Zhang Yuxi, Kuo Luke, Woodhouse Kimberly A, Fitzpatrick Lindsay E
Department of Chemical Engineering, Queen's University, Kingston, ON K7L 3N6, Canada.
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
ACS Pharmacol Transl Sci. 2024 Jul 3;7(8):2544-2556. doi: 10.1021/acsptsci.4c00363. eCollection 2024 Aug 9.
Continuous subcutaneous insulin infusion for Type 1 diabetes relies upon insulin infusion sets (IIS) to reliably deliver insulin to a subcutaneous depot, where it is absorbed into systemic circulation. However, IIS are plagued by short wear times and high failure rates, due in part to inconsistent insulin absorption that can arise over time. While emerging evidence suggests that the local inflammatory response to the IIS cannula may impact both wear times and unreliable insulin adsorption, the mechanisms are poorly understood. Here, we investigated the effects of local infused insulin concentrations on the biomaterial host response to better understand the underlying factors that limit the IIS performance. We first modeled the insulin concentration for a constant basal infusion rate to select a relevant insulin concentration range of 0.1-10 U/mL within the infusion site. We then examined the influence of a commercial insulin analogue (Humulin-N) using an in vitro macrophage-material model, which uses adsorbed fibroblast lysate (containing damage-associated molecular patterns) to activate macrophages and recapitulates macrophage responses on implanted biomaterials. RAW-Blue macrophages cultured on lysate-adsorbed surfaces had increased nuclear factor-κB (NF-κB) and activating protein 1 (AP-1) activity and intracellular reactive oxygen species (ROS) accumulation compared to control surfaces. Humulin-N concentration (0.5-10 U/mL) enhanced the NF-κB/AP-1 activity and ROS accumulation in macrophages on lysate-adsorbed surfaces. However, Humulin-N had no effect on NF-κB/AP-1 or ROS in the absence of the inflammatory stimulus. Additionally, high insulin concentrations arising from therapeutic doses induced macrophage apoptosis with and without adsorbed lysate. This study contributes to emerging evidence that infused insulin affects the tissue response to IIS.
1型糖尿病的持续皮下胰岛素输注依赖于胰岛素输注装置（IIS）将胰岛素可靠地输送到皮下储库，然后在那里被吸收进入体循环。然而，IIS存在佩戴时间短和故障率高的问题，部分原因是随着时间的推移胰岛素吸收不一致。虽然新出现的证据表明，对IIS套管的局部炎症反应可能会影响佩戴时间和不可靠的胰岛素吸附，但其中的机制尚不清楚。在这里，我们研究了局部输注胰岛素浓度对生物材料宿主反应的影响，以更好地了解限制IIS性能的潜在因素。我们首先对恒定基础输注速率下的胰岛素浓度进行建模，以选择输注部位内0.1 - 10 U/mL的相关胰岛素浓度范围。然后，我们使用体外巨噬细胞 - 材料模型研究了一种商业胰岛素类似物（优泌林 - N）的影响，该模型使用吸附的成纤维细胞裂解物（包含损伤相关分子模式）来激活巨噬细胞，并概括植入生物材料上的巨噬细胞反应。与对照表面相比，在裂解物吸附表面培养的RAW - Blue巨噬细胞具有增加的核因子 - κB（NF - κB）和激活蛋白1（AP - 1）活性以及细胞内活性氧（ROS）积累。优泌林 - N浓度（0.5 - 10 U/mL）增强了裂解物吸附表面上巨噬细胞的NF - κB/AP - 1活性和ROS积累。然而，在没有炎症刺激的情况下，优泌林 - N对NF - κB/AP - 1或ROS没有影响。此外，治疗剂量引起的高胰岛素浓度在有或没有吸附裂解物的情况下均诱导巨噬细胞凋亡。这项研究为新出现的证据做出了贡献，即输注的胰岛素会影响组织对IIS的反应。
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