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: 7266156
• 负责人: Sushil K Jain
• 金额: $ 30.03万
• 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/7266156
• 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) 的血液水平升高有关。白细胞介素 (IL)-6 和组织坏死因子 (TNF)-a 是血管炎症的标志物，是 CVD 的已知危险因素。除了高血糖之外，1 型糖尿病患者还经常出现酮症。在使用 U937 单核细胞的细胞培养模型中，乙酰乙酸 (AA) 可以产生超氧自由基并增加 IL-6 和 TNF-a 的分泌；与正常酮血症的 1 型糖尿病患者相比，高酮血症患者血液中的 IL-6 和 TNF-a 较高；并且铬 (Cr3+) 抑制细胞培养模型中 AA 引起的 TNF-a 和 IL-6 的分泌。有两个假设：第一个假设是酮症会增加 1 型糖尿病中血管炎症标记物的血液水平，第二个假设是补充 Cr3+ 可以预防/降低 1 型糖尿病中血管炎症标记物的血液水平。这些假设将在 1 型糖尿病患者体内进行体内测试，并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) 进行体内、高酮血症和补充的影响。将检查安慰剂 (P) 或 Cr3+ 对血管炎症标志物水平的影响。 在体外，将从补充 P 或 Cr3+ 的患者中分离的单核细胞或 HAEC 进行培养。这是一项新颖的研究，因为之前没有研究探讨酮症或 Cr3+ 对 1 型糖尿病血管炎症的影响。为了实现这些目标，将从 1 型糖尿病儿童（n = 141，年龄 12-18 岁）中采集血液，并补充 P 或 200 或 。 500€ g Cr3+-烟酸/天，持续 3 个月，将使用多重 PCR 等先进方法对数据进行统计分析。了解酮症在 CVD 中的作用，并发现一种相对低成本的膳食补充剂，可用作 1 型糖尿病 CVD 预防的辅助疗法。