An In Vivo Rat α-D-glucose Stable Isotope Homeostasis Drug Discovery Screen: A Targeted Metabolomics Approach

Area of Science:

• Metabolomics
• Pharmacology
• Animal Models

Background:

• Assessing drug effects on glucose metabolism is crucial for metabolic disease research.
• Existing methods for evaluating glucose homeostasis can be time-consuming and complex.

Purpose of the Study:

• To develop and validate a novel dual isotopic oral glucose tolerance test (DIS-OGTT) in rats.
• To enable efficient screening of drug candidates for their impact on glucose absorption, hepatic glucose production, and glucose disposal.

Main Methods:

• Utilized two isotopically labeled glucose compounds ([6-13C1-6, 6 omino-2H2]-glucose intravenously and [U-13C6] glucose orally) in rats.
• Monitored glucose homeostasis by quantifying glucose isotopomers in plasma via liquid chromatography-tandem mass spectrometry.
• Analyzed drug effects on glucose absorption, gluconeogenesis, and insulin-mediated glucose disposal.

Main Results:

• The DIS-OGTT assay successfully differentiated between "on"-target and "off"-target drug effects.
• Demonstrated sensitivity in evaluating drug candidates' postprandial effects on glucose metabolism.
• Achieved higher sample throughput due to the elimination of glucose derivatization.

Conclusions:

• The DIS-OGTT is a sensitive and high-throughput method for evaluating drug candidates targeting glucose metabolism.
• This assay provides valuable insights into the mechanisms of drug action on glucose homeostasis.
• Facilitates the selection of effective drug candidates for metabolic disorders.