Pregnane X receptor agonists impair postprandial glucose tolerance

Area of Science:

• Pharmacology
• Endocrinology
• Metabolism

Background:

• The pregnane X receptor (PXR) is a nuclear receptor involved in xenobiotic metabolism.
• PXR activation can influence various physiological processes, including glucose homeostasis.
• Understanding PXR's role in glucose metabolism is crucial for metabolic disease management.

Purpose of the Study:

• To investigate the effect of a PXR agonist, rifampin, on glucose tolerance in healthy humans.
• To explore the impact of PXR activation on glucose and insulin responses during an oral glucose tolerance test (OGTT).
• To examine the effect of a rat PXR agonist (PCN) on glucose metabolism in rats.

Main Methods:

• A randomized, open-label, placebo-controlled crossover trial was conducted in 12 healthy volunteers.
• Participants received rifampin (600 mg daily) or placebo for 7 days, followed by an OGTT on day 8.
• Rat studies involved 4-day treatment with PCN, followed by OGTT and hepatic gene expression analysis.

Main Results:

• Rifampin significantly increased mean incremental glucose AUC(incr) by 192% (P=0.008) and insulin AUC(incr) by 45% (P=0.031) during OGTT.
• Fasting glucose, insulin, C-peptide, and HOMA-IR were not affected by rifampin treatment.
• PCN treatment in rats also increased glucose AUC(incr) and downregulated hepatic Glut2 mRNA.

Conclusions:

• Both human and rat PXR agonists induce postprandial hyperglycemia.
• PXR activation appears to have a detrimental effect on glucose tolerance.
• These findings highlight a potential negative role of PXR in glucose metabolism regulation.