Exogenous and endogenous insulin separation with in-silico modeling

We have developed an innovative dynamic model-based methodology to separately quantify the contributions of externally administered (exogenous) and internally secreted (endogenous) insulin to total plasma insulin levels [1].

We then applied the approach to evaluate the effects of inhaled insulin on endogenous insulin secretion during a meal.

What is the motivation for conducting this study?

The Role of Endogenous Insulin in Precision Diabetes Treatment. The administration of exogenous insulin serves as the cornerstone of treatment for individuals with type 1 diabetes (T1D) and as a critical option for managing type 2 diabetes (T2D) when oral antidiabetic medications fail to achieve glucose control [2,3]. Despite impairments in endogenous insulin secretion, this component can still contribute meaningfully to total plasma insulin levels alongside exogenous insulin [4,5]. Accurate quantification of this variable endogenous insulin secretory capacity is therefore critical to support precision treatment strategies tailored to individual needs.

The Importance of Quantifying Endogenous Insulin in Clinical Trials for Drug Development. Quantifying endogenous insulin secretion is particularly relevant during early-phase trials that evaluate the pharmacokinetics and safety of new exogenous insulin formulations [6]. These trials are typically conducted in healthy individuals with intact endogenous insulin secretion, making it crucial to accurately differentiate the endogenous contribution to total plasma insulin levels.

The Exploration of Alternative Routes of Insulin Administration. Although insulin is typically delivered by subcutaneous injection, alternative routes of administration are also utilized, including pulmonary delivery via inhalation. In addition to reducing patient burden, inhaled insulin has demonstrated advantages in treating both T1D and T2D patients [7-9].

Study Design and Methodology

Our study focused on 21 healthy subjects who underwent two standardized meal tests on separate days. In one test, participants inhaled a Technosphere® Insulin dose before the meal, while the other test did not include insulin administration. This design allowed us to isolate and compare the effects of inhaled insulin on endogenous insulin secretion and its overall contribution to plasma insulin levels.

Our approach employs a two-compartment model for C-peptide kinetics and a one-compartment model for insulin kinetics [10, 11]. Parameters are tailored to each subject’s characteristics, such as body surface area, age, and sex, ensuring individualized accuracy. The piece-wise linear function used for C-peptide secretion rates allows flexibility and precision in modeling insulin dynamics.

Key Findings

Individual Bioavailability. We successfully quantified the percentage of exogenous insulin dose reaching the plasma, offering a measure of exogenous insulin bioavailability. The approach provides individual bioavailability.

Impact on Endogenous Insulin. In the 30-120 minute interval after the meal, we observed a divergence in the time course of endogenous insulin between tests with and without inhaled insulin. Specifically, the area-under-the-curve (AUC) for endogenous insulin was significantly lower during the test with inhaled insulin. This reduction in endogenous insulin secretion can be attributed to a negative feedback mechanism wherein exogenous insulin suppresses endogenous production. The suppression of endogenous insulin secretion by exogenous insulin, observed in this study, may contribute to preserving beta-cell function. This is particularly relevant for patients with type 2 diabetes, where beta-cell preservation is critical to disease management.

Advantages of the Methodology

Physiological Testing Conditions: Unlike traditional methods requiring suppression of endogenous insulin secretion, our approach is compatible with meal tolerance tests, enabling evaluation under realistic physiological conditions.

Simplified Experimental Design: The method avoids the need for intravenous insulin administration and complex setups, making it more practical and less invasive for clinical application.

Individual Bioavailability Estimates: By quantifying intra- and inter-individual variability in insulin absorption, our approach broadens the scope of bioavailability studies and aligns with the goals of personalized medicine.

Dynamic Behavior Analysis: The ability to separately quantify exogenous and endogenous insulin contributions, along with their dynamic interactions, offers insights into patient-specific responses to insulin therapy. Evidence suggests a log-linear relationship between glycemic variability and endogenous insulin secretion. By incorporating time-course data of endogenous insulin, our methodology can help identify target glucose trends and refine exogenous insulin dosing to achieve better glycemic control.

Potential Applications

• The methodology could be developed into user-friendly software for routine clinical use, enabling real-time quantification of exogenous and endogenous insulin contributions during meal tests.
• Personalized insulin therapy could benefit from tools that account for individual variability in bioavailability, enhancing treatment accuracy and patient outcomes.
• Although tested on inhaled insulin the method can be applied to any kind of insulin administration.

Conclusion

Our dynamic model-based approach effectively separates exogenous and endogenous insulin contributions to plasma insulin levels. It provides individual bioavailability estimates and insights into the interplay between exogenous insulin administration and endogenous secretion. The ability to assess individual bioavailability and the dynamic interaction between exogenous and endogenous insulin opens new possibilities for tailoring insulin therapy.

References

1. Piersanti, A., Pacini, G., Tura, A. et al. An in-silico modeling approach to separate exogenous and endogenous plasma insulin appearance, with application to inhaled insulin. Sci Rep 14, 10936 (2024).
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