Incorporating a generic model of subcutaneous insulin absorption into the AIDA v4 diabetes simulator. 3. Early plasma insulin determinations

Abstract

Introduction: AIDA is an interactive educational diabetes simulator that has been available without charge via the Internet for over 12 years. Recent articles have described the incorporation of a novel generic model of insulin absorption into AIDA as a way of enhancing its capabilities. The basic model components to be integrated have been overviewed, with the aim being to provide simulations of regimens utilizing insulin analogues, as well as insulin doses greater than 40 IU (the current upper limit within the latest release of AIDA [v4.3a]). Some preliminary calculated insulin absorption results have also recently been described.

Methods: This article presents the first simulated plasma insulin profiles from the integration of the generic subcutaneous insulin absorption model, and the currently implemented model in AIDA for insulin disposition. Insulin absorption has been described by the physiologically based model of Tarín and colleagues. A single compartment modeling approach has been used to specify how absorbed insulin is distributed in, and eliminated from, the human body. To enable a numerical solution of the absorption model, a spherical subcutaneous depot for the injected insulin dose has been assumed and spatially discretized into shell compartments with homogeneous concentrations, having as its center the injection site. The number of these compartments will depend on the dose and type of insulin. Insulin inflow arises as the sum of contributions to the different shells. For this report the first bench testing of plasma insulin determinations has been done.

Results: Simulated plasma insulin profiles are provided for currently available insulin preparations, including a rapidly acting insulin analogue (e.g., lispro/Humalog or aspart/Novolog), a short-acting (regular) insulin preparation (e.g., Actrapid), intermediate-acting insulins (both Semilente and neutral protamine Hagedorn types), and a very long-acting insulin analogue (e.g., glargine/Lantus), as well as for insulin doses up to 50 IU.

Discussion: The methodology to be adopted for implementing the generic absorption model within AIDA has been overviewed, and the first plasma insulin profiles based on this approach have been demonstrated. Ideas for future work and development are discussed. It is expected that an updated release of AIDA (v4.5), based on this collaborative approach, will become available for free--in due course--via the www.2aida.org Web site. Readers who wish to be informed when the new software is launched can join the very low volume AIDA announcement list by sending a blank email note to subscribe@2aida.org.

Keywords: absorption; computer; diabetes; insulin; model; simulation; software.

Figure 1.

Block diagram of the overall AIDA v4 model structure incorporating the generic subcutaneous insulin absorption submodel described by Tarín and colleagues. IU = injection of international units of a class of insulin preparation. t = time. I_ex = exogenous insulin flow profile. I_p = plasma insulin.

Figure 2.

Graph summarizing the dimeric–hexameric association process utilized in the generic subcutaneous insulin absorption model to be implemented in AIDA v4.5. The resulting association rate is shown for the different insulin formulations. The association rate for an intermediate-acting insulin (NPH-type) preparation and a very long-acting insulin analogue is substantially greater than for a short-acting (regular) insulin preparation and a rapidly acting insulin analogue.

Figure 3.

A 24-hour plasma insulin profile showing the superposition principle in operation following the injection of regular insulin (10 IU) and intermediate-acting insulin (NPH type)(20 IU) given twice daily at 7 am and 7 pm.

Figure 4A.

Injection of different doses of regular insulin (10, 20, 30, and 40 IU) and a 40-IU intermediate-acting insulin (NPH type). Plasma insulin (in mIU/liter) versus time. Results reflect both insulin absorption and elimination kinetics.

Figure 4B

. Simulated plasma insulin profiles for five classes of insulin preparations following five separate subcutaneous 20-IU injections. Plasma insulin (mIU/liter) versus time. Results reflect both insulin absorption and elimination kinetics.

Figure 6.

Superposition of three insulin injections for an insulin-resistant patient: one injection of 45 IU of regular insulin at 7 am and a further regular insulin injection at 7 pm together with an injection of 50 IU of intermediate-acting insulin (Semilente type) at 10 pm (bedtime).

Figure 5.

Comparison of separate injections of 10, 20, 30, 40, and 50 IU for different classes of insulin preparations. Plasma insulin (mIU/liter) is shown for (A) a rapidly acting insulin analogue, (B) a regular insulin preparation, (C) an intermediate-acting insulin (Semilente type), (D) an intermediate-acting insulin (NPH type), and (E) a very long-acting insulin analogue.

Figure 5.

Comparison of separate injections of 10, 20, 30, 40, and 50 IU for different classes of insulin preparations. Plasma insulin (mIU/liter) is shown for (A) a rapidly acting insulin analogue, (B) a regular insulin preparation, (C) an intermediate-acting insulin (Semilente type), (D) an intermediate-acting insulin (NPH type), and (E) a very long-acting insulin analogue.

Figure 7.

Detemir model structure, suggested for future work, that includes adaptation of the time constants defining the transformation rates of association/dissociation and the introduction of new states regarding insulin bound to albumin. These model modifications, together with adequate parameterization, should be able to take into account the delaying mechanisms of insulin detemir and allow reproduction of the delayed absorption profile of the preparation.