ESTIMATION OF BETA CELL MASS EVOLUTION IN KETOSIS-PRONE DIABETES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 酮症易发糖尿病(KPD)是一种以糖尿病患者的酮症酸中毒(DKA)为特征的异质性综合征。多种严重形式的β细胞功能障碍似乎是KPD的病理生理学基础。利用大量纵向追踪的KPD患者队列，通过重复的临床和生化测量、免疫学测试和基因分析，我们鉴定了四种临床和病理生理上不同的KPD亚型，区别于有或没有β细胞自身免疫(A+或A-)和有或不存在β细胞功能储备(B+或B-)。由此得到的KPD的AB分类系统是准确的，并对临床结果具有高度的预测性。 KPD的一个独特亚型是新发的、无端的A-B+KPD，其特征是：1)以DKA为首发症状；2)DKA没有特定的应激或其他诱发事件；3)通常在40岁以后发病；4)肥胖/超重；5)3：1男性占优势。在DKA急性发作恢复后，A-B+KPD患者通常表现为β细胞功能储备增加，长期血糖控制良好，超过45%的患者胰岛素依赖性。本研究的目的是确定A-B+KPD患者最初的严重缺陷和随后部分恢复的β细胞功能是否与β细胞质量的变化有关。这项先导性研究的设计是为了比较A-B+KPD患者、典型(非酮症)2型糖尿病患者和非糖尿病对照组的β细胞功能和质量随时间的变化。我们假设，在典型的2型糖尿病患者中，随着时间的推移，β细胞质量将呈现进行性下降，而KPD患者(从DKA恢复后)将显示出最初的增加，随后β细胞质量将长期保持。为了验证这一假设，我们建议进行一项具有以下特定目的的初步研究：1.测量3组受试者对精氨酸、葡萄糖和葡萄糖增强精氨酸的胰岛素分泌反应：a)新发的、无缘无故的A-B+KPD，b)新发的“典型”(非酮症)2型糖尿病，c)正常的糖耐量对照组，在基线、6个月和12个月后；2.使用这些生理测试与已知的移植胰岛细胞数量相关的先前(已发表的)数据，在基线时以及6个月和12个月后估计这三组中的β细胞质量；3.使用AIMS 1和2的数据来估计测量中的反应和效应大小的变化，从而设计一项统计上严格的更大规模的试验。 将通过测量胰岛素对精氨酸和葡萄糖的定量分泌反应以及葡萄糖增强的精氨酸诱导的胰岛素分泌(GPAIS)来比较这三组之间的β细胞功能和质量。GPAIS已被证明与β细胞质量有很好的相关性。在整个研究期间，这两组糖尿病患者将在我们位于本陶布综合医院的专用DKA诊所使用标准算法接受糖尿病治疗。 在典型的2型糖尿病患者中，GPAIS估计的β细胞质量将在12个月内呈进行性下降，而KPD患者将呈现先增加后长期维持的β细胞质量。KPD患者的β细胞质量始终低于正常血糖对照组。 目的1.测定3组受试者对精氨酸、葡萄糖和葡萄糖强化精氨酸的胰岛素分泌反应，这些受试者包括：a)新发的、无诱因的A-B+KPD患者，b)新发的“典型”(非酮症)2型糖尿病患者，以及c)正常的糖耐量对照组，在基线、6个月和12个月后。 目的2.使用这些生理测试与已知的移植胰岛细胞数量相关的先前(已发表的)数据，估计这三组受试者在基线、6个月和12个月后的β细胞质量。 目的3.使用目标1和目标2的数据来估计测量中反应和效应大小的变化，从而设计一项统计上严格的更大规模的试验。

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. Ketosis-prone diabetes (KPD) is a heterogeneous syndrome characterized by adult patients who present with diabetic ketoacidosis (DKA). Multiple, severe forms of beta cell dysfunction appear to underlie the pathophysiology of KPD. Utilizing a large, longitudinally followed cohort of KPD patients, with repeated clinical and biochemical measurements, immunologic tests and genetic analysis, we have identified four clinically and pathophysiologically distinct subgroups of KPD, distinguished by the presence or absence of beta cell autoimmunity (A+ or A-) and the presence or absence of beta cell functional reserve (B+ or B-). The resulting ¿??AB¿?¿ classification system of KPD is accurate and highly predictive of clinical outcomes. One unique subgroup of KPD is new-onset, unprovoked A-B+ KPD, characterized by: 1) presentation with DKA as the first manifestation of diabetes; 2) absence of a specific stress or other precipitating event for the DKA; 3) onset usually after age 40; 4) obese / overweight; 5) 3:1 male predominance. Following recovery from the acute episode of DKA, A-B+ KPD patients usually manifest increased beta cell functional reserve, good long-term glycemic control, and insulin independence in over 45%. The purpose of this study is to determine if the initial severe defect and subsequent partial recovery of beta cell function in A-B+ KPD is associated with changes in beta cell mass. The design of this pilot study is to compare beta cell function and mass over time in A-B+ KPD patients, ¿??typical¿?¿ (non-ketotic) type 2 diabetics, and non-diabetic controls. We hypothesize that beta cell mass will show a progressive decline over time in the ¿??typical¿?¿ type 2 diabetic patients, while the KPD patients (following recovery from DKA) will show an initial increase followed by long-term maintenance of beta cell mass. To test this hypothesis, we propose to carry out a Pilot Study with the following Specific Aims: 1. To measure insulin secretory responses to arginine, glucose, and glucose-potentiated arginine in 3 groups of 10 adult subjects: a) new-onset, unprovoked A-B+ KPD, b) new onset "typical" (non-ketotic) type 2 diabetes, and c) normal, glucose-tolerant controls; at baseline and after 6 months and 12 months; 2. To estimate beta cell mass in these 3 groups at baseline, and after 6 and 12 months, using prior (published) data correlating these physiologic tests with known quantities of transplanted islet cells; 3. To use the data from Aims 1 and 2 to estimate variations of response and effect size in the measurements, and thus design a statistically rigorous larger-scale trial in the future. Beta cell function and mass will be compared between these 3 groups by measuring quantitative insulin secretory responses to arginine and glucose, as well as glucose-potentiated arginine-induced insulin secretion (GPAIS). GPAIS has been shown to correlate well with beta cell mass. The two diabetic groups will receive treatment for diabetes using standard algorithms in our dedicated DKA Clinic at Ben Taub General Hospital throughout the study period. Beta cell mass as estimated by GPAIS will show progressive decline over 12 months in the patients with typical type 2 diabetes, while the KPD patients will demonstrate initial increase followed by long-term maintenance of beta cell mass. Beta cell mass in the KPD patients will always remain lower than in the normoglycemic controls. Aim 1. To measure insulin secretory responses to arginine, glucose, and glucose-potentiated arginine in 3 groups of 10 subjects: a) persons with new-onset, unprovoked A-B+ KPD, b) persons with new onset "typical" (non-ketotic) type 2 diabetes, and c) normal, glucose-tolerant controls; at baseline and after 6 months and 12 months. Aim 2. To estimate beta cell mass in these 3 groups of subjects at baseline, and after 6 months and 12 months, using prior (published) data correlating these physiologic tests with known quantities of transplanted islet cells. Aim 3. To use the data from Aims 1 and 2 to estimate variations of response and effect size in the measurements, and thus design a statistically rigorous larger-scale trial in the future.