Ceramides and Sphingolipids as Predictors of Incident Dysglycemia

神经酰胺和鞘脂作为血糖异常事件的预测因子

• 批准号: 10361527
• 负责人: SAMUEL DAGOGO-JACK, M.D., D.Sc.
• 金额: $ 50.46万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361527
• 关键词: Affect; Age; Ancillary Study; Animal Model; Authorization documentation; Automobile Driving; Beta Cell; Biological Assay; Blood Vessels; Body mass index; Cardiovascular Diseases; Cell physiology; Ceramides; Chronic; Cohort Studies; Complications of Diabetes Mellitus; Control Groups; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Diagnosis; Dihydrosphingosine; Enrollment; Ethnic Origin; Etiology; Family; Family history of; Fatty Acids; Functional disorder; Funding; Galactosylceramides; Glucose; Glucosylceramides; Human; Individual; Intervention; Kidney Diseases; Knowledge; Lactosylceramides; Life Style; Link; Lipids; Longitudinal cohort; Measures; Mediating; Metabolic Diseases; Metabolism; Metformin; Microvascular Dysfunction; Minor; Monitor; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Outcome Study; Participant; Pathogenesis; Phenotype; Plasma; Population; Prediabetes syndrome; Process; Prognostic Marker; Randomized; Recording of previous events; Regulation; Resources; Retinal Diseases; Risk Factors; Role; Sampling; Sampling Studies; Secure; Specimen; Sphingolipids; Sphingomyelins; Sphingosine; Subgroup; Testing; Time; Treatment Efficacy; United States National Institutes of Health; Variant; base; biracial; blood glucose regulation; case control; cohort; coronary calcium scoring; design; diabetes prevention program; dihydrosphingosine 1-phosphate; follow-up; insulin sensitivity; lifestyle intervention; lipidomics; macrovascular disease; novel; novel marker; pandemic disease; placebo group; predictive marker; prevent; prospective; recruit; response; sex; specific biomarkers; sphinganine; sphingosine 1-phosphate

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.

2型糖尿病（T2D）是一种慢性代谢疾病，导致许多使人衰弱的并发症，例如糖尿病性视网膜病变，神经病，肾病和心血管疾病。在T2D的发病机理中隐含了生物活性脂质（例如鞘脂），最近的研究专门将神经酰胺（CER）与肥胖症的病理生理和T2D联系起来。我们假设CER和其他SPL是病理生理过程的关键调节剂，从而推动了从正常葡萄糖调节（NGR），通过糖尿病前，T2D和相关糖尿病并发症的进展。我们建议在混血儿组（POP-ABC）中使用储存的标本（POP-ABC），对具有T2D的父母病史的正常参与者和预防糖尿病预防计划/预防糖尿病预防计划结果研究（DPP/DPPO）的标本（DPP/DPPO），该研究（DPP/DPPOS）已被诊断为已诊断出对T2d的参与者进行了诊断。我们将注册和分析来自没有糖尿病家族史的200个正常血糖个体的样本，这些样本将作为正常对照。在特定的目标1中，我们将从未经糖尿病的家族史和未经Prop-abc研究中的两个群体病史的血浆样本中分析CER和相关的SPL（糖基神经酰胺，鞘磷脂和长链鞘脂碱基）。多年随访。我们希望确定CER燃烧与预测者和家族史的新型关联。在特定的目标2（例如AIM 1）中，我们将在基线时纵向对CER和SPLS DPP/DPPOS样品进行全面分析，并在2年DPP和11年的DPPO中对随机分配给“安慰剂”组的参与者（无干预）。我们将比较糖尿病前参与者与未在DPPO的11年级升级为T2D的参与者。在特定的目标3中，我们将评估SPL签名与反向前糖尿病和预防T2D的干预措施的效率有关。使用来自POP-ABC和DPP/DPPOS研究的三个不同组，我们将在纵向定义的参与者亚组的纵向随访期间分析CER和SPL水平作为入射前糖尿病和T2D的预测指标。我们的结果将使我们能够确定CER和SPL是否调节干预措施对血糖结果的影响和幅度。在特定目标4中，我们将在病例对照设计中分析现有的DPP/DPPO数据，以确定CERS与糖尿病的微血管和大血管并发症之间的关联。总体而言，这里提出的研究的结果将提高我们对CER在糖尿病前期，糖尿病和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糖尿病前，T2D和血管并发症的新型预测，预后和特定生物标志物的发现。