Advancing continuous subcutaneous insulin infusion in vivo: New insights into tissue challenges

Abstract

Continuous Subcutaneous Insulin Infusion (CSII) is superior to conventional insulin therapy as it improves glycemic control thus reducing the probability of diabetic complications. Notwithstanding CSII's benefits, insulin dependent diabetic patients rarely achieve optimal glucose control. Moreover, CSII is only FDA approved for 3 days and often fails prematurely for reasons that have not been fully elucidated. We hypothesize that phenolic compounds, such as m‐cresol and phenol, which are present in all commercial insulin formulations are responsible for the tissue reaction occurring at the insulin infusion site. This hypothesis was examined with in vitro cell cultures and a mouse air‐pouch model to determine cellular and tissue reactions following infusions with saline, phenolic compounds, (i.e., commercial diluent), and insulin. We demonstrated that diluent and insulin were cytotoxic to cells in culture at sub‐clinical concentrations (e.g., >1:10 of commercial insulin). Air pouch studies demonstrated that infusion of either diluted insulin or diluent itself induced three to five‐fold level of recruited leukocytes as compared to saline. At both 3‐ and 7‐days post infusion, these were predominantly neutrophils and macrophages. We conclude that phenolic compounds in commercial insulin preparations are cell and tissue toxic, which contributes to the failure of effective insulin infusion therapy.

Characteristics and morphology of lipohypertrophic lesions in adults with type 1 diabetes with ultrasound screening: an exploratory observational study

“… 32 Rodent studies have shown that phenolic compounds found in insulin are associated with increased inflammatory stress and increased leucocyte activation. 33 Insulin antibodies have also been associated with the development of lipohypertrophic tissue. 34 35 It may also be that in people with higher insulin antibodies, localized insulin exposure mediates an inflammatory response causing tissue change.…”

Inflammation at Site of Insulin Infusion Diminishes Glycemic Control

“…[11][12][13] Skin irritation derived from the catheter materials, insulin formulations or mechanical/biophysical properties of the infusion devices and fluids itself, are all possible contributors to the short CSII lifespan (Table 1). 8,9,[11][12][13][14][15] Currently, all commercial CSII compatible insulin formulations contain insulin phenolic preservatives (IPP), (e.g. phenol and/or m-cresol), which stabilize insulin in a hexameric form and thus prevent denaturation and degradation, while maintaining Abbreviations: CSII, Continuous Subcutaneous Insulin Infusion; S, saline; D, diluent; I, insulin; T/S, thioglycolate/saline; T/I, thioglycolate/insulin; PMNs, neutrophils; MQ/ Mo, macrophages/monocytes; IPP, insulin phenolic preservatives.…”

“…16,17 However, previous studies in our laboratory have shown that IPP are cytotoxic and induce an inflammatory cascade. 15,18 IPP induces a significant influx of inflammatory cells-specifically neutrophils (PMNs) and macrophages/monocytes (MQ/Mo). 15 Inflammatory cells release proteases that result in protein degradation.…”

“…15,18 IPP induces a significant influx of inflammatory cells-specifically neutrophils (PMNs) and macrophages/monocytes (MQ/Mo). 15 Inflammatory cells release proteases that result in protein degradation. [19][20][21] We recently reported that the accumulation of leukocytes at insulin infusion sites leads to increased insulin and insulin fibril uptake by inflammatory cells.…”

“…We modified the classic murine air pouch model to determine total leukocyte influx into the mouse air pouch by lavage, and leukocyte subpopulations using flow cytometry. 15,18,22 The murine air pouch was adapted in an effort to quantitatively evaluate the tissue response to infused commercial insulin-containing IPP, the phenolic preservative, sterile diluent, alone, as well as saline alone into the air pouch. Specifically, we focused on sterile diluent, provided by Eli Lilly and Company, as our phenolic preservative, which has a combined m-cresol and phenol concentration of 2.25 mg/ml.…”