ESTIMATION OF BETA CELL MASS EVOLUTION IN KETOSIS-PRONE DIABETES

酮症倾向糖尿病中 β 细胞质量进化的估计

• 批准号: 8356774
• 负责人: ASHOK BALASUBRAMANYAM
• 金额: $ 0.08万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356774
• 关键词: Acute; Adult; Age; Algorithms; Arginine; Autoimmunity; Beta Cell; Biochemical; Cell physiology; Classification; Clinic; Clinical; Clinical Research; Data; Defect; Diabetes Mellitus; Diabetic Ketoacidosis; Event; Evolution; Functional disorder; Funding; Future; General Hospitals; Glucose; Grant; Immunologic Tests; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Maintenance; Measurement; Measures; National Center for Research Resources; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Overweight; Patients; Physiological; Pilot Projects; Principal Investigator; Publishing; Recovery; Research; Research Infrastructure; Resources; Source; Stress; Subgroup; Syndrome; System; Testing; Time; United States National Institutes of Health; Variant; cohort; cost; design; diabetic; diabetic patient; genetic analysis; glycemic control; insulin secretion; male; non-diabetic; partial recovery; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT 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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 摘要 酮症倾向性糖尿病（KPD）是一种异质性综合征，其特征是成年患者出现糖尿病酮症酸中毒（DKA）。 多种严重形式的β细胞功能障碍似乎是KPD病理生理学的基础。 利用一个大的，纵向随访的KPD患者队列，重复的临床和生化测量，免疫学测试和遗传分析，我们已经确定了四个临床和病理生理学上不同的亚组KPD，区分β细胞自身免疫（A+或A-）的存在或不存在和β细胞功能储备（B+或B-）的存在或不存在。由此产生的KPD的AB分类系统是准确的，并且高度预测临床结果。 KPD的一个独特亚组是新发、非诱因A-B+ KPD，其特征为：1）以DKA作为糖尿病的首次表现; 2）DKA没有特定的应激或其他突发事件; 3）通常在40岁以后发病; 4）肥胖/超重; 5）3：1男性优势。 从DKA急性发作恢复后，A-B+ KPD患者通常表现出β细胞功能储备增加，长期血糖控制良好，胰岛素依赖性超过45%。 本研究的目的是确定A-B+ KPD中β细胞功能的初始严重缺陷和随后的部分恢复是否与β细胞质量的变化相关。 这项初步研究的设计是比较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中β细胞功能和质量随时间的变化。 我们假设，β细胞质量将随着时间的推移在典型的2型糖尿病患者中显示进行性下降，而KPD患者（从DKA恢复后）将显示初始增加，随后长期维持β细胞质量。 为了验证这一假设，我们建议进行一项试点研究，具体目标如下：1。在3组10名成人受试者中测量对精氨酸、葡萄糖和葡萄糖增强精氨酸的胰岛素分泌反应：a）新发的、无诱因的A-B + KPD，B）新发的“典型”（非酮症）2型糖尿病，和c）正常的、葡萄糖耐受对照;在基线和6个月和12个月后; 2.在基线时以及6个月和12个月后，使用将这些生理测试与已知数量的移植胰岛细胞相关联的先前（公开）数据来估计这3组中的β细胞质量; 3.使用目标1和2的数据来估计测量中的响应和效应量的变化，从而在未来设计统计学上严格的大规模试验。 将通过测量对精氨酸和葡萄糖的定量胰岛素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3组之间的β细胞功能和质量。 GPAIS已显示与β细胞质量良好相关。在整个研究期间，这两个糖尿病组将在Ben Taub General Hospital的DKA专用诊所使用标准算法接受糖尿病治疗。