Markers of Beta Cell Dysfunction and Hypoglycemia in ACCORD

描述(申请人提供)：低血糖是糖尿病治疗的一种可怕的并发症，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。这个项目的目的是使用ACCORD队列来确定可以预测严重低血糖的生物标记物，长期目标是基于为每个患者选择最安全的方法来个体化糖尿病治疗。在这个项目中，我们将检验两个胰岛素缺乏的生物标志物--空腹血清C肽浓度降低和与胰岛自身免疫相关的可检测抗体水平--与ACCORD队列中的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：目标1a：测量在ACCORD试验期间死亡并经历严重低血糖的受试者的基线空腹血清C-肽，并与在试验期间未经历死亡和严重低血糖的匹配的ACCORD受试者测量的基线值进行比较。目的1b：检测ACCORD试验中死亡和发生严重低血糖的受试者的GAD 65(GAD 65)、酪氨酸磷酸酶样蛋白IA-2胞浆内结构域(IA-2A)和胰岛素(IAA)的基线自身抗体，并与在试验期间没有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：测量强化组受试者基线时的空腹血清C-肽水平，这些受试者在研究完成或死亡前的任何一次就诊时均未达到6.0%的血红蛋白A1c&lt；但仍经历严重低血糖，并与强化组中至少一次达到目标血糖且在试验结束时未出现严重低血糖的配对符合受试者的测定值进行比较。目的2b：测量强化组受试者基线时的GAD、IA-2A和IAA，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一次就诊都未能达到6.0%的血红蛋白，并与强化组中至少一次达到目标血糖并完成试验且没有严重低血糖的匹配ACACH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.