Pharmacokinetics and pharmacodynamics of different modes of insulin pump delivery. A randomized, controlled study comparing subcutaneous and intravenous administration of insulin aspart.

AIMS: To study the pharmacokinetics and pharmacodynamics of three different modes of insulin infusion delivered by means of an insulin pump: subcutaneous bolus insulin injection once an hour, continuous subcutaneous insulin infusion and continuous intravenous insulin infusion. METHODS: In random order, ten patients with Type 1 diabetes mellitus received insulin aspart with subcutaneous bolus insulin injection, continuous subcutaneous insulin infusion and continuous intravenous insulin infusion. The insulin aspart doses were individualized. RESULTS: A non-random, sinus-like variation of serum insulin aspart over time was found with subcutaneous bolus insulin injection compared with continuous subcutaneous insulin infusion and continuous intravenous insulin infusion (P<0.0001). Random variation of serum insulin aspart over time was significantly higher with continuous intravenous insulin infusion compared with subcutaneous bolus insulin injection (P=0.023) and continuous subcutaneous insulin infusion (P=0.013). Mean serum insulin aspart did not differ significantly between subcutaneous bolus insulin injection, continuous subcutaneous insulin infusion and continuous intravenous insulin infusion (P=0.17). Thus, absolute bioavailability was near 100% for both subcutaneous bolus insulin injection and continuous subcutaneous insulin infusion. Statistically significant differences were seen in mean plasma glucose and mean glucose infusion rate, with the highest mean plasma glucose and the lowest mean glucose infusion rate with continuous intravenous insulin infusion, suggesting a slightly lower bioefficacy of continuous intravenous insulin infusion compared with subcutaneous bolus insulin injection and continuous subcutaneous insulin infusion. CONCLUSIONS: Small but statistically significant differences in pharmacokinetics and pharmacodynamics between subcutaneous bolus insulin injection, continuous subcutaneous insulin infusion and continuous intravenous insulin infusion were observed. However, no major clinically relevant differences were found, suggesting that, for a basal subcutaneous insulin aspart pump therapy, relatively infrequent pump stroke frequency may suffice.

Pharmacokinetics following continuous subcutaneous insulin infusion of insulin aspart with or without initial subcutaneous bolus.

AIM: To evaluate time to steady state insulin concentration (C(ss)) following continuous subcutaneous insulin infusion (CSII) of insulin aspart (IAsp) with or without an initial s.c. bolus. METHODS: In random order 10 healthy volunteers were given a basal insulin infusion rate (0.5 U/h) for 8 h with or without an initial s.c. bolus (1.4 U). Serum IAsp was measured until 3 h after infusion was stopped. RESULTS: An overshoot of IAsp was seen before C(ss) was achieved following an initial bolus of insulin as compared to no bolus. The apparent half-life (t((1/2))) with or without bolus did not differ (p = 0.15). Time to steady state (T(ss)) was evaluated in two ways: (1) T(ss) defined as the first point within an interval of C(ss)+/- 2 x CV was 233 vs. 166 min with and without a bolus respectively (p = 0.068). (2) A t-test was performed for each concentration-time point vs. mean C(ss), and the first point with no significance was defined, T(ss). This gave 208 (p = 0.09) and 178 min (p = 0.24) with and without bolus respectively. Mathematical modelling suggests that an ideal mean bolus should be 0.89 U, and that this bolus dose may result in a shorter T(ss). CONCLUSION: A bolus of 1.4 U resulted in an overshoot of serum IAsp before C(ss) and a longer period before C(ss) is achieved. Mathematical modelling suggests that a mean bolus of 0.89 U would result in a faster achievement of C(ss) compared to no bolus.

Excitation wave propagation as a possible mechanism for signal transmission in pancreatic islets of Langerhans.

In response to glucose application, beta-cells forming pancreatic islets of Langerhans start bursting oscillations of the membrane potential and intracellular calcium concentration, inducing insulin secretion by the cells. Until recently, it has been assumed that the bursting activity of beta-cells in a single islet of Langerhans is synchronized across the whole islet due to coupling between the cells. However, time delays of several seconds in the activity of distant cells are usually observed in the islets of Langerhans, indicating that electrical/calcium wave propagation through the islets can occur. This work presents both experimental and theoretical evidence for wave propagation in the islets of Langerhans. Experiments with Fura-2 fluorescence monitoring of spatiotemporal calcium dynamics in the islets have clearly shown such wave propagation. Furthermore, numerical simulations of the model describing a cluster of electrically coupled beta-cells have supported our view that the experimentally observed calcium waves are due to electric pulses propagating through the cluster. This point of view is also supported by independent experimental results. Based on the model equations, an approximate analytical expression for the wave velocity is introduced, indicating which parameters can alter the velocity. We point to the possible role of the observed waves as signals controlling the insulin secretion inside the islets of Langerhans, in particular, in the regions that cannot be reached by any external stimuli such as high glucose concentration outside the islets.