Markers of normoglycemic remission in obese diabetics

描述（由申请人提供）： 非裔美国人（AA）的肥胖提出了一个独特的模型，以帮助确定相关的代谢紊乱的标志物和机制。超过一半的新诊断AA表现为严重高血糖和/或无端糖尿病酮症酸中毒（DKA），显示2型糖尿病的代谢和免疫遗传学特征。2型糖尿病的这种变体被称为非典型糖尿病，Flatbush糖尿病，最近被称为酮症倾向性糖尿病（KPDM）。我们发现KPDM患者胰岛素分泌明显减少，胰岛素敏感性受损，但积极治疗可改善β-细胞功能和胰岛素敏感性，从而停止胰岛素治疗。我们还发现，骨骼肌缓解的独特标志物是Akt 2 Ser 474和其他关键信号转导激酶和磷酸酶的表达和胰岛素刺激磷酸化的改善。我们假设β细胞功能、肌肉胰岛素刺激的信号转导和蛋白质表达的测量之间的相关性将确定指示短期和长期接近正常血糖缓解和/或持续高血糖风险的特异性标志物。第一个目的是确定临床，代谢和免疫遗传学标志物预测短期和长期近正常血糖缓解或缺乏肥胖AA与KPDM。将在初次就诊时测量β细胞功能和胰岛素敏感性，并在接近正常血糖缓解或胰岛素治疗12周时再次测量。第二个目的是测量胰岛素刺激的蛋白磷酸化和信号转导蛋白表达的肌肉活检中获得的介绍和在后续行动。对治疗的反应（接近正常血糖缓解或缺乏）将与β细胞功能、胰岛素敏感性、肌肉胰岛素刺激的信号传导和蛋白质表达的测量相关。由于其独特的临床特征，KPDM患者代表了一个理想的人群，在其中识别指示短期和长期缓解和/或持续高血糖风险的标志物。识别这些标志物将促进和指导未来的治疗干预，并可能识别有发生糖尿病慢性并发症风险的患者

DESCRIPTION (provided by applicant): Obesity in African-Americans (AA) presents a unique model to help identify the markers and mechanisms of associated metabolic disorders. Over half of newly diagnosed AA presenting with severe hyperglycemia and/or unprovoked diabetic ketoacidosis (DKA) display metabolic and immunogenetic features of type 2 diabetes. This variant of type 2 diabetes is referred to as atypical diabetes, Flatbush diabetes, and more recently as ketosis-prone diabetes (KPDM). We have shown that patients with KPDM have markedly decreased insulin secretion and impaired insulin sensitivity, but aggressive management can result in improvement in (-cell function and insulin sensitivity to allow discontinuation of insulin therapy. We also showed that distinctive markers of remission in skeletal muscle are improved expression and insulin-stimulated phosphorylation of Akt2 Ser474 and other key signal transduction kinases and phosphatases. We hypothesize that the correlation between measures of beta-cell function, muscle insulin-stimulated signal transduction and protein expression will identify specific markers indicative of short- and long-term near-normoglycemic remission and/or risk for continued hyperglycemia. The first aim is to identify clinical, metabolic, and immunogenetic markers predictive of short- and long-term near-normoglycemic remission or lack thereof in obese AA with KPDM. Beta-cell function and insulin sensitivity will be measured at initial presentation and again at either near-normoglycemic remission or 12 weeks of insulin therapy. The second aim is to measure insulin-stimulated protein phosphorylation and signal transduction protein expression in the muscle biopsies obtained at presentation and at follow-up. Response to treatment (near-normoglycemic remission or lack thereof) will be correlated with measurements of beta-cell function, insulin sensitivity, muscle insulin-stimulated signaling and protein expression. Because of their unique clinical characteristics, patients with KPDM represent an ideal population in which to identify markers indicative of short- and long-term remission and/or risk for continued hyperglycemia. Identifying such markers will facilitate and guide future therapeutic interventions and may identify patients at risk to develop chronic complications of diabetes