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: 7500667
• 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/7500667
• 关键词: Acetoacetates; Adjuvant Therapy; Age; Arts; Blinded; Blood; Blood specimen; Cardiovascular Diseases; Caring; Cell Adhesion Molecules; Child; Cholesterol; Chromium; Cultured Cells; Data; Diabetes Mellitus; End Point; 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; Numbers; Oxidative Stress; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Placebo Effect; Placebos; Play; Polymerase Chain Reaction; Production; Public Health; Randomized; Research Personnel; Risk Factors; Role; Signal Pathway; Signaling Molecule; Standards of Weights and Measures; Study Subject; Superoxides; Supplementation; Testing; Tissues; Translational Research; Triglycerides; Vascular Cell Adhesion Molecule-1; cardiovascular disorder prevention; cost; cytokine; day; diabetic; dietary supplements; experience; genetic regulatory protein; in vivo; insight; monocyte; novel; prevent; 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（由应用程序提供）：此应用程序对NIH的三个计划公告高度响应：PAR-06-457（糖尿病转化研究），PA-01-114（糖尿病中的铬铬疗法）和PA-01-071（药物中的金属）。 1型糖尿病与心血管疾病（CVD）的发生率过多有关。促炎性细胞因子白细胞介素（IL）-6和组织坏死因子（TNF）-A的血液水平升高是血管感染的标志物，是CVD的已知危险因素。除高血糖外，1型糖尿病患者经常患酮症。我们的初步研究表明，使用U937单核细胞在细胞培养模型中，酮体乙酸乙酸酯（AA）可以产生超氧化物自由基，并增加IL-6和TNF-A的分泌；与1型糖尿病患者相比，高酮血症血液中IL-6和TNF-A的氧化应激和水平更高。该铬（CR3+）抑制了细胞培养模型中AA引起的TNF-A和IL-6的分泌。该提议有两个假设。首先是酮症增加1型糖尿病中血管感染标记的血液水平。第二个是补充CR3+可以预防1型糖尿病中血管炎症标记的血液水平。这些假设将在1型糖尿病患者的体内进行测试，以及使用从受试者的血液中分离并购买的人主动脉内皮细胞（HAEC）的单核细胞（HAEC）进行的研究。在体内，将检查体内高酮血症的作用以及安慰剂（P）或CR3+补充对血管感染标记水平的补充。在体外，从P或CR3+补充患者或HAEC中分离出的单核细胞将用酮培养，以检查其对单核细胞和HAEC中细胞因子产生和粘附分子相关的血管感染和基因表达的直接影响。这是一项新的研究，因为没有先前的研究检查了酮症或CR3+对1型糖尿病血管感染的影响。为了实现这些目标，将从1型糖尿病儿童中收集血液。患者（n = 141岁，年龄12-18岁）将补充3个月的P或200或500®GCR3+ - 辛酸/天。将使用艺术方法论，例如多重PCR。数据将进行统计分析。糖尿病事件已成为流行病，仍然是一个主要的公共卫生问题。长期的目标是了解酮症在CVD中的作用，并发现一种相对低成本的饮食补充剂，该补充剂可以用作1型糖尿病中CVD预防的可调节疗法。