title: Pregnane X receptor agonists impair postprandial glucose tolerance.
abstract: We conducted a randomized, open, placebo-controlled crossover trial to investigate the effects of the pregnane X receptor (PXR) agonist rifampin on an oral glucose tolerance test (OGTT) in 12 healthy volunteers. The subjects were administered 600 mg rifampin or placebo once daily for 7 days, and OGTT was performed on the eighth day. The mean incremental glucose and insulin areas under the plasma concentration-time curves (AUC(incr)) increased by 192% (P = 0.008) and 45% (P = 0.031), respectively. The fasting glucose, insulin, and C-peptide, and the homeostasis model assessment for insulin resistance, were not affected. The glucose AUC(incr) during OGTT was significantly increased in rats after 4-day treatment with pregnenolone 16α-carbonitrile (PCN), an agonist of the rat PXR. The hepatic level of glucose transporter 2 (Glut2) mRNA was downregulated by PCN. In conclusion, both human and rat PXR agonists elicited postprandial hyperglycemia, suggesting a detrimental role of PXR activation on glucose tolerance.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Rysä
authors.forename: M
authors.initials: M
authors.lastname: Buler
authors.forename: M J
authors.initials: MJ
authors.lastname: Savolainen
authors.forename: H
authors.initials: H
authors.lastname: Ruskoaho
authors.forename: J
authors.initials: J
authors.lastname: Hakkola
authors.forename: J
authors.initials: J
authors.lastname: Hukkanen
mesh_terms: D000328:Adult; D000818:Animals; D002096:C-Peptide / Q000378:metabolism; D018592:Cross-Over Studies; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005951:Glucose Tolerance Test / Q000706:statistics & numerical data; D051273:Glucose Transporter Type 2 / Q000096:biosynthesis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019518:Postprandial Period; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology*; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000819:agonists*; D012293:Rifampin / Q000494:pharmacology*
chemical_list: D002096:C-Peptide; D051273:Glucose Transporter Type 2; D007328:Insulin; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D011285:Pregnenolone Carbonitrile; D012293:Rifampin