Ceramides and Sphingolipids as Predictors of Incident Dysglycemia

2型糖尿病(T2D)是一种慢性代谢紊乱，可导致多种衰弱并发症，如糖尿病视网膜病变、神经病变、肾病和心血管疾病。神经鞘脂(SPLs)等生物活性脂类与T2D的发病机制有关，最近的研究特别将神经酰胺(CER)与肥胖和T2D的病理生理联系起来。我们假设CER和其他SPL是推动从正常血糖调节(NGR)到糖尿病前期、T2D和相关糖尿病并发症进展的病理生理过程的关键调节器。我们建议使用来自糖尿病前期病理生物学的储存样本进行双相队列研究(POP-ABC)，研究对象是父母有T2D病史的血糖正常的参与者，以及糖尿病预防计划/糖尿病预防计划结果研究(DPP/DPPOS)，该研究跟踪了已经被诊断为糖尿病前期的参与者，以发展T2D。我们将登记和分析200名无糖尿病家族史的血糖正常个体的样本，作为标准对照。在具体目标1中，我们将从无糖尿病家族史的正常血糖参与者和POP-ABC研究的两个队列中分析Cer和相关的SPLs(糖基神经酰胺、鞘磷脂和长链狮身人面像碱基)，两个队列：发生糖尿病前期(进展者)和没有发展为糖尿病前期(非进展者)的正常血糖参与者，每个人都在基线上和在5年的随访中。我们期望确定一个新的Cer负担与糖尿病前期和家族史之间的联系。在特定的目标2中，与目标1一样，我们将对被随机分到安慰剂组(无干预)的参与者的Cer和SPLs DPP/DPPOS样本进行纵向综合分析，包括基线、2年DPP和11年DPPOS。在DPPOS中，我们将比较进展到T2D的糖尿病前期参与者和到第11年还没有进展到T2D的参与者。在具体目标3中，我们将评估SPL信号与逆转糖尿病前期和预防T2D的干预措施的疗效相关。使用POP-ABC和DPP/DPPOS研究中的三个不同的组，我们将分析Cer和SPLs水平作为糖尿病前期事件和T2D的预测因子，在明确定义的参与者亚组的纵向随访中。我们的结果将使我们能够确定Cer和SPLs是否调节了干预对血糖结果的影响和程度。在具体目标4中，我们将用病例对照设计分析现有的DPP/DPPOS数据，以确定CERs与糖尿病微血管和大血管并发症的相关性。总体而言，本文提出的研究结果将促进我们对CERs在糖尿病前期、糖尿病及相关并发症的病理生理学中的作用的理解。此外，我们计划的脂质组学分析旨在促进发现糖尿病前期、T2D和血管并发症的新的预测、预后和特异性生物标记物。

Type 2 diabetes (T2D) is a chronic metabolic disorder responsible for a number of debilitating complications such as diabetic retinopathy, neuropathy, nephropathy, and cardiovascular diseases. Bioactive lipids like sphingolipids (SPLs) have been implicated in the pathogenesis of T2D, and recent studies specifically link ceramides (Cers) with the pathophysiology of obesity and T2D. We hypothesize that Cers and other SPLs are critical modulators of pathophysiological processes driving the progression from normal glucose regulation (NGR), through prediabetes, to T2D and associated diabetic complications. We propose to use stored specimens from the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study of normoglycemic participants with parental history of T2D and the Diabetes Prevention Program/Diabetes Prevention Program Outcome Study (DPP/DPPOS) which followed participants already diagnosed with prediabetes for the development of T2D. We will enroll and analyze samples from 200 normoglycemic individuals with no family history of diabetes, which will serve as normative controls. In Specific Aim 1, we will analyze Cer and related SPLs (glycosyl ceramides, sphingomyelins and long-chain sphingoid bases) from plasma samples of normoglycemic participants with no family history of diabetes and two cohorts from the POP-ABC study: normoglycemic participants who developed prediabetes (progressors) and who did not develop prediabetes (non-progressors), each at base line and at 5 years follow-up. We expect to determine a novel association of Cer burden with prediabetes and family history. In Specific Aim 2, like Aim 1, we will perform a comprehensive profiling of Cer and SPLs DPP/DPPOS samples longitudinally at baseline, at 2 year DPP and at 11 year DPPOS from participants who were randomized to ‘placebo’ group (no intervention). We will compare prediabetic participants who progressed to T2D with participants who had not progress to T2D by year 11 in DPPOS. In Specific Aim 3, we will evaluate SPL signatures in relation to the efficacy of interventions that reverse prediabetes and those that prevent T2D. Using three different groups from the POP-ABC and DPP/DPPOS studies, we will analyze Cer and SPLs levels as predictors of incident prediabetes and T2D during longitudinal follow-up of well-defined subgroups of participants. Our results will enable us to determine whether Cer and SPLs modulate the impact and magnitude of the interventions on glycemic outcome. In Specific Aim 4, we will analyze existing DPP/DPPOS data in a case- control design, to determine associations between Cers and microvascular and macrovascular complications of diabetes. Overall, results of the studies proposed here will advance our understanding of the role of Cers in the pathophysiology of prediabetes, diabetes and related complications. Further, our planned lipidomics analyses are designed to facilitate the discovery of novel predictive, prognostic and specific biomarkers for prediabetes, T2D, and vascular complications.