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.

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推进体内连续皮下胰岛素输注：对组织挑战的新见解

连续皮下胰岛素输注 (CSII) 优于常规胰岛素治疗，因为它可以改善血糖控制，从而降低糖尿病并发症的可能性。尽管 CSII 有好处，但胰岛素依赖型糖尿病患者很少能达到最佳的血糖控制。此外，CSII 仅获得 FDA 批准 3 天，并且经常由于尚未完全阐明的原因而过早失败。我们假设存在于所有商业胰岛素制剂中的酚类化合物，如间甲酚和苯酚，是胰岛素输注部位发生组织反应的原因。该假设通过体外细胞培养和小鼠气囊模型进行检验，以确定输注盐水、酚类化合物（即商用稀释剂）和胰岛素后的细胞和组织反应。我们证明了稀释剂和胰岛素在亚临床浓度（例如 >1:10 的商用胰岛素）下对培养的细胞具有细胞毒性。气袋研究表明，与盐水相比，输注稀释的胰岛素或稀释剂本身会诱导三到五倍水平的白细胞募集。在输注后 3 天和 7 天，这些细胞主要是中性粒细胞和巨噬细胞。我们得出结论，商用胰岛素制剂中的酚类化合物对细胞和组织具有毒性，这会导致有效的胰岛素输注治疗失败。气袋研究表明，与盐水相比，输注稀释的胰岛素或稀释剂本身会诱导三到五倍水平的白细胞募集。在输注后 3 天和 7 天，这些细胞主要是中性粒细胞和巨噬细胞。我们得出结论，商用胰岛素制剂中的酚类化合物对细胞和组织具有毒性，这会导致有效的胰岛素输注治疗失败。气袋研究表明，与盐水相比，输注稀释的胰岛素或稀释剂本身会诱导三到五倍水平的白细胞募集。在输注后 3 天和 7 天，这些细胞主要是中性粒细胞和巨噬细胞。我们得出结论，商用胰岛素制剂中的酚类化合物对细胞和组织具有毒性，这会导致有效的胰岛素输注治疗失败。