Ulrike Klueh, United States of America
Wayne State University Biomedical EngineeringPresenter of 1 Presentation
INFLAMMATION AND SUBSEQUENT FIBROSIS UNDERLIES INSULIN INFUSION SET FAILURES: PROOF OF CONCEPT IN ANIMAL MODELS
Abstract
Background and Aims
Continuous subcutaneous insulin infusion (CSII) is only FDA approved for 3 days. We believe that excipient-induced tissue reactions are responsible for the short-lived CSII functionality, skin complications and pharmacokinetic variation. The objective is to determine the role of inflammation in insulin-excipient induced tissue reaction in both murine and porcine models.
Methods
We modified the classic murine “air pouch” model to investigate CSII causes and mechanisms associated with compromised blood glucose control. The addition of an inline home-made filter also permits the removal of excipients prior to insulin infusion into the mouse air pouch. Tissue responses to insulin infusion, excipients, excipient-free insulin and control solutions (e.g. saline) over a 7-day period were investigated. These studies were also extended into a pre-clinical porcine animal model.
Results
Our data indicate that 1) phenol-based insulin diluents trigger infusion site inflammation in both murine and porcine models; 2) that the acute inflammation alters infusion site tissue architecture and functions and 3) the resulting fibrosis eliminates future use of the same infusion site. Pharmacokinetic evaluations demonstrated that insulin absorption is delayed and maximum plasma concentration is decreased in inflamed tissue suggesting a role of inflammatory cells in insulin absorption. In-line removal of excipients immediately prior to insulin infusion minimized the loss of insulin function as well as insulin infusion associated tissue inflammation and subsequent fibrosis at CSII infusion sites.
Conclusions
These studies directly demonstrate the toxicity of excipients in commercial insulin formulations in both murine and porcine models.