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

项目总结/摘要 酮症倾向性糖尿病（KPDM）影响约20-50%的新诊断的非裔美国人患者， 糖尿病酮症酸中毒（DKA）。在出现DKA时，这些患者有严重的 胰岛素分泌失调（β细胞功能），伴有严重的胰岛素抵抗。不像 1型糖尿病患者，在强化胰岛素治疗后，这些患者中的许多表现出 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， HbA1c < 7%）。接近正常的缓解期是可变的， 患者最终经历高血糖复发或甚至DKA。因此，研究底层 导致胰岛素分泌和敏感性变化以及接近正常胰岛素缓解的机制， 对大量非裔美国糖尿病患者的影响。 DNA甲基化和基因表达已被认为是影响胰岛素分泌的机制， 胰岛素敏感性在这项提案中，根据初步结果，PI Priyathama Vellanki，医学博士，将测试 特定途径中的纵向基因表达和DNA甲基化变化是否影响定量 胰岛素敏感性和分泌特征沿着血糖接近正常的实现和维持 缓解。在Aim 1中，她将描述葡萄糖代谢中基因表达和DNA甲基化是否发生变化。 感测和胰岛素分泌途径与来自以下的胰岛素分泌的定量测量相关： 胰高血糖素刺激试验。在目标2中，她将描述葡萄糖摄取和胰岛素信号通路， 来自频繁采样的IV葡萄糖耐量试验（FSIVGTT）的胰岛素敏感性的定量性状。她将 还测试了这些途径中的基因表达和甲基化是否与短期和长期的 接近正常的缓解。此外，为了开发基于血液的生物标志物，她将测试是否 肌肉中的基因表达和DNA甲基化与血液中的基因表达和DNA甲基化相关。成功完成这些 aims将对胰岛素敏感性和分泌变化的机制产生重要的见解 KPDM患者的临床过程。 拟议的目标将在一个专家跨学科指导小组的指导下执行，该小组由 她主要导师Umpierrez博士（KPDM专家）和共同导师Alicia K.史密斯（表观遗传学专家） 沿着的还有一个由统计遗传学专家组成的咨询委员会（卡伦·康尼利博士）， 计算生物学（Darko Stefanovski博士）。埃默里大学是一所世界级的机构， 和充足的资源进行研究的目标，包括格鲁吉亚临床和翻译 科学联盟。她的结构化培训计划有正式的教学培训在埃默里沿着动手培训 在表型研究和数据分析的性能。该提案沿着结构化的职业生涯 发展计划将使Vellanki博士成为一名成功的独立NIH资助的临床研究者。

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.