），是否受PXR激动剂影响，因为这些肠道分泌的激素是餐后葡萄糖代谢的主要调节因子。Rifa-2研究采用单阶段开放标签设计。12名受试者每天服用600毫克利福平，持续一周。在利福平给药前后进行了葡萄糖、胰岛素和肠促胰岛素激素测量的OGTT。在孕烯醇酮16α-腈（PCN）或对照处理4天后，对先前收集的大鼠OGTT样本中的肠促胰岛素和胰岛素进行分析。利福平治疗对葡萄糖、胰岛素、GLP-1、GIP、胰高血糖素和肽YY水平没有统计学上的显著影响。葡萄糖和胰岛素的增量AUC（AUCincr）有增加趋势（葡萄糖AUCincr增加41%，P = 0.21，差异的95%置信区间（CI）为-47, 187；胰岛素AUCincr增加24%，P = 0.084，差异的CI为-110, 1493）。利福平给药后，女性的胰高血糖素AUC增加（增加53%，P = 0.028），男性的胰高血糖素AUC降低（降低19%，P < 0.001）。在人类Rifa-1和Rifa-2研究的联合分析中，葡萄糖AUCincr升高了63%（P = 0.010），胰岛素AUCincr升高了37%（P = 0.011）。PCN在60分钟时间点增加了大鼠胰岛素水平，但对肠促胰岛素和胰岛素AUC没有统计学上的显著影响。总之，PXR激动剂不影响肠促胰岛素激素的分泌。PXR对胰高血糖素分泌的调节在人类中可能存在性别差异。PXR激活诱导葡萄糖代谢紊乱的机制需要进一步研究。
