Markers of Beta Cell Dysfunction and Hypoglycemia in ACCORD

描述（由申请人提供）：低血糖是糖尿病治疗的一种可怕并发症，其后果从不便到死亡不等。在雅阁队列中，重度症状性低血糖与死亡风险增加相关。本项目的目的是使用雅阁队列来确定可预测严重低血糖的生物标志物，长期目标是根据为每位患者选择最安全的方法来个性化糖尿病治疗。在本项目中，我们将检验以下总体假设：胰岛素缺乏的两种生物标志物-空腹血清C肽浓度降低和胰岛自身免疫相关抗体的可检测水平-与雅阁队列中的严重低血糖和死亡密切相关。我们的具体目标是：目标1a：测量雅阁试验期间死亡和发生重度低血糖的受试者的基线空腹血清C肽，并与试验期间未发生死亡和重度低血糖的匹配雅阁受试者的基线测量值进行比较。目标1b：在雅阁试验期间死亡并发生重度低血糖的受试者中测量基线GAD 65（GAD）、酪氨酸磷酸酶样蛋白IA-2（IA-2A）胞浆内结构域和胰岛素（IAA）自身抗体，并与试验期间未发生死亡和重度低血糖的匹配雅阁受试者中测量的基线值进行比较。目标2a：在研究完成前或死亡前的任何访视时，尽管未能达到血红蛋白A1 c < 6.0%，但仍发生重度低血糖的强化治疗组受试者中测量基线时的空腹血清C肽，并与至少有一次达到目标糖化血红蛋白且完成试验且无重度低血糖的强化治疗组匹配雅阁受试者中测量的值进行比较。目标2b：在研究完成或死亡前的任何访视时，尽管未能达到血红蛋白A1 c < 6.0%，但仍发生重度低血糖的强化治疗组受试者基线时测量GAD、IA-2A和IAA，并与至少有一次达到目标糖化血红蛋白且完成试验且无重度低血糖的强化治疗组匹配雅阁受试者的测量值进行比较。

DESCRIPTION (provided by applicant): Hypoglycemia is a feared complication of diabetes therapy, with consequences ranging from inconvenience to death. In the ACCORD cohort, severe symptomatic hypoglycemia was associated with an increased risk for mortality. The purpose of this project is to use the ACCORD cohort to identify biomarkers that would predict severe hypoglycemia, with the long-range goal of individualizing diabetes therapy based on selection of the safest approach for each patient. In this project we will test the overall hypothesis that two biomarkers of insulin deficiency - reduced fasting serum C-peptide concentrations and detectable levels of antibodies associated with islet autoimmunity - are strongly associated with severe hypoglycemia and death in the ACCORD cohort. Our specific aims are: Aim 1a: To measure baseline fasting serum C-peptide at baseline in subjects who died and experienced severe hypoglycemia during the ACCORD trial and compare to baseline values measured in matched ACCORD subjects who did not experience death and severe hypoglycemia during the trial. Aim 1b: To measure baseline autoantibodies to GAD 65 (GAD), intracytoplasmic domain of the tyrosine phosphatase-like protein IA-2 (IA-2A) and insulin (IAA) in subjects who died and experienced severe hypoglycemia during the ACCORD trial and compare to baseline values measured in matched ACCORD subjects who did not experience death and severe hypoglycemia during the trial. Aim 2a: To measure fasting serum C-peptide at baseline in subjects in the intensive arm who experienced severe hypoglycemia despite failing to achieve a hemoglobin A1c < 6.0% at any visit prior to study completion or death and compare to values measured in matched ACCORD subjects in the intensive arm who achieved target glycemia on at least one occasion and completed the trial without severe hypoglycemia. Aim 2b: To measure GAD, IA-2A, and IAA at baseline in subjects in the intensive arm who experienced severe hypoglycemia despite failing to achieve a hemoglobin A1c < 6.0% at any visit prior to study completion or death and compare to values measured in matched ACCORD subjects in the intensive arm who achieved target glycemia on at least one occasion and completed the trial without severe hypoglycemia.