Preservatives in Insulin Preparations Impair Leukocyte Function: In vitro study

Abstract

m-Cresol and methyl p-hydroxybenzoate are preservatives in insulin preparations. As previously reported, in diabetic patients on continuous subcutaneous insulin infusion, users of insulin-containing m-cresol had significantly more inflamed infusion sites than users of insulin with methyl p-hydroxybenzoate. This study assessed the influence of insulin with and without these preservatives on leukocyte function. Leukocyte function was investigated in a killing experiment, expressed as the percentage of bacteria killed after 60 min incubation of bacteria (Staphylococcus aureus), polymorphonuclear leukocytes, serum, and insulin preparations. Because preservative is retained by the infusion device, insulin with preservative was tested before and after 1 and 4 days perfusion with a PVC pump catheter. After perfusion, the amount of preservative was reduced (percentage of original concentration after 1 and 4 days 8 and 30% m-cresol and 42 and 72% methyl p-hydroxybenzoate, respectively). The killing percentage in insulin with m-cresol reduced compared with insulin without preservative (mean ± SE 95.4 ± 0.8%) and the control without insulin (95.8 ± 0.8%), both before and after 1 and 4 days perfusion (74.8 ± 0.7, 80.2 ± 2.8, and 80.6 ± 1.6%, respectively; P < 0.01). The same occurred in insulin with methyl p-hydroxybenzoate (85.0 ± 0.9% before and 88.4 ± 0.9 and 86.2 ± 0.8% after 1 and 4 days perfusion; P < 0.05). All insulin preparations with m-cresol caused lower killing percentages than corresponding insulin preparations with methyl p-hydroxybenzoate (P < 0.05). These results demonstrate that both preservatives impaired leukocyte function, but m-cresol was the most noxious in this respect. This indicates that preservatives in insulin preparations are possibly implicated in the pathogenesis of local infections in continuous subcutaneous insulin infusion.