Ceramides and Sphingolipids as Predictors of Incident Dysglycemia

2型糖尿病（T2 D）是一种慢性代谢紊乱，可导致许多使人衰弱的并发症，如糖尿病性视网膜病变、神经病变、肾病和心血管疾病。生物活性脂质如鞘脂（SPL）与T2 D的发病机制有关，最近的研究特别将神经酰胺（Cers）与肥胖和T2 D的病理生理学联系起来。我们假设Cers和其他SPL是病理生理过程的关键调节剂，其驱动从正常葡萄糖调节（NGR）到糖尿病前期到T2 D和相关糖尿病并发症的进展。我们建议在父母有T2 D病史的血糖正常受试者的一项糖尿病前期病理学队列（POP-ABC）研究和糖尿病预防计划/糖尿病预防计划结局研究（DPP/DPPOS）中使用储存的样本，该研究对已诊断为糖尿病前期的受试者进行了T2 D的研究。我们将从200名血糖正常且无糖尿病家族史的个体中招募并分析样本，这些样本将作为正常对照。在具体目标1中，我们将分析来自无糖尿病家族史的血糖正常受试者和POP-ABC研究的两个队列的血浆样本中的Cer和相关SPL（糖基神经酰胺、鞘磷脂和长链鞘氨醇碱）：血糖正常的受试者发生前驱糖尿病（进展者）和未发生前驱糖尿病（非进展者），分别在基线和5年随访时。我们希望确定一种新的关联，血清钙负荷与糖尿病前期和家族史。在具体目标2中，与目标1一样，我们将对随机分配至“安慰剂”组（无干预）的受试者在基线、2年DPP和11年DPPOS时的Cer和SPLs DPP/DPPOS样本进行纵向综合分析。我们将在DPPOS中比较进展为T2 D的糖尿病前期受试者与第11年未进展为T2 D的受试者。在具体目标3中，我们将评估SPL特征与逆转前驱糖尿病和预防T2 D的干预措施的有效性。使用POP-ABC和DPP/DPPOS研究的三个不同组，我们将分析Cer和SPL水平作为明确定义的参与者亚组纵向随访期间糖尿病前期和T2 D事件的预测因子。我们的研究结果将使我们能够确定Cer和SPL是否调节干预对血糖结果的影响和程度。在具体目标4中，我们将在病例对照设计中分析现有DPP/DPPOS数据，以确定Cers与糖尿病微血管和大血管并发症之间的关联。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，T2 D和血管并发症的新型预测，预后和特异性生物标志物。

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.