Relationship between glucose volume of distribution and the extracellular space: a multiple tracer study

Although the use of radioisotopes in the investigation of glucose metabolism dates back more than 50 years, several relevant quantitative aspects have not been definitively determined. These include the volume of distribution (V(d)) of glucose and recycling of glucose radioisotopes from liver glycogen. These problems are further complicated by methodological issues such as the following: (1) glucose tracers have different metabolic fates that may influence volume estimates, and (2) the calculation method needs to be based on physical principles to avoid some limitations of compartmental models. To address these issues, we administered boluses of an extracellular marker ([1-(14)C]-l-glucose, 30 μCi) and 2 glucose tracers ([2-(3)H]-d-glucose and [3-(3)H]-d-glucose, 120 μCi of each), followed by a 1-mg glucagon bolus (in the presence of somatostatin) 245 minutes later, in conscious beagles to account for potential problems in recycling of the label through glycogen. We used modeling methods based on physical principles (circulatory model), which yield volume estimates with a clear physiological interpretation. Glucose V(d) (mL/kg) were 204 ([1-(14)C]-l-glucose), 191 ([2-(3)H]-d-glucose), and 206 ([3-(3)H]-d-glucose). These values were not different and correlated. The amount of recycled [3-(3)H]-d-glucose in response to glucagon was small (∼1.7% of the injected tracer dose). An additional result of this analysis is the determination of the parameters of the circulatory model in beagles for the standard [3-(3)H]-d-glucose tracer. Using multiple tracers in beagles and calculation methods based on physical principles, we have provided direct proof that the glucose V(d) equals the extracellular space in beagles under basal conditions.