Quantitation of the roles played by the main determinants of meal glucose tolerance in patients with type 1 diabetes on insulin pump therapy

The relative roles of each component of the glucose (G)/insulin (I) system in determining after meal hyperglycemia in type 1 diabetes (T1DM) are still under debate. Metabolic Control Analysis (MCA) quantifies the control exerted by each component of a system on a variable of interest, by computing the relevant coefficients of control (CCs), which are systemic properties. We applied MCA to a mixed meal test (MMT) to quantify the CCs of the main components of the G/I system on G concentration. 7 T1DM patients (age: 41±5 yrs; BMI: 24.3±0.6 kg.m-2; HbA1c: 7.9±0.2%) on insulin pump therapy and continuous glucose monitoring (CGM) participated in 2 separate studies:1. A standard euglycemic insulin (240 pmol.min-1.m-2 BSA) clamp (duration: 120 min, M value: 1209±169 µmol.min-1.m-2 BSA) including CGM; 2. A standardized MMT (292 Kcal; 38.9 g complex CHO, 8.9 g lipids, 14 g proteins) with plasma I/G monitoring and CGM. With our modeling strategy, data from the clamp and from the MMT are sufficient to build an in silico replica (“virtual patient”) of the G/I system of each patient (CGM included), which behaves as the real patient during the MMT. Virtual patients were used to compute the CCs of plasma G and G measured by CGM. During the MMT, plasma glucose and insulin peaked at (time ) and at (time ), respectively, and leveled at and at time 300’. The CCs exerted by some primary components of the G/I system on plasma G are summarized in the Table. Size of s.c. insulin depot had the highest CCs (p<0.01 or less vs other CCs). The CCs of meal insulin bolus peaked at 300’ (p<0.01 vs CCs at 30’-60’). The CCs of CHO transit time across the gut, including also absorption, was relevant in the first half and became negligible in the second half of the meal (p<0.01 CCs 180-300’ vs CCs 30’-120’). The CCs of CGM measured G were parallel, but not superimposable to CCs of plasma G, with some statistically significant difference (p<0.03-0.01) in CCs exerted by gut CHO transit time. Conclusions. In patients with T1DM on insulin pump therapy, after a mixed meal: 1. the most relevant factor of after meal G may be the size of subcutaneous insulin depot; 2. Pre-meal insulin bolus may be much more influential in the last 3 than in the initial 2 hours. These findings may have important implications for the development and the refinement of closed loop control of insulin delivery systems.