Cellular pathways of inflammation in type 1 diabetes

描述（由申请人提供）： I型糖尿病（T1 DM）与血管并发症增加有关。虽然其确切机制尚未阐明，但有几条线指出这些大血管病和微血管病发病机制中的氧化应激和炎症增加。单核-巨噬细胞是动脉粥样硬化形成的关键细胞。然而，有和没有微血管并发症的T1 DM单核细胞功能和炎症的数据很少。我们的初步数据显示，T1 DM受试者的炎症和单核细胞功能增加。然而，没有数据检查T1 DM中炎症增加的分子机制。T1 DM还表现出显著且独特的微血管并发症，但对其研究甚少。他汀类药物已被证明可改善T1 DM患者的内皮功能和斑块稳定性。然而，关于他汀类药物对T1 DM炎症、单核细胞功能和微血管并发症的影响的数据很少。该提案的中心假设是T1 DM与炎症增加和内皮炎性损伤相关，导致血管异常，这可以通过他汀类药物治疗得到改善。具体目标是：i）检查具有和不具有微血管并发症的T1 DM中炎症的生物标志物，并阐明与对照相比具有和不具有微血管并发症的T1 DM中炎症增加的分子机制; ii）使用新的方法定义T1 DM的微血管成分，经验证的计算机辅助活体显微镜检查（CALM）技术，以及iii）检查低剂量和高剂量阿托伐他汀干预是否有效与安慰剂相比，阿托伐他汀（10 mg/d和40 mg/d）可改善T1 DM的炎症和微血管并发症（即微血管病变）。本研究的结果可能对炎症在糖尿病微血管疾病中的作用以及阿托伐他汀联合治疗预防血管并发症的抗炎作用具有重要意义。

DESCRIPTION (provided by applicant): Type I diabetes (T1DM) is associated with increased vascular complications. While the precise mechanism(s) for this has not been elucidated, several lines point to increased oxidative stress and inflammation in the pathogenesis of these macro- and microangiopathies. The monocyte-macrophage is a pivotal cell in atherogenesis. However, there are scanty data on monocyte function and inflammation in T1DM with and without microvascular complications. Our preliminary data show that T1DM subjects have increased inflammation and monocyte function. However, there is no data examining the molecular mechanisms for increased inflammation in T1DM. T1DM also exhibits significant and unique microvascular complications which has been very poorly studied. Statins have been shown to improve endothelial function and plaque stability in T1DM. However, there is a paucity of data on the effect of statins on inflammation, monocyte function and microvascular complications in T1DM. The central hypothesis of the proposal is that T1DM is associated with increased inflammation and inflammatory damage to the endothelium resulting in vascular abnormalities, and that this could be ameliorated with statin therapy. The specific aims are: i) to examine biomarkers of inflammation in T1DM with and without microvascular complications and to elucidate molecular mechanisms of increased inflammation in T1DM with and without microvascular complications compared to controls;ii) to define the microvascular component to T1DM using the novel, validated technique of computer-assisted intravital microscopy (CALM) and iii) to examine if intervention with low and high dose atorvastatin (10 and 40 mg/day) compared to placebo will improve inflammation and micro-vascular complications (i.e microangiopathy) of T1DM.The results from this study could have major implications with regard to the role of inflammation in diabetic microvascular disease and the anti-inflammatory effect of combined atorvastatin therapy in the prevention of vascular complications.