Objective: Insulin infusion pump sets are only FDA approved for 3 days as device failure often ensues from an inflammatory response driven by insulin excipients. However, removal of excipients can result in insulin fibril formation, which is more toxic than excipients alone. Our objective was to determine excipient and fibril toxicity and optimize the parameters of insulin excipient removal.
Methods: A modified murine air pouch model with an inline filter removed excipients prior to insulin infusion/injection. Protein analysis by circular dichroism (CD) measured protein stability upon excipient removal. A separate analysis determined cytotoxicity for insulin fibrils in cell and tissue. These studies were also extended into a porcine model.
Results: Excipient removal significantly reduced the inflammatory response in vivo. However, this resulted in a loss of insulin oligomeric state. In vitro and in vivo studies demonstrated toxicity of excipients (in vitro and in vivo) and fibrils (in vivo) (Figures 1A-D).
Conclusions: These studies demonstrate that insulin excipients result in cell and tissue toxicity. Complete removal of these excipients alters protein stability. Since inflammation is minimized with removal of excipients, current studies are directed at optimizing the infusion parameters and excipient concentrations.
B. Lewis: None. A. Mulka: None. C. Kesserwan: None. D. Kreutzer: Other Relationship; Self; Abbott Laboratories, cell and molecualar tissue enginnering (cmte). U. Klueh: Research Support; Self; Abbott. Other Relationship; Self; Cell and Molecular Tissue Engineering, LLC.
The Leona M. and Harry B. Helmsley Charitable Trust