Ketosis, Vascular Inflammation and Its Therapy in Type 1 Diabetic Patients

1型糖尿病患者的酮症、血管炎症及其治疗

• 批准号: 7663095
• 负责人: Sushil K Jain
• 金额: $ 29.43万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663095
• 关键词: Acetoacetates; Adjuvant Therapy; Age; Arts; Blinded; Blood; Blood specimen; Blood typing procedure; Cardiovascular Diseases; Cell Adhesion Molecules; Cell Culture Techniques; Child; Cholesterol; Chromium; Data; Diabetes Mellitus; Endothelial Cells; Epidemic; Gene Expression; Gene Expression Regulation; Glucose; Goals; Human; Hydroxybutyrates; Hyperglycemia; In Vitro; Incidence; Inflammatory; Insulin-Dependent Diabetes Mellitus; Intercellular adhesion molecule 1; Interleukin-6; Ketone Bodies; Ketones; Ketoses; Ketosis; MAPK14 gene; Medicine; Metals; Methodology; Methods; Modeling; NIH Program Announcements; Necrosis; Oxidative Stress; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Placebo Effect; Placebos; Play; Production; Public Health; Randomized; Research Personnel; Risk Factors; Role; Signal Pathway; Signaling Molecule; Study Subject; Superoxides; Supplementation; Testing; Tissues; Translational Research; Triglycerides; Vascular Cell Adhesion Molecule-1; cardiovascular disorder prevention; cost; cytokine; diabetic patient; dietary supplements; experience; genetic regulatory protein; in vivo; inflammatory marker; insight; monocyte; novel; prevent; standard care; type I diabetic; vascular inflammation

DESCRIPTION (provided by applicant): This application is highly responsive to three program announcements of the NIH: PAR-06-457 (Translational Research in Diabetes), PA-01-114 (Chromium as Adjuvant Therapy in Diabetes), and PA-01- 071 (Metals in Medicine). Type-1 diabetes is associated with excessive incidence of cardiovascular disease (CVD). Elevated blood levels of the pro-inflammatory cytokines interleukin (IL)-6 and tissue necrosis factor (TNF)-a are markers of vascular inflammation, a known risk factor for CVD. In addition to hyperglycemia, type 1 diabetic patients frequently experience ketosis. Our preliminary studies have demonstrated that the ketone body acetoacetate (AA) can generate superoxide radicals and increase secretion of IL-6 and TNF-a in a cell culture model using U937 monocytes; that oxidative stress and levels of IL-6 and TNF-a are higher in the blood of hyperketonemic compared with normoketonemic type 1 diabetic patients; and that chromium (Cr3+) inhibits the secretion of TNF-a and IL-6 caused by AA in a cell culture model. This proposal has two hypotheses. The first is that ketosis increases blood levels of markers of vascular inflammation in type 1 diabetes. The second is that Cr3+ supplementation can prevent/lower blood levels of vascular inflammation markers in type 1 diabetes. These hypotheses will be tested both in vivo in type 1 diabetic patients as well as in vitro in studies using monocytes isolated from subject's blood and purchased human aortic endothelial cells (HAEC). In vivo, the effects of hyperketonemia, and supplementation with either placebo (P) or Cr3+ on the levels of markers of vascular inflammation will be examined. In vitro, monocytes isolated from P or Cr3+ supplemented patients or HAEC will be cultured with ketones to examine their direct effect on markers of vascular inflammation and gene expression related to cytokine production and adhesion molecules in monocytes and HAEC. This is a novel study because no prior study has examined the effect of ketosis or Cr3+ on vascular inflammation in type 1 diabetes. To accomplish these objectives, blood will be collected from type 1 diabetic children. Patients (n=141, ages 12- 18 yrs) will be supplemented with either P or 200 or 500¿g Cr3+-niacinate/day for 3 months. State of the art methodology, such as multiplex PCR, will be used. Data will be analyzed statistically. Diabetes incidence has become epidemic and remains a major public health issue. The long-term goal is to understand the role of ketosis in CVD and to discover a relatively low-cost dietary supplement that could be used as an adjuvant therapy for CVD prevention in type 1 diabetes.

描述（由申请人提供）：本申请高度响应NIH的三个项目公告：PAR-06-457（糖尿病转化研究），PA-01-114（铬作为糖尿病的辅助治疗）和PA-01- 071（医学中的金属）。1型糖尿病与心血管疾病（CVD）的高发病率相关。血液中促炎细胞因子白细胞介素(IL)-6和组织坏死因子(TNF)-a水平升高是血管炎症的标志，是心血管疾病的已知危险因素。除了高血糖外，1型糖尿病患者还经常出现酮症。我们的初步研究表明，在U937单核细胞培养模型中，酮体醋酸酯（AA）可以产生超氧自由基，增加IL-6和TNF-a的分泌；高酮血症患者血液中的氧化应激和IL-6、TNF-a水平高于正常酮血症患者；铬（Cr3+）在细胞培养模型中抑制AA引起的TNF-a和IL-6的分泌。这个提议有两个假设。首先，酮症会增加1型糖尿病患者血管炎症标志物的血液水平。其次，补充Cr3+可以预防/降低1型糖尿病患者血管炎症标志物的血液水平。这些假设将在1型糖尿病患者的体内和体外研究中进行测试，研究使用从受试者血液中分离的单核细胞和购买的人主动脉内皮细胞（HAEC）。在体内，将检查高酮血症、安慰剂(P)或Cr3+的补充对血管炎症标志物水平的影响。在体外，从P或Cr3+补充患者或HAEC中分离的单核细胞与酮培养，研究酮对单核细胞和HAEC中血管炎症标志物、细胞因子产生相关基因表达和粘附分子的直接影响。这是一项新颖的研究，因为之前没有研究检查酮症或Cr3+对1型糖尿病血管炎症的影响。为了实现这些目标，将采集1型糖尿病儿童的血液。患者（n=141，年龄12- 18岁）将补充P或200或500克Cr3+-烟酸盐/天，持续3个月。将使用最先进的方法，如多重聚合酶链反应。数据将进行统计分析。糖尿病发病率已成为流行病，并且仍然是一个主要的公共卫生问题。长期目标是了解酮症在心血管疾病中的作用，并发现一种相对低成本的膳食补充剂，可作为1型糖尿病心血管疾病预防的辅助治疗。