Stable Isotope Tracer Methodologies
Stable isotopes have been safely used for more than 75 years to assess the turnover rates of proteins, lipids and carbohydrates in animals and humans. The quantitative nature of these flux measurements make them valuable tools for early clinical trials of investigational drugs to assess mechanisms of action, dose response and pharmacokinetic/pharmacodynamic (PF/PD) relationships.
- Fasting endogenous glucose production, hepatic insulin sensitivity and peripheral insulin sensitivity can be assessed simultaneously using a primed-continuous infusion of stable isotope labeled glucose in combination with a hyperinsulinemic-euglycemic clamp.
- The contribution of gluconeogenesis and glycogenolysis to fasting endogenous glucose production can be quantified using primed-continuous infusions of stable isotope labeled glycerol and glucose and the use of mass isotopomer distribution analysis (MIDA).
- Postprandial glucose fluxes such as intestinal glucose absorption, suppression of endogenous glucose production and total glucose disposal can be assessed during an oral glucose tolerance test (OGTT) or a mixed meal using a dual stable isotope tracer approach and non-steady-state Steele calculations.
- Whole-body glycolytic disposal of oral glucose during an OGTT or a mixed meal can be determined using oral administration of deuterated glucose and the measurement of deuterated water in blood. This method can be combined with the dual tracer method described above.
- Hepatic de novo lipogenesis (DNL) is an important pathway reflecting metabolic health and a useful pharmacodynamic marker for certain therapeutic targets of obesity, diabetes and fatty liver disease. DNL can be assessed using a variety of stable isotope methodologies (13C acetate or deuterated water) and can be combined with measurements such as cholesterol synthesis, bile acid synthesis and triglyceride synthesis.
- Whole-body lipolysis is the catabolic process leading to the breakdown of triglycerides stored in fat cells and can be quantified by measuring the glycerol appearance rate in the fasting state and during a hyperinsulinemic-euglycemic clamp using a stable isotope labeled glycerol infusion.
- The assessment of lipoprotein fluxes to understanding mechanism of lipid lowering of novel agents in early clinical studies can be assessed using stable isotope labeled leucine or deuterated water.
- Total energy expenditure in free-living humans can be measured using the doubly labeled water (DLW) method.
- Total body water and body composition can be determined using a single oral bolus stable isotope labeled water.