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Modeling the Effect of Neonatal Diabetes Mutations on Electrical Activity and Insulin Secretion in Pancreatic Beta Cells

机译：建模的新生儿糖尿病突变对胰腺β细胞电活动和胰岛素分泌的影响。

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摘要

Diabetes is caused by dysfunctional beta (beta) cells found in the multicellular pancreatic islet of Langerhans, an essential micro-organ to maintaining glucose homeostasis via the secretion of insulin. beta cells are highly coupled within the islet, functioning to coordinate a global response to elevated glucose levels and suppressing insulin secretion at basal glucose levels. Despite intrinsic heterogeneity in beta cells, the islet displays network behavior where global activation and suppression are a result of the intracellular coupling between beta cells by means of gap junctions. Previous work has shown that under the influence of gap junction coupling there exists a critical number of inexcitable cells (~15%) that can act as a dominate negative to the system, and suppress activity in stimulatory glucose conditions. This was done by using an inducible mutation that renders specific cells inexcitable, producing a functional form of Neonatal Diabetes Mellitus (NDM), and was simulated by a multi-cellular model for beta cell electrophysiology. We explore this critical behavior further by altering the level of cell-cell coupling by removing gap junction expression in mice and simulating an uncoupled multi-cellular islet with multiple forms of the inactivating (NDM) mutation. We find that critical behavior is diminished when coupling is removed, and islet electrical activity can persist into the realm of severe NDM mutation. Further, we add completeness to the model of the beta cell by accounting for stochastic channel noise and insulin secretion. We show that critical behavior in physiological parameters, e.g. insulin secretion, and electrical activity as measured by real time and simulated calcium dynamics and can be rescued when cell-cell coupling is removed. We present these results as further characterization of the emergent critical behavior in the islet and uncover possible treatment methods for Neonatal Diabetes Mellitus, and other monogenic forms of diabetes.
机译：糖尿病是由朗格罕氏多细胞胰岛中发现的功能失调的β（β）细胞引起的，该细胞是通过胰岛素分泌维持葡萄糖稳态的必要微器官。 β细胞在胰岛内高度耦合，起到协调对升高的葡萄糖水平的总体反应并在基础葡萄糖水平抑制胰岛素分泌的作用。尽管在β细胞中存在固有的异质性，但胰岛仍显示出网络行为，其中全局激活和抑制是β细胞之间通过间隙连接的细胞内偶联的结果。先前的研究表明，在间隙连接偶联的影响下，存在一定数量的不可激发细胞（约15％），它们可作为系统的主要阴性反应，并在刺激性葡萄糖条件下抑制活性。这是通过使用可诱导的突变来实现的，该突变使特定的细胞变得难以激发，从而产生功能性形式的新生儿糖尿病（NDM），并通过用于β细胞电生理的多细胞模型进行了模拟。我们通过消除小鼠中的间隙连接表达并模拟具有多种形式的失活（NDM）突变的未偶联多细胞胰岛来改变细胞-细胞偶联的水平，从而进一步探索这种关键行为。我们发现，去除偶联后，临界行为会减弱，并且胰岛的电活动可以持续进入严重的NDM突变领域。此外，通过考虑随机通道噪声和胰岛素分泌，我们为β细胞模型增加了完整性。我们证明了生理参数中的关键行为，例如通过实时和模拟的钙动力学测定的胰岛素分泌和电活动可以在细胞-细胞偶联被去除后得以挽救。我们将这些结果作为胰岛中紧急关键行为的进一步表征，并揭示新生儿糖尿病和其他单基因糖尿病的可能治疗方法。

著录项

  • 作者

    Notary, Aleena.;

  • 作者单位

    University of Colorado at Denver.;

  • 授予单位 University of Colorado at Denver.;
  • 学科 Biomedical engineering.
  • 学位 M.S.
  • 年度 2015
  • 页码 93 p.
  • 总页数 93
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 石油、天然气工业;
  • 关键词

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