Accurate measurement of postprandial glucose turnover: Why is it difficult and how can it be done (relatively) simply?

Fasting hyperglycemia occurs when an excessive rate of endogenous glucose production (EGP) is not accompanied by an adequate compensatory increase in the rate of glucose disappearance (R_d). The situation following food ingestion is more complex as the amount of glucose that reaches the circulation for disposal is a function of the systemic rate of appearance of the ingested glucose (referred to as the rate of meal appearance [Ra_meal]), the pattern and degree of suppression of EGP, and the rapidity of stimulation of the R_d. In an effort to measure these processes, Steele et al. proposed what has come to be referred to as the dual-tracer method in which the ingested glucose is labeled with one tracer while a second tracer is infused intravenously at a constant rate. Unfortunately, subsequent studies have shown that although this approach is technically simple, the marked changes in plasma specific activity or the tracertotracee ratio, if stable tracers are used, introduce a substantial error in the calculation of Ra_meal, EGP, and R_d, thereby leading to incorrect and at times misleading results. This Perspective discusses the causes of these so-called "nonsteady-state" errors and how they can be avoided by the use of the triple-tracer approach.