Epigenetic Markers of Short- and Long- Term Near-Normoglycemia Remission in Patients with Ketosis-Prone Diabetes

项目摘要/摘要 酮症易感性糖尿病(KPDM)影响到约20%-50%的新诊断的非洲裔美国人患者 出现糖尿病酮症酸中毒(DKA)的糖尿病患者。在出现DKA时，这些患者有严重的 伴随严重的胰岛素抵抗的胰岛素分泌失代偿(β细胞功能)。不像 1型糖尿病患者，在强化胰岛素治疗后，其中许多患者表现出 改善胰岛素分泌和胰岛素敏感性，并能够停止胰岛素治疗(接近- 血糖正常缓解，糖化血红蛋白7%)。接近正常的血糖缓解期是可变的 患者最终会经历高血糖复发，甚至是DKA。因此，研究潜在的 导致胰岛素分泌和敏感性改变以及接近正常血糖缓解的机制 对相当数量的非裔美国人糖尿病患者的影响。 DNA甲基化和基因表达，已被认为是影响胰岛素分泌和 胰岛素敏感性。在这项提案中，根据初步结果，医学博士Pi Priyathama Vellanki将测试 特定途径中纵向基因表达和DNA甲基化的变化是否会影响定量 胰岛素敏感性和分泌特点与近正常血糖的达成和维持 减刑。在Aim1中，她将描述葡萄糖中的基因表达和DNA甲基化是否发生变化 感觉和胰岛素分泌途径与胰岛素分泌的定量测量有关 胰高血糖素刺激试验。在目标2中，她将描述葡萄糖吸收和胰岛素信号通路的特征 从频繁采样的四次葡萄糖耐量试验(FSIVGTT)中检测胰岛素敏感性的数量性状。她会的 还要测试这些途径中的基因表达和甲基化是否与短期和长期 血糖接近正常的缓解。此外，为了开发基于血液的生物标记物，她将测试 肌肉中的基因表达和DNA甲基化与血液中的相关。成功完成这些任务 AIMS将对胰岛素敏感性和分泌变化的机制产生重要的见解 通过对KPDM患者的临床病程进行分析。 拟议的目标将在一个专家跨学科指导小组的指导下实现，该小组由 她的首席导师Umpierrez博士(KPDM方面的专业知识)和共同导师Alicia K.Smith博士(表观遗传学专家) 以及由统计遗传学专家组成的咨询委员会(Karen Conneely博士)和 计算生物学(Darko Stefan ovski博士)。埃默里大学是一所世界级的大学，拥有足够的 以及实现研究目标所需的充足资源，包括佐治亚州临床和翻译 科学联盟。她的结构化培训计划包括在埃默里的正式授课培训和动手培训 在表型研究和数据分析方面的表现。求婚和有组织的职业生涯 开发计划将使Vellanki博士成为一名成功的由NIH资助的独立临床研究员。

Project Summary/Abstract Ketosis-prone diabetes mellitus (KPDM) affects ~20-50% of African American patients with newly diagnosed diabetes who present with diabetic ketoacidosis (DKA). At presentation of DKA, these patients have a severe decompensation in insulin secretion (beta-cell function) accompanied by severe insulin resistance. Unlike patients with type 1 diabetes, following intensive insulin treatment, many of these patients exhibit improvements in insulin secretion and insulin sensitivity and are able to discontinue insulin therapy (near- normoglycemia remission, HbA1c < 7%). The period of near-normoglycemia remission is variable and many patients eventually experience a hyperglycemic relapse or even DKA. Therefore, studying the underlying mechanisms leading to changes in insulin secretion and sensitivity and near-normoglycemia remission has implications for a significant number of African American patients with diabetes. DNA methylation and gene expression, have been proposed as mechanisms that affect insulin secretion and insulin sensitivity. In this proposal, based on preliminary results, the PI Priyathama Vellanki, MD, will test whether longitudinal gene expression and DNA methylation changes in specific pathways affect quantitative traits of insulin sensitivity and secretion along with achievement and maintenance of near-normoglycemia remission. In Aim1, she will characterize whether gene expression and DNA methylation changes in glucose sensing and insulin secretion pathways associate with quantitative measures of insulin secretion derived from glucagon stimulation tests. In Aim 2, she will characterize glucose uptake and insulin signaling pathways with quantitative traits of insulin sensitivity from frequently-sampled IV glucose tolerance tests (FSIVGTT). She will also test whether gene expression and methylation in these pathways associate with short- and long-term near-normoglycemia remission. Further, in order to develop blood-based biomarkers, she will test whether gene expression and DNA methylation in muscle correlate with those in blood. Successful completion of these aims will yield important insights into mechanisms that underlie changes in insulin sensitivity and secretion through the clinical course of patients with KPDM. The proposed aims will be performed under the guidance of an expert interdisciplinary mentorship team led by her lead mentor Dr. Umpierrez (expertise in KPDM) and co-mentor Dr. Alicia K. Smith (expert in epigenetics) along with an advisory committee comprised of experts in statistical genetics (Dr. Karen Conneely) and computational biology (Dr. Darko Stefanovski). Emory University is a world-class institution that has adequate and ample resources necessary to carry out the research aims, including the Georgia Clinical and Translation Science Alliance. Her structured training plan has formal didactic training at Emory along with hand-on training in performance of phenotyping studies and data analyses. The proposal along with the structured career development plan will poise Dr. Vellanki to become a successful independent NIH-funded clinical investigator.