VITAMIN D DEFICIENCY, INSULIN RESISTANCE AND CARDIOVASCULAR DISEASE

描述（由申请人提供）：心血管疾病是2型糖尿病（Type 2 DM）患者发病和死亡的主要原因。尽管已知血管炎症是该人群中观察到的动脉粥样硬化加速发展的关键决定因素，但缺乏对这些患者血管炎症和动脉粥样硬化易感性增加的机制的了解。我们的初步数据表明，维生素D受体信号调节巨噬细胞的粘附、迁移和泡沫细胞形成，似乎可以降低人类高血压和小鼠动脉粥样硬化。我们的建议的目的是描述的机制，维生素D调节血管炎症和动脉粥样硬化的易感性2型糖尿病。我们假设维生素D缺乏引起的血管炎症会升高血压，减少动脉血流，并促进糖尿病患者的动脉粥样硬化。我们将通过两条主要的调查路线来检验这一假设。在Aim 1中，我们将确定维生素D缺乏诱导的动脉粥样硬化是否依赖于应激相关激酶（JNK2）的激活，已知会影响小鼠动脉粥样硬化，并确定动脉粥样硬化增加的机制是否依赖于巨噬细胞中的维生素D受体（VDR）。在Aim 2中，将我们的初步观察结果转化为人类，我们将研究维生素D替代高血压，维生素D缺乏的糖尿病患者是否会降低血压，改善血管内皮功能，并促进巨噬细胞的抗动脉粥样硬化表型。本研究结果可能揭示了2型糖尿病患者心血管疾病高发的新见解，并提出了降低该人群高血压和心血管风险的潜在新治疗靶点。此外，这些发现可能提供关键信息，将确定需要广泛筛查维生素D缺乏症或在这一高危人群中常规补充。最后，这些研究可以为进一步研究维生素D和/或新的维生素D类似物对糖尿病患者常见并发症（如脑血管病、痴呆、糖尿病肾病和视网膜病变）的影响提供基础。

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of morbidity and mortality in patients with Type 2 diabetes mellitus (Type 2 DM). Despite the knowledge that vascular inflammation is a critical determinant for the development of the accelerated atherosclerosis observed in this population, there is a lack of knowledge about the mechanism(s) responsible for the increased susceptibility to vascular inflammation and atherosclerosis in these patients. Our preliminary data indicates that vitamin D receptor signaling modulates adhesion, migration, and foam cell formation in macrophages and appears to decrease hypertension in humans and atherosclerosis in mice. The objective of our proposal is to delineate the mechanism(s) by which vitamin D modulates the susceptibility to vascular inflammation and atherosclerosis in Type 2 diabetes. We hypothesize that vascular inflammation induced by vitamin D deficiency elevates blood pressure, diminishes arteriovascular flow, and promotes atherosclerosis in diabetes. We will examine this hypothesis through two main lines of investigation. In Aim 1 we will determine whether vitamin D deficiency-induced atherosclerosis depends on activation of stress-related kinase (JNK2), known to affect atherosclerosis in mice, and define whether the mechanism for increased atherosclerosis is vitamin D receptor (VDR) dependent in macrophages. In Aim 2, translating our preliminary observations to humans, we will examine if vitamin D replacement in hypertensive, diabetic patients with vitamin D deficiency decreases blood pressure, improves vascular endothelial function, and promotes an anti-atherogenic phenotype in macrophages. The results of this research may reveal novel insights into the high incidence of cardiovascular disease in patients with Type 2 DM, and suggest a potential new therapeutic target to reduce hypertension and cardiovascular risk in this population. In addition, these findings may offer critical information that will establish the need for widespread screening for vitamin D deficiency or routine supplementation in this high-risk population. Finally, these studies could provide the foundation for future research to evaluate the effects of vitamin D and/or the new vitamin D analogs on common complications affecting diabetic patients, such as cerebrovascular disease, dementia, diabetic nephropathy, and retinopathy.