Sphingolipids, Diabetes, and Cardiovascular Disease

描述(申请人提供)：2型糖尿病已经在世界范围内达到流行的程度，并带有很高的心血管发病率和死亡率负担。这项申请寻求确定与糖尿病和心血管疾病风险相关的新的可修改因素，即血浆神经酰胺和鞘磷脂物种。神经酰胺和鞘磷脂是影响代谢过程的脂类，与糖尿病和心血管疾病的病理生理有关，包括细胞凋亡、脂肪毒性、胰岛素抵抗、葡萄糖稳态和动脉粥样硬化。直到最近，所有的鞘脂都被认为具有相似的生理作用；然而，现在有令人信服的证据表明，携带不同饱和脂肪酸的鞘脂物种表现出非常不同的生物学活性。我们首次建议研究特定的循环神经酰胺和鞘磷脂种类与糖尿病和糖尿病相关心血管疾病的相关性。我们假设，含有饱和脂肪酸棕榈酸(16：0)的血浆神经酰胺和鞘磷脂种类与发生糖尿病和糖尿病相关心血管疾病的风险较高。相反，我们假设血浆神经酰胺和鞘磷脂物种含有20个或更多碳(20：0、22：0或24：0)的饱和脂肪酸与较低的糖尿病和心血管疾病风险相关。我们将在强心家族研究中调查这些假设，这是一项基于社区的前瞻性研究，对来自13个不同部落的美洲印第安人的心血管疾病风险因素进行研究。由于糖尿病和早期心血管疾病的高发病率，前瞻性地研究美洲印第安人中神经鞘脂类与糖尿病和心血管疾病的关联可能会揭示其中涉及的途径和过程的重要机制。使用最先进的光谱分析技术，我们将从3665名强心家族研究参与者的现有基线样本中测量血浆中8种神经酰胺和鞘磷脂，并将这些新数据与现有的关于危险因素的信息和随访数据结合起来，以检查以下特定目标：(目的1)前瞻性地检查含有16：0、20：0、22：0和24：0脂肪酸的神经酰胺和鞘磷脂与糖尿病发病的关系，以及基线时非糖尿病参与者的空腹血糖、空腹胰岛素、HOMA-IR(胰岛素抵抗的稳态模型评估)和血红蛋白A1C的变化；以及(目的2)前瞻性研究这些鞘脂与糖尿病相关心血管疾病(包括心肌梗死、缺血性中风和心血管死亡率)的相关性。与糖尿病及其心血管并发症相关的精准鞘脂物种的发现，将指出未来干预措施需要针对的潜在原因途径。

DESCRIPTION (provided by applicant): Type 2 diabetes has reached epidemic proportions world-wide and carries a high burden of cardiovascular morbidity and mortality. This application seeks to identify novel modifiable factors, namely plasma ceramide and sphingomyelin species, associated with risks of incident diabetes and cardiovascular disease. Ceramides and sphingomyelins are lipids ("sphingolipids") that influence metabolic processes implicated in the pathophysiology of diabetes and cardiovascular diseases, including apoptosis, lipotoxicity, insulin resistance, glucose homeostasis and atherosclerosis. Until recently, all sphingolipids were thought to have similar physiological effects; however, there is now compelling evidence that sphingolipid species that carry different saturated fatty acids exhibit vastly different biological activities. We propose for the first time to examine the association of specific circulating ceramide and sphingomyelin species with incident diabetes and diabetes-related cardiovascular disease. We hypothesize that plasma ceramide and sphingomyelin species that contain the saturated fatty acid palmitic acid (16:0) are associated with higher risks of incident diabetes and diabetes-related cardiovascular disease. In contrast, we hypothesize that plasma ceramide and sphingomyelin species that contain a saturated fatty acid with 20 or more carbons (20:0, 22:0 or 24:0) are associated with lower risks of incident diabetes and cardiovascular disease. We will investigate these hypotheses in the Strong Heart Family Study, a community-based, prospective study of risk factors for cardiovascular disease among American Indians from 13 different tribes. Because of the high incidence of diabetes and early cardiovascular disease, prospectively studying the association of sphingolipid species with diabetes and cardiovascular disease among American Indians may reveal important mechanistic insights as to the pathways and processes involved. Using state-of-the-art spectrometry, we will measure 8 ceramide and sphingomyelin species in plasma from existing baseline samples from 3665 Strong Heart Family Study participants, and combine these new data with existing information on risk factors and follow- up data to examine the following specific aims: (Aim 1) To prospectively examine the associations of ceramides and sphingomyelins containing the fatty acids 16:0, 20:0, 22:0 and 24:0 with incident diabetes, and changes in fasting glucose, fasting insulin, HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) and hemoglobin A1C among participants without diabetes at baseline; and (Aim 2) To prospectively examine the associations of these sphingolipids with incident diabetes-related cardiovascular disease (including myocardial infarction, ischemic stroke, and cardiovascular mortality). The discovery of precise sphingolipid species associated with diabetes and its cardiovascular complications will point to the potentially causal pathways that need to be targeted for future interventions.