Mechanisms of ketosis and near-normoglycemia remission in obese African Americans with ketosis-prone diabetes

项目总结/摘要 据估计，酮症倾向性糖尿病（KPDM）影响20-50%的非裔美国人患者， 新诊断的糖尿病患者出现糖尿病酮症酸中毒（DKA）。在介绍DKA时，这些 患者的胰岛素分泌严重失调，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， 正常血糖缓解，HbA 1c <7%，空腹血糖< 130 mg/dl，同时停用胰岛素至少一周）。 接近正常的缓解期是可变的，许多患者最终会经历 高血糖复发或甚至DKA，而一些患者由于持续的胰岛素分泌而保持缓解。尽管 表型被公认多年，导致酮症的潜在机制， β细胞功能的维持是未知的。此外，增加的器官内（胰腺和肝脏）脂肪也可以 在缓解中发挥作用。高分辨率代谢组学和磁共振成像提供了一个全面的 评估多个途径和成像特征的方法。该提案将利用已收集的 PI K23提案中的样本和参与者，以检查导致酮病和持续酮病的途径 缓解。目的1将比较DKA患者和无DKA的高血糖症患者之间的代谢组学特征 酮症目的2将比较胰岛素停药时的代谢组学特征及其与 维持β细胞功能目的3将探讨胰腺和肝脏脂肪的差异是否与 持续缓解和β细胞功能。目标，与新的合作者一起， 专业知识将产生数据，以探索PI新独立提案的新假设。

Project Summary/Abstract It is estimated that 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 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%, fasting glucose < 130 mg/dl while off insulin for at least one week). The period of near-normoglycemia remission is variable and many patients eventually experience a hyperglycemic relapse or even DKA while some stay in remission due to sustained insulin secretion. Despite the phenotype being recognized for many years, the underlying mechanisms leading to ketosis and maintenance of beta-cell function are unknown. Further, increased intra-organ (pancreas and liver) fat can also play a role in remission. High resolution metabolomics and magnetic resonance imaging offer a comprehensive way to assess multiple pathways and imaging characteristics. This proposal will leverage already collected samples and participants from the PI’s K23 proposal to examine pathways leading to ketosis and sustained remission. Aim 1 will compare metabolomic signatures between people with DKA and hyperglycemia without ketosis. Aim 2 will compare metabolomic signatures at time of insulin discontinuation and their relationship with sustained beta-cell function. Aim 3 will explore whether differences in pancreatic and hepatic fat associate with sustained remission and beta-cell function. The Aims, together with new collaborators with complementary expertise will generate data to explore novel hypotheses for new independent proposals by the PI.