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

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该提案延续了十年来在生物行为监测方法方面的工作，通过从系统生物学的角度进行研究，这些方法已被证明可用于评估 1 型糖尿病 (T1DM)：(i) 触发和伴随低血糖的功能机制，以及 (ii) 与反复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反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 2 阶段）和反调节（第 3 阶段）内部反馈回路的研究。具体来说： 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态的关系。我们计划评估低血糖风险低或高的受试者中胰岛素从循环转移到间质的时间过程，这取决于他们的中度或重度低血糖史。 这种方法将提供对毛细血管反应的时间过程的洞察，并将允许对胰岛素和葡萄糖的间质浓度进行动态定量评估，否则即使在孤立的时间点也极难测量，并且作为一个动态过程肯定无法获得。 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 T1DM 受试者低血糖相关自主神经衰竭的发展时间过程和动态特征。 结合起来，第 2 阶段和第 3 阶段的结果将阐明反调节损伤和个体胰岛素敏感性对严重低血糖发生的相对影响。与低风险受试者相比，严重低血糖高风险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.