Effects of Hyperglycemia on Glucose Production and Utilization in Humans: Measurement With 23H-, 33H-, and 614CGlucose

Studies with tritiated isotopes of glucose have demonstrated that hyperglycemia per se stimulates glucos utilization and suppresses glucose production in humans. These conclusions rely on the assumption that tritiated glucose provides an accurate measure of glucose turnover. However, if in the presence of hyperglycemia the isotope either loses its label during “futile” cycling or retains its label during cycling through glycogen, then this assumption is not valid. To examine this question, glucose utilization and glucose production rates were measuredin nine normal subjects with a simultaneous infusion of 23Hglucose, an isotope that may undergo futile cycling but does not cycle through glycogen; 614Cglucose, an isotope that may cycle through glycogen but does not futile cycle; and 33Hglucose, an isotope that can both undergo futile cycling and cycle through glycogen. In the postabsorptive state at plasma glucose concentration of 95 mg dl−1, glucose turnover determined with 614Cglucose (2.3 ±0.1 mg kg−1 min−1) was greater than that determined with 33Hglucose (2.1 ± 0.1 mg kg−1 min−1 P = 0.002) and slightly less than that determined with 23Hglucose (2.7 ± 0.2 mg kg−1 min−1 P = 0.08). Plasma glucose was then raised from 95 to 135 to 175 mg dl−1 while insulin secretion was inhibited, and circulating insulin, glucagon, and growth hormone concentrations were maintained constant by infusion of these hormones and somatostatin. Glucose production and utilization rates determined with 614C-glucose continued to be less than those determined with 23Hglucose and greater than those seen with 33Hglucose. However, the decrements in glucose production and increments in glucose utilization were identical with all isotopes. Glucagon was then infused at a high rate to stimulate endogenous glucose release. This resulted in a significant (P 0.05) increase in both 614C- and 33H- but not 23Hgiucose, indicating release of the former two isotopes from glycogen. This resulted in a significantly lower (P 0.04) estimate of glucose production and utilization during the glucagon infusion determined with 614C- and 33Hglucose compared with that determined with 23Hglucose. Thus, whereas neither 23H- nor 33Hglucose precisely reflect glucose turnover measured by 614Cglucose, all three isotopes provide an equivalent assessment of the effects of hyperglycemia on glucose production and utilization in humans. However, release of either 614C- or 33Hglucose from glycogen may result in an underestimate Of glucose turnover.