Characterizing the evolution of impaired hypoglycemia awareness in people with type 1 diabetes and the impact of automated insulin delivery and exercise on restoring hypoglycemia awareness

摘要 低血糖意识受损(IAH)影响25%的成年1型糖尿病患者，并与 患严重低血糖的风险高出六倍。那些受严重影响的人估计死亡率为3.4%。 IAH的特征是肾上腺素能症状和对 低血糖症。关于IAH的演化，只有有限的数据可用。到目前为止，恢复 人们对低血糖的认识主要集中在尽量减少低血糖暴露。而胰岛细胞 移植已经取得了成功，这种方法只适用于目前受影响最严重的人 侵入性的，有严格的资格标准，需要长期的免疫抑制，并且是资源密集型的。所以 纳入教育和技术的FAR干预措施，包括持续血糖监测 (CGM)和胰岛素自动给药(AID)的成功有限，尽管研究规模很小 而且持续时间很短。我们假设IAH经过许多年的演化，由周期性的推动 低血糖症。在没有恢复胰高血糖素反应的情况下，IAH的逆转可能需要延长 近乎绝对的低血糖避免期。我们还假设高强度间歇运动 (HIIT)，即使在那些患有严重IAH的人中，也会引起反调节的激素反应，可能有 在恢复低血糖意识中的辅助作用。 我们建议在一组成人1型糖尿病合并IAH患者中进行随机对照试验。 胰岛素剂量。所有人都将接受低血糖认知和回避心理教育。 参与者(总共500人，其中50人在我们的网站进行研究)将被随机分成两年的胰岛素注射组 使用具有和不具有对HIIT计划的辅助支持的可用的最先进的AID系统， 这将与通常的护理进行比较。主要结果将是同情的复合体 低血糖钳夹研究期间的症状和内源性葡萄糖产生(EGP)反应。 其他结果是(I)钳制研究期间的反调节反应；(Ii)CGM低- 真实世界条件下的血糖范围；以及(Iii)个人报告的结果，包括低血糖 意识症状评分。没有IAH的1型糖尿病队列和那些有成功的 将在单个时间点对胰岛移植进行研究，以提供积极的对照数据。此外，我们还将 跟踪超过1000名儿童的基于人口的儿科队列，其中93%使用CGM。CGM的变化 低血糖时间将与Gold和Clarke评分在4年内的变化有关，并有可能延长 这需要单独的资金。 来自该研究计划的数据将极大地促进对IAH的了解，并指导实际和 有意义的干预。

Abstract Impaired hypoglycemia awareness (IAH) affects 25% of adults with type 1 diabetes and is associated with a six-fold higher risk of severe hypoglycemia. Those severely affected have an estimated mortality of 3.4%. IAH is characterized by defects in adrenergic symptoms and the counter-regulatory hormone response to hypoglycemia. Only limited data are available regarding the evolution of IAH. To date, strategies to restore hypoglycemia awareness have focused upon minimizing hypoglycemia exposure. While islet-cell transplantation has met with success, this approach is reserved for only the most severely affected as it is invasive, has strict eligibility criteria, requires long-term immunosuppression and is resource-intensive. So far interventions incorporating education and technologies, including continuous glucose monitoring (CGM) and automated insulin delivery (AID), have had limited success, though studies have been small and of short duration. We hypothesize that IAH evolves over many years, promoted by recurrent hypoglycemia. In the absence of restoration of a glucagon response, IAH reversal may require an extended period of near-absolute hypoglycemia avoidance. We also hypothesize that high intensity interval exercise (HIIT), which elicits a counter-regulatory hormone response, even in those with severe IAH, may have an adjunctive role in the restoration of hypoglycemia awareness. We propose a randomized-controlled trial in a cohort of adults with type 1 diabetes with IAH using manual insulin dosing. All will be provided with hypoglycemia recognition and avoidance psycho-education. Participants (n=500 in total with 50 studied at our site) will be randomized to 2-years of insulin delivery using the most advanced AID system available with and without adjunctive support for an HIIT program, which will be compared with usual care. The primary outcome will be a composite of sympathetic symptoms and the endogenous glucose production (EGP) response during hypoglycemic clamp studies. Other outcomes are (i) counter-regulatory responses during clamp studies; (ii) percent time in CGM low- glucose ranges in real-world conditions; and (iii) person reported outcomes, including hypoglycemia awareness symptom scores. Type 1 diabetes cohorts without IAH and those who have had a successful islet-transplant will be studied at a single time-point to provide positive control data. In addition, we will follow a population-based pediatric cohort of over 1000 children, with 93% using CGM. Changes in CGM low glucose time will be related to changes in Gold and Clarke scores over 4-years, with potential to extend this with separate funding. Data from this program of research will substantially advance knowledge of IAH and guide practical and meaningful interventions.