VITAMIN D DEFICIENCY, INSULIN RESISTANCE AND CARDIOVASCULAR DISEASE

描述(申请人提供)：心血管疾病是2型糖尿病(2型DM)患者发病率和死亡率的主要原因。尽管已经知道血管炎症是在这些人群中观察到的加速动脉粥样硬化发展的关键决定因素，但对于导致这些患者对血管炎症和动脉粥样硬化易感性增加的机制(S)缺乏了解。我们的初步数据表明，维生素D受体信号调节巨噬细胞的黏附、迁移和泡沫细胞的形成，似乎可以降低人类的高血压和小鼠的动脉粥样硬化。我们建议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(S)。我们假设维生素D缺乏引起的血管炎症会升高血压，减少动脉血流量，并促进糖尿病患者的动脉粥样硬化。我们将通过两条主线调查来检验这一假设。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已知的影响小鼠动脉粥样硬化的应激相关激酶(JNK2)的激活，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缺乏的高血压和糖尿病患者的维生素D替代是否会降低血压，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。这项研究的结果可能会揭示2型糖尿病患者心血管疾病的高发病率的新见解，并建议一个潜在的新的治疗目标，以降低这一人群的高血压和心血管风险。此外，这些发现可能会提供关键信息，确定在这一高危人群中广泛筛查维生素D缺乏或常规补充维生素D的必要性。最后，这些研究可能为未来评估维生素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，如脑血管疾病、痴呆、糖尿病肾病和视网膜病变的效果提供基础。

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.