Insulin induces a progressive increase in the resistance of subcutaneous tissue to fluid flow: Implications for insulin pump therapy

Abstract

Aim: To determine the effect of insulin on the resistance of subcutaneous tissue to the flow of infusion fluids.Materials and methods: Thirty subjects with type 1 diabetes wore two Accu-Chek Spirit Combo insulin pumps with Accu-Chek FlexLink infusion sets (Roche Diabetes Care, Mannheim, Germany) for 7 days. One pump was filled with insulin aspart (Novo Nordisk, Bagsvaerd, Denmark) and used for continuous subcutaneous insulin infusion (CSII). The other pump was filled with insulin diluting medium (IDM; Novo Nordisk) and used to deliver IDM subcutaneously at rates identical to those employed for CSII.Both infusion sites were assessed daily by measuring the pressure required to infuse various bolus amounts of IDM.Results: On day 1, maximum pressure (P max ) and tissue flow resistance (TFR; calculated from measured pressure profiles) were similar for both infusion sites (P > 0.20).During the subsequent study days, the P max and TFR values observed at the IDM infusion site remained at levels comparable to those seen on day 1 (P > 0.13). However, at the site of CSII, P max and TFR progressively increased with CSII duration. By the end of day 7, P max and TFR reached 25.8 */2.11 kPa (geometric mean */geometric standard deviation) and 8.64 */3.48 kPa*s/μL, respectively, representing a remarkable 3.5-and 20.6-fold increase relative to the respective P max and TFR values observed on day 1 (P < 0.001). Conclusion:Our results suggest that insulin induces a progressive increase in the resistance of subcutaneous tissue to the introduction of fluid; this has important implications for the future design of insulin pumps and infusion sets.

Therapeutic Insulin Analogue Concentrations at Infusion Sites Enhanced the Pro-Inflammatory Response and Apoptosis in an In Vitro Macrophage-Material Interaction Model

“…Furthermore, other studies provide evidence that the insulin molecule is responsible for the pro-inflammatory tissue response at infusion sites. A recent study demonstrated that prolonged use of IIS over 3 days was associated with an increased tissue-related flow resistance (TFR) . This increase in TFR was attributed to the accumulation of macrophages and fibroblasts at the infusion site, as well as the deposition of collagen fibrils in response to the infused insulin .…”

“…A recent study demonstrated that prolonged use of IIS over 3 days was associated with an increased tissue-related flow resistance (TFR) . This increase in TFR was attributed to the accumulation of macrophages and fibroblasts at the infusion site, as well as the deposition of collagen fibrils in response to the infused insulin . Additionally, the infusion of insulin via an insulin pump in diabetic swine was shown to impede insulin diffusion at the infusion site after 3 days of infusion, while infusion on the insulin buffer alone (without insulin) had no effect …”

“…23 This increase in TFR was attributed to the accumulation of macrophages and fibroblasts at the infusion site, as well as the deposition of collagen fibrils in response to the infused insulin. 23 Additionally, the infusion of insulin via an insulin pump in diabetic swine was shown to impede insulin diffusion at the infusion site after 3 days of infusion, while infusion on the insulin buffer alone (without insulin) had no effect. 20 Our study supports emerging evidence that commercial insulin analogues play a role in promoting an inflammatory response at the infusion site and adds insight into the cellular mechanism through which insulin analogues affect this response.…”

“…Emerging evidence from small clinical studies and animal models of insulin infusion show that infusion of commercial insulin preparations causes an inflammatory response at the infusion site. 20−23 While there is conflicting evidence regarding whether the inflammatory response is due to the insulin molecule itself 20,23 or the phenolic preservatives within the buffer, 20−22 there is consensus that insulin infusion induces an adverse host response to the IIS cannula, and that the resulting inflammatory tissue response contributes to variable insulin adsorption. However, the mechanism through which the commercial insulin preparations induce this response has not been investigated in depth.…”

“…Macrophages are the primary immune cell that mediates material recognition by adhering to the material surface, releasing a plethora of pro-inflammatory cytokines and chemokines, fusing into foreign body giant cells and recruiting fibroblast to deposit a fibrous capsule, effectively walling the implant off from the surrounding tissue. , While IIS are not implanted long enough to be encapsulated in fibrous tissue, changes to the local tissue at the infusion site likely impact insulin adsorption. Emerging evidence from small clinical studies and animal models of insulin infusion show that infusion of commercial insulin preparations causes an inflammatory response at the infusion site. − While there is conflicting evidence regarding whether the inflammatory response is due to the insulin molecule itself , or the phenolic preservatives within the buffer, − there is consensus that insulin infusion induces an adverse host response to the IIS cannula, and that the resulting inflammatory tissue response contributes to variable insulin adsorption. However, the mechanism through which the commercial insulin preparations induce this response has not been investigated in depth.…”