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。虽然确切的机制(S)尚未阐明，但有几条线索指出在这些大血管和微血管病变的发病机制中氧化应激和炎症增加。单核巨噬细胞是动脉粥样硬化形成过程中的关键细胞。然而，关于有或无微血管并发症的T1 DM患者的单核细胞功能和炎症反应的数据很少。我们的初步数据显示，T1 DM受试者炎症和单核细胞功能增加。然而，目前还没有研究T1 DM炎症增加的分子机制的数据。T1 DM还表现出显著而独特的微血管并发症，这方面的研究非常少。他汀类药物已被证明可以改善T1 DM患者的内皮功能和斑块稳定性。然而，有关他汀类药物对T1 DM患者炎症、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与炎症和内皮炎症损伤增加有关，导致血管异常，这可以通过他汀类药物治疗得到改善。其具体目的是：1)检测伴有和不伴有微血管并发症的T1 DM患者炎症的生物标志物，并阐明与对照组相比，伴有和不伴有微血管并发症的T1 DM患者炎症增加的分子机制；Ii)使用新的、有效的计算机辅助活体显微镜(Calm)技术确定T1 DM的微血管成分；III)与安慰剂相比，检查低剂量和大剂量阿托伐他汀(每天10 mg和40 mg/d)干预是否会改善T1 DM的炎症和微血管并发症(即微血管病变)。这项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联合阿托伐他汀治疗在预防血管并发症中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.