Lymphatic Absorption Is a Significant Contributor to the Subcutaneous Bioavailability of Insulin in a Sheep Model

Purpose: This study was conducted to explore the role of the peripheral lymphatics in insulin absorption following subcutaneous (SC) administration using a sheep model that allows continuous collection of peripheral lymph and simultaneous assessment of systemic bioavailability.Methods: In a parallel group design, soluble human insulin (0.5 IU/kg) was administered by bolus SC injection into the interdigital space of the hind leg of non-cannulated control sheep, and sheep in which the efferent popliteal lymph duct was cannulated. A separate group received a bolus IV injection (0.15 IU/kg). Blood was sampled from all animals, and lymph was collected continuously over 12 h post-dosing. Samples were assayed for insulin by ELISA.Results: The SC bioavailability of insulin in control sheep was 31.5 ± 3.2%, which was significantly higher than when the peripheral lymph was continuously collected (18.4 ± 1.7%). In the lymph-cannulated animals, 17.3 ± 1.0% of the dose was collected in peripheral lymph.Conclusions: Based on the direct measurement of insulin in regional lymph and on the decrease in the systemic bioavailability when regional lymph was continuously collected, the results demonstrate that lymphatic absorption contributed significantly to the overall insulin bioavailability following SC administration to sheep.