Nocturnal Glucose Metabolism in Type 1 Diabetes: A Study Comparing Single Versus Dual Tracer Approaches

Background: Understanding the effect size, variability, and underlying physiology of the dawn phenomenon is important for next-generation closed-loop control algorithms for type 1 diabetes (T1D). Subjects and Methods: We used an iterative protocol design to study 16 subjects with T1D on individualized insulin pump therapy for two successive nights. Endogenous glucose production (EGP) rates at 3 a.m. and 7 a.m. were measured with [6,6-²H₂]glucose as a single tracer, infused from midnight to 7 a.m. in all subjects. To explore possibility of tracer recycling due to prolonged [6,6-²H₂]glucose infusion, which was highly probable after preplanned interim data analyses, we infused a second tracer, [6-³H]glucose, from 4 a.m. to 7 a.m. in the last seven subjects to measure EGP at 7 a.m. Results: Cortisol concentrations increased during both nights, but changes in glucagon and insulin concentration were inconsistent. Although the plasma glucose concentrations rose from midnight to 7 a.m. during both nights, EGP measured with [6,6-²H₂]glucose between 3 a.m. and 7 a.m. did not differ during Night 1 but fell in Night 2. However, EGP measured with [6-³H]glucose at 7 a.m. was higher than that measured with [6,6-²H₂]glucose during both nights, thereby suggesting tracer recycling probably underestimating EGP calculated at 7 a.m. with [6,6-²H₂]glucose. Likewise, EGP was higher at 7 a.m. with [6-³H]glucose than at 3 a.m. with [6,6-²H₂]glucose during both nights. Conclusions: The data demonstrate a consistent overnight rise in glucose concentrations through increased EGP, mediated likely by rising cortisol concentrations. The observations with the dual tracer approach imply significant tracer recycling leading to underestimation of EGP measured by longer-duration tracer infusion.