Cellular pathways of inflammation in type 1 diabetes

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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.