Adjuvant Therapy for Vascular Inflammation in Diabetes

描述（由申请人提供）：血管炎症及其并发症是糖尿病人群发病率和死亡率的主要原因，其预防和治疗仍然是一个主要的公共卫生问题。促炎细胞因子肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）是血管炎症的标志物。除了高血糖症，1型糖尿病患者经常发生酮症。我们的初步研究已经证明，在使用U937单核细胞的细胞培养模型中，酮体乙酰乙酸酯（AA）可以产生超氧自由基并增加促炎细胞因子IL-6和TNF-α的分泌，并且与正常酮血症的1型糖尿病患者相比，高酮血症患者血液中的氧化应激、IL-6和TNF-α水平更高。我们的初步研究还表明，铬（Cr 3+）和维生素E（VE）抑制TNF-α和IL-6的分泌所引起的酮（AA）和高糖（HG）在细胞培养模型中使用U937单核细胞和新鲜的外周血单核细胞（PBMC）。 基于这些新的发现，这个建议有两个假设。首先，酮增加促炎细胞因子（IL-6，TNF-α）分泌，并改变与分离的人单核细胞和主动脉内皮细胞（HAEC）中细胞因子产生和粘附分子相关的基因表达。第二，亲水性Cr 3+和亲脂性VE的组合补充可以有效地防止氧化应激、TNF-α和IL-6分泌以及与暴露于酮和HG的分离的人单核细胞和主动脉内皮细胞（HAEC）中的细胞因子和粘附分子产生相关的基因的过表达。 为了实现这些目标，将在不存在和存在HG的情况下用酮培养U937、PBMC和HAEC。将使用最先进的技术，如基因阵列和多重PCR。将对数据进行统计分析。长期目标是了解酮症在血管炎症中的作用，并发现一种相对低成本的膳食补充剂，如Cr 3+和VE，用作预防1型糖尿病血管炎症和并发症的辅助治疗。

DESCRIPTION (provided by applicant): Vascular inflammation and its complications are the leading cause of morbidity and mortality in the diabetic population and their prevention and treatment remain a major public health issue. The pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are markers of vascular inflammation. 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 pro-inflammatory cytokines IL-6 and TNF-alpha in a cell culture model using U937 monocytes, and the oxidative stress, IL-6 and TNF-alpha levels are higher in the blood of hyperketonemic compared with normoketonemic type 1 diabetic patients. Our preliminary studies also show that chromium (Cr3+) and vitamin E (VE) inhibit the secretion of TNF-alpha and IL-6 caused by ketones (AA) and high glucose (HG) in a cell culture model using U937 monocytes and fresh peripheral blood mononuclear cells (PBMC). Based upon these novel findings, this proposal has two hypotheses. First, ketones increase pro-inflammatory cytokine (IL-6, TNF-alpha) secretion and alter gene expression relating to cytokine production and adhesion molecules in isolated human monocytes and aortic endothelial cells (HAEC). Second, combined supplementation with hydrophilic Cr3+ and lipophilic VE can efficiently prevent oxidative stress, TNF-alpha and IL-6 secretion, and the over-expression of genes relating to cytokine and adhesion molecule production in isolated human monocytes and aortic endothelial cells (HAEC) exposed to ketones and HG. To accomplish these objectives, U937, PBMC and HAEC will be cultured with ketones without and with HG. State of the art techniques, such as gene array and multiplex PCR, will be used. Data will be analyzed statistically. The long-term objective is to understand the role of ketosis in vascular inflammation and to discover a relatively low-cost dietary supplement, such as Cr3+ and VE, to be used as an adjuvant therapy for prevention of the vascular inflammation and complications of type 1 diabetes.