Effect of cutaneous blood flow on absorption of insulin: a methodological study in healthy male volunteers

Abstract

Absorption of drugs from subcutaneous tissue depends on several factors, including tissue perfusion at the administration site. Tissue perfusion can be manipulated by e.g. application of local heat. This may subsequently alter the rate or amount of absorption of drugs from a subcutaneous depot. The aim of the present study was to investigate if increased tissue perfusion after controlled local heating can change the absorption of subcutaneously administered short-acting insulin (Actrapid®, 100IU/ml). Thirteen healthy Caucasian males participated in two randomized experimental sessions; one session with locally applied controlled heat at the injection site, and a control session without local heat application. Tissue perfusion (blood flow) was monitored with Laser Doppler Imaging, and blood samples were taken to assess the levels of glucose and insulin. Local heat application at the site of insulin injection significantly enhanced tissue perfusion by approximately 145%. However, no correlation was found between insulin absorption and tissue perfusion. Based on our findings, it was concluded that tissue perfusion is not the rate-limiting factor in the absorption of high-concentration short-acting insulin from a subcutaneous depot. It is suggested that dissociation of insulin hexamers into dimers and monomers is a major rate limiting factor to the absorption.

Keywords: Actrapid®; Local heat; absorption; insulin; skin perfusion; subcutaneous depot.

Figure 1

Schematic overview of the study design and time point of the measurements.

Figure 2

Photographs depicting the ROI after definition by use of a template. A) typical image taken without heating at the injection site. B) typical image immediately after heating (43°C for 60 sec).

Figure 3

Typical laser scan results of the ROI from a single subject at time point 31.5 min at control session (A) and following the application of local controlled heat (B) heat session.

Figure 4

Line-scatter graphs of total insulin levels (A) Cpeptide levels (B) measured over time in blood samples collected at the designated time points. Blue graphs depict changes seen in control sessions, while red graphs depict changes seen in heat sessions. Data points noted are mean values of 13 subjects with standard error of the mean.

Figure 5

Line-scatter graph of exogenous insulin levels calculated from total insulin and C-peptide levels measured in all blood samples collected at designated time points. The blue graph depicts changes seen in control sessions, while the red graph depicts changes seen in heat sessions. Data points noted are mean values of all 13 subjects with standard error of the mean.

Figure 6

Line-scatter graph of blood glucose levels measured in the blood samples collected at designated time points. The blue graph depicts changes seen in control sessions, while the red graph depicts changes seen in heat sessions. Data points noted are mean values of 13 subjects with standard error of the mean.