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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 该提案延续了10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研究，证明了该方法对1型糖尿病（T1 DM）评估的实用性：（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。具体而言： 第2阶段将研究低血糖症及其与胰岛素转移的微血管和网络动力学的关系。我们计划评估根据中度或重度低血糖病史确定的低血糖或高血糖风险受试者中胰岛素从循环转移至胰岛素的时间过程。 这种方法将提供对毛细血管反应的时间过程的了解，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，并且作为动态过程肯定是不可接近的。 III期将使用动态网络模型研究低血糖与高血糖风险的T1 DM受试者中低血糖相关自主神经功能衰竭的发展时间过程和动态特征。 结合2期和3期的结果，将阐明反调节功能障碍和个体胰岛素敏感性对重度低血糖发生的相对贡献。与低风险受试者相比，重度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.