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中一种可怕的并发症，其后果从不便到死亡不等。在ACCORD队列中，严重的症状性低血糖与死亡风险增加相关。该项目的目的是使用ACCORD队列来识别可预测严重低血糖的生物标志物，其长期目标是在为每位患者选择最安全的方法的基础上实现糖尿病个体化治疗。在这个项目中，我们将测试胰岛素缺乏的两个生物标志物——空腹血清c肽浓度降低和与胰岛自身免疫相关的抗体检测水平——与ACCORD队列中严重低血糖和死亡密切相关的总体假设。我们的具体目标是：目的1a：在ACCORD试验中死亡并经历严重低血糖的受试者中测量基线空腹血清c肽，并与在试验中没有经历死亡和严重低血糖的匹配ACCORD受试者的基线值进行比较。目的1b：在ACCORD试验中死亡并经历严重低血糖的受试者中测量GAD 65 （GAD）、酪氨酸磷酸酶样蛋白IA-2 （IA-2A）和胰岛素（IAA）的基线自身抗体，并与在试验中没有经历死亡和严重低血糖的匹配ACCORD受试者的基线值进行比较。目的2a：测量强化组受试者空腹血清c肽基线值，这些受试者经历了严重低血糖，但在研究完成或死亡前的任何访问中未能达到血红蛋白A1c < 6.0%，并与至少一次达到目标血糖且完成试验无严重低血糖的匹配ACCORD组受试者的测量值进行比较。目的2b：测量强化组受试者的GAD、IA-2A和IAA基线值，这些受试者在研究完成或死亡前的任何访问中均未能达到血红蛋白A1c < 6.0%，但经历了严重低血糖，并与至少一次达到目标血糖且完成试验无严重低血糖的匹配ACCORD组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.