Faster insulin action is associated with improved glycaemic outcomes during closed‐loop insulin delivery and sensor‐augmented pump therapy in adults with type 1 diabetes

We aimed to evaluate the relationship between insulin pharmacodynamics and glycaemic outcomes during closed‐loop insulin delivery and sensor‐augmented pump therapy. We retrospectively analysed data from a multicentre randomized control trial involving 32 adults with type 1 diabetes receiving day‐and‐night closed‐loop insulin delivery and sensor‐augmented pump therapy over 12 weeks. We estimated time‐to‐peak insulin action (t max, IA) and insulin sensitivity (S I) during both interventions, and correlated these with demographic factors and glycaemic outcomes. During both interventions, t max, IA was positively correlated with pre‐ and post‐intervention HbA1c (r = 0.50‐0.52, P < .01) and mean glucose (r = 0.45‐0.62, P < .05), and inversely correlated with time sensor glucose, which was in target range 3.9 to 10 mmol/L (r = −0.64 to −0.47, P < .05). Increased body mass index was associated with higher t max, I and lower S I (both P < .05). During closed‐loop insulin delivery, t max, IA was positively correlated with glucose variability (P < .05). Faster insulin action is associated with improved glycaemic control during closed‐loop insulin delivery and sensor‐augmented pump therapy.


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We aimed to evaluate the relationship between insulin pharmacodynamics and glycaemic outcomes during closed-loop insulin delivery and sensor-augmented pump therapy. We retrospectively analysed data from a multicentre randomized control trial involving 32 adults with type 1 diabetes receiving day-and-night closed-loop insulin delivery and sensor-augmented pump therapy over 12 weeks. We estimated time-to-peak insulin action (t max,IA ) and insulin sensitivity (S I ) during both interventions, and correlated these with demographic factors and glycaemic outcomes. During both interventions, t max,IA was positively correlated with pre-and postintervention HbA1c (r = 0.50-0.52, P < .01) and mean glucose (r = 0.45-0.62, P < .05), and inversely correlated with time sensor glucose, which was in target range 3.9 to 10 mmol/L (r = −0.64 to −0.47, P < .05). Increased body mass index was associated with higher t max,I and lower S I (both P < .05). During closed-loop insulin delivery, t max,IA was positively correlated with glucose variability (P < .05). Faster insulin action is associated with improved glycaemic control during closed-loop insulin delivery and sensor-augmented pump therapy.
CSII, glycaemic control, insulin delivery, insulin pump therapy, pharmacodynamics, type 1 diabetes We retrospectively analysed data obtained from a multicentre (UK, Germany and Austria), randomized crossover study involving 32 participants with type 1 diabetes and conducted in free-living home settings. 2 Participants were randomly assigned to receive 12 weeks of automated closed-loop insulin delivery first and sensor-augmented pump therapy (open-loop) second, or vice versa applying rapid-acting insulin analogue, aspart or lispro, to follow their pre-study insulin use.
Day-and-night closed-loop insulin delivery was applied using a hybrid approach, during which participants administered prandial insulin using standard pump bolus wizard. The participants underwent 4 to 6 weeks of run-in period using the study insulin pump and real-time continuous glucose monitoring device prior to randomization to fully optimize insulin delivery.
Using a validated modelling approach analysing continuous glucose monitoring, insulin delivery and meal content data (outlined in File S1), 3

| RESULTS
Data from 32 adults with type 1 diabetes [male 17, age 39.9  (Table S1, File S1), supporting the validity of the estimates. Table 1 reports the Pearson correlation coefficients between time-to-peak insulin action and insulin sensitivity, and demographic factors and glycaemic outcomes. During both interventions, time-topeak insulin action was positively correlated with pre-and postintervention HbA1c (P < .01) and mean glucose levels (P < .05-.01), whilst being inversely correlated with time sensor glucose, which was in target range of 3.9 to 10 mmol/L (P < .05-.01). A higher BMI was associated with higher time-to-peak insulin action (P < .05-.01) and lower insulin sensitivity (P < .05). A positive correlation was observed between time-to-peak insulin action and glucose variability during

| DISCUSSION
We estimated time-to-peak insulin action and insulin sensitivity in adults with type 1 diabetes during 12-week closed-loop insulin delivery and conventional insulin pump therapy, and demonstrated associations with clinical factors of interest.
Time-to-peak insulin action reflects the timespan for the subcutaneously delivered rapid-acting insulin to reach the peak glucoselowering effect. The population estimates 79 minutes during the closed-loop intervention and 72 minutes during sensor-augmented insulin therapy, which compares well with 90 to 100 minutes 4 measured during glucose clamp studies when higher insulin doses were administered resulting in endogenous glucose production to be maximally suppressed and the measurements reflecting primarily slower insulin action through augmentation of glucose disposal in the muscle. During both interventions, significant correlations were observed between time-to-peak insulin action and glycaemic outcomes including pre-and post-intervention HbA1c, mean glucose and percentage of time spent with glucose in the target range. These correlations suggest that faster insulin absorption may be associated with improved glycaemic control, and that acceleration may provide further benefit. The observation is in agreement with previous findings that showed that treatment with rapid-acting insulin analogues in type 1 diabetes resulted in improved glucose control compared with regular human insulin, [5][6][7] even under the condition that regular human insulin meal time bolus was titrated 30 minutes ahead of meals whilst rapid-acting insulin bolus was titrated at meal time. The sole difference between rapid-acting insulin and regular human insulin is the faster insulin absorption and thus action. A recent trial evaluated the efficacy of faster-acting insulin aspart and demonstrated a greater reduction in HbA1c (−0.15%) for meal time faster aspart compared with insulin aspart after 26 weeks treatment. 8 The time-to-maximum plasma insulin concentration of faster-acting insulin aspart is 26 minutes left-shifted compared with that of insulin aspart during insulin pump therapy. 9 The highly significant correlation between time-to-peak insulin action and mean glucose levels accounts for about 40% of the between-subject variability in glucose levels. respectively. These estimates are in concordance with published data reporting 0.0005/min per mU/L at a glucose concentration of 8 to 10 mmol/L. 12 However, we have not compared our estimates of insulin sensitivity with those obtained with the gold standard euglycaemic hyperinsulinaemic clamp test. We observed a negative correlation between insulin sensitivity and BMI in agreement with previously reported data in adults with type 1 diabetes. 13 The main novelty of the present study is the finding of the positive correlation between time-to-peak insulin action and HbA1c level, which highlights the need for new insulin formulations or other novel delivery methods that could result in faster insulin absorption and action. The development of faster-acting insulin aspart, 9 inhaled insulin 14 and infusion site warming devices 15 may contribute towards this goal. These new formulations and delivery methods may benefit both conventional insulin pump therapy and the closed-loop insulin delivery system.
In conclusion, faster insulin action was associated with better glycaemic control during closed-loop insulin delivery and sensoraugmented pump therapy, justifying further research to be directed towards accelerating insulin absorption and action.