VITAMIN D DEFICIENCY, INSULIN RESISTANCE AND CARDIOVASCULAR DISEASE

描述（由申请方提供）：心血管疾病是2型糖尿病（2型DM）患者发病和死亡的主要原因。尽管知道血管炎症是在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，但缺乏对这些患者中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中的粘附、迁移和泡沫细胞形成，似乎可以降低人类的高血压和小鼠的动脉粥样硬化。本研究的目的是阐明维生素D调节2型糖尿病患者血管炎症和动脉粥样硬化易感性的机制。我们推测，在糖尿病患者中，维生素D缺乏引起的血管炎症升高血压，减少动脉血管流量，并促进动脉粥样硬化。我们将通过两条主要的调查路线来检验这一假设。在目标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（JNK 2）的激活，已知会影响小鼠的动脉粥样硬化，并确定增加动脉粥样硬化的机制是否是维生素D受体（VDR）依赖于巨噬细胞。在目标2中，将我们的初步观察转化为人类，我们将检查维生素D缺乏的高血压、糖尿病患者的维生素D替代是否降低血压，改善血管内皮功能，并促进巨噬细胞中的抗动脉粥样硬化表型。这项研究的结果可能揭示了2型糖尿病患者心血管疾病高发病率的新见解，并提出了一个潜在的新的治疗靶点，以降低这一人群的高血压和心血管风险。此外，这些发现可能提供关键信息，将建立广泛筛查维生素D缺乏症或在这一高风险人群中进行常规补充的必要性。最后，这些研究可以为未来的研究提供基础，以评估维生素D和/或新的维生素D类似物对影响糖尿病患者的常见并发症的影响，如脑血管疾病，痴呆，糖尿病肾病和视网膜病变。 公共卫生相关性：糖尿病患者心血管疾病的有效治疗仍然是公共卫生领域最大的未满足需求之一。该提案假定维生素D作为一种新型治疗剂，可减少2型糖尿病患者的血管炎症和心血管疾病。此外，这些发现可能提供关键信息，将建立广泛筛查维生素D缺乏症或在这一高风险人群中进行常规补充的必要性。最后，这些研究可以为未来的研究提供基础，以评估维生素D/维生素D类似物对影响糖尿病患者的常见并发症的影响，如脑血管疾病，痴呆，糖尿病肾病和视网膜病变。

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. PUBLIC HEALTH RELEVANCE: Effective treatments for cardiovascular disease in patients with diabetes remain one of the largest unmet needs in the public health. This proposal postulates vitamin D as a novel therapeutic agent to decrease vascular inflammation and cardiovascular disease in patients with Type 2 diabetes mellitus. 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/ vitamin D analogs on common complications affecting diabetic patients, such as cerebrovascular disease, dementia, diabetic nephropathy and retinopathy.