COUNTER-REGULATORY IMPAIRMENT AND MICROVASCULAR INSULIN TRANSFER IN TYPE 1 DM

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这项建议延续了十年的生物行为监测方法的工作，已被证明对1型糖尿病(T1 DM)的评估有用，从系统生物学的角度研究：(I)触发和伴随低血糖的功能机制，以及(Ii)与复发性低血糖相关的反馈机制，包括胰岛素敏感性增加的微血管生理学和逆调节受损的时间模式。因此，拟议的研究计划包括基于GCRC的胰岛素转移(第二阶段)和反调节(第三阶段)内部反馈回路的调查。具体地说，就是： 第二阶段将研究低血糖及其与胰岛素转移的微血管和网络动力学的关系。我们计划评估低血糖或高低血糖风险受试者的胰岛素从循环到间质转移的时间进程，这取决于他们的中度或严重低血糖病史。这一方法将提供对毛细血管反应时间进程的洞察，并将允许动态定量评估胰岛素和葡萄糖的间质浓度，否则即使在孤立的时间点也极难测量，并且肯定无法作为动态过程进行测量。 第三阶段将使用动态网络模型来研究低血糖风险与高风险低血糖的T1 DM受试者的发展过程和低血糖相关自主神经衰竭的动态特征。 综合来看，2期和3期的结果将阐明反调节功能受损和个体胰岛素敏感性对严重低血糖发生的相对贡献。与低风险受试者相比，严重低血糖高危受试者将经历更高的胰岛素敏感性和更快的自主神经衰竭。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This proposal continues ten years of work on biobehavioral monitoring methods with proven utility to the assessment of Type 1 Diabetes Mellitus (T1DM) by investigating from a systems biology point of view: (i) functional mechanisms triggering and accompanying hypoglycemia, and (ii) feedback mechanisms related to recurrent hypoglycemia, including microvascular physiology of increased insulin sensitivity and temporal patterns of impaired counter-regulation. Consequently, the proposed research plan includes GCRC-based investigations of the internal feedback loops of insulin transfer (Phase 2) and counter-regulation (Phase 3). Specifically: Phase 2 will investigate hypoglycemia and its relationship to microvascular and network dynamics of insulin transfer. We plan to assess the time course of insulin transfer from circulation to interstitium in subjects at low or high risk of hypoglycemia as determined by their history of moderate or severe hypoglycemia. This approach will provide insight on the time course of capillary responses and will allow for a dynamic quantitative assessment of the interstitial concentrations of insulin and glucose that are otherwise extremely difficult to measure even at isolated points in time and are certainly inaccessible as a dynamic process. Phase 3 will use a dynamic network model to investigate the time course of development and the dynamic characteristics of hypoglycemia-associated autonomic failure in T1DM subjects at low vs. high risk for hypoglycemia. In combination, the results from Phases 2 and 3 will clarify the relative contribution of counter-regulatory impairment and individual insulin sensitivity to occurrence of severe hypoglycemia. Subjects at high risk for severe hypoglycemia will experience a combination of higher insulin sensitivity and faster autonomic failure compared with subjects at low risk.