Glucose-stimulated insulin release: Parallel perifusion studies of free and hydrogel encapsulated human pancreatic islets
Glucose-stimulated insulin release: Parallel perifusion studies of free and hydrogel encapsulated human pancreatic islets
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DOI：
10.1002/bit.26442
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发表时间：
2018-01-01
影响因子：
3.8
通讯作者：
Stabler, Cherie L.
中科院分区：
文献类型：
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作者：
Buchwald, Peter;Tamayo-Garcia, Alejandro;Stabler, Cherie L.
为了探讨免疫隔离封装对胰岛胰岛素分泌的影响，并提高我们定量描述胰岛葡萄糖刺激的胰岛素释放（GSIR）的能力，我们用离体人胰岛进行了动态灌流实验。使用自动化多通道系统并行灌注游离（未包封）和水凝胶包封的胰岛，该系统允许以高时间分辨率收集样品。结果表明，游离人胰岛分泌的每单位质量胰岛素或胰岛当量（IEQ）比鼠胰岛少，第一相峰不太明显。虽然小的微胶囊（d=700 μ m）与未包封的胰岛相比仅引起轻微延迟和钝化的第一相胰岛素反应，但较大的胶囊（d= 1，800 μ m）完全钝化了第一相峰并降低了释放的胰岛素总量。实验获得的胰岛素时间曲线与我们复杂的胰岛素分泌计算模型拟合。这允许进一步微调该模型的释放参数，该模型在COMSOL Multiphysics中实现，以将激素分泌和营养消耗动力学与扩散和对流运输相结合。这些GSIR实验的结果也得到了计算模型的支持，表明较大的胶囊必然导致第一时相胰岛素反应的抑制和持续释放型胰岛素分泌，其只能缓慢地响应葡萄糖浓度的变化。生物人工胰腺型装置可以提供长期的和生理上理想的解决方案，只有当免疫隔离和生物相容性考虑与优化的营养扩散和胰岛素释放特性相结合的设计。
To explore the effects immune-isolating encapsulation has on the insulin secretion of pancreatic islets and to improve our ability to quantitatively describe the glucose-stimulated insulin release (GSIR) of pancreatic islets, we conducted dynamic perifusion experiments with isolated human islets. Free (unencapsulated) and hydrogel encapsulated islets were perifused, in parallel, using an automated multi-channel system that allows sample collection with high temporal resolution. Results indicated that free human islets secrete less insulin per unit mass or islet equivalent (IEQ) than murine islets and with a less pronounced first-phase peak. While small microcapsules (d=700 mu m) caused only a slightly delayed and blunted first-phase insulin response compared to unencapsulated islets, larger capsules (d=1,800 mu m) completely blunted the first-phase peak and decreased the total amount of insulin released. Experimentally obtained insulin time-profiles were fitted with our complex insulin secretion computational model. This allowed further fine-tuning of the hormone-release parameters of this model, which was implemented in COMSOL Multiphysics to couple hormone secretion and nutrient consumption kinetics with diffusive and convective transport. The results of these GSIR experiments, which were also supported by computational modeling, indicate that larger capsules unavoidably lead to dampening of the first-phase insulin response and to a sustained-release type insulin secretion that can only slowly respond to changes in glucose concentration. Bioartificial pancreas type devices can provide long-term and physiologically desirable solutions only if immunoisolation and biocompatibility considerations are integrated with optimized nutrient diffusion and insulin release characteristics by design.