title: The effect of pregnane X receptor agonists on postprandial incretin hormone secretion in rats and humans.
abstract: 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.
authors.affiliation: Research Unit of Internal Medicine, University of Oulu, Oulu, Finland. janne.hukkanen@oulu.fi.|Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.|Biocenter Oulu, Oulu, Finland.|Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Hukkanen
authors.affiliation: Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.|School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.|Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Rysa
authors.affiliation: Biocenter Oulu, Oulu, Finland.|Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.|Research Unit of Biomedicine, Physiology, University of Oulu, Oulu, Finland.
authors.forename: K A
authors.initials: KA
authors.lastname: Makela
authors.affiliation: Biocenter Oulu, Oulu, Finland.|Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.|Research Unit of Biomedicine, Physiology, University of Oulu, Oulu, Finland.
authors.forename: K-H
authors.initials: KH
authors.lastname: Herzig
authors.affiliation: Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.|Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Hakkola
authors.affiliation: Research Unit of Internal Medicine, University of Oulu, Oulu, Finland.|Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.|Biocenter Oulu, Oulu, Finland.|Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: M J
authors.initials: MJ
authors.lastname: Savolainen
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000097:blood; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D019894:Peptide YY / Q000097:blood; D019518:Postprandial Period / Q000502:physiology; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000819:agonists*; D012293:Rifampin / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007328:Insulin; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D019894:Peptide YY; D011285:Pregnenolone Carbonitrile; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D012293:Rifampin