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

项目摘要/摘要 据估计，20-50%的非洲裔美国人患有酮症易发糖尿病(KPDM)。 出现糖尿病酮症酸中毒(DKA)的新诊断的糖尿病患者。在介绍DKA时，这些 患者存在严重的胰岛素分泌失调，并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，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%，空腹血糖130 mg/dl，停用胰岛素至少一周)。 血糖接近正常的缓解期是可变的，许多患者最终经历了 高血糖复发，甚至DKA，而一些人由于持续的胰岛素分泌而处于缓解状态。尽管 多年来一直被认识到的表型，导致酮症和 β细胞功能的维持尚不清楚。此外，器官内(胰腺和肝脏)脂肪的增加也可能 在缓解方面发挥作用。高分辨率代谢组学和磁共振成像提供了全面的 评估多路径和成像特征的方法。这项建议将利用已经收集到的资金 来自PI的K23提案的样本和参与者，以检查导致酮病和持续性酮病的途径 减刑。Aim 1将比较DKA患者和无DKA的高血糖患者之间的代谢特征 酮病。AIM 2将比较停用胰岛素时的代谢特征及其与 持续的β细胞功能。目标3将探索胰腺和肝脏脂肪的差异是否与 持续缓解和β细胞功能。AIMS，与新的合作者一起， 专业知识将产生数据，为PI提出的新的独立提案探索新的假设。

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.