Vitamin D and Developmental Origins of Insulin Resistance

摘要 2型糖尿病(T2 DM)是世界范围内导致死亡和残疾的主要原因。近四分之一的退伍军人 患有2型糖尿病，估计到2025年这一患病率将增加到36%。生活方式干预旨在 减肥在降低糖尿病风险方面是成功的，但长期的体重维持策略一直是 发现是不可持续的。更有趣的是，相当大的糖尿病风险(~40%-50%)即使在 成功减肥，这表明其他决定因素在疾病易感性中发挥了作用。多项研究 为宫内环境因素影响胎儿和婴儿生长模式的假设提供证据 这会增加人们在晚年对胰岛素抵抗(IR)和代谢紊乱的易感性。 大约100万名退伍军人是育龄妇女，其中一半缺乏维生素D。维生素D 怀孕期间的缺陷与青春期前儿童的胰岛素抵抗有关。然而，没有事先的干预 对人类的研究评估了产前补充维生素D对后代IR和 代谢并发症。在啮齿动物中，母体维生素D缺乏会导致促炎免疫细胞 计划在子代和增加水平的全身性炎症细胞因子之前发展 IR.出生后补充维生素D并不能逆转任何这些免疫或代谢变化， 这表明，免疫细胞的持续性表观遗传编程参与其中。我们的初步数据显示 这是第一次IR可移植。维生素D对胎儿造血干细胞的影响 子宫缺陷可导致永久性IR，并使骨髓(BM)造血向更大的祖细胞转移 以及维生素D充足的成年小鼠的髓系细胞，这意味着表观遗传免疫重新编程。甲基化 多个不同来源维生素D缺乏与充足的HSCs受者骨髓分析 甲基化区域。这个项目的重点是Jarid2启动子中的一个超甲基化区域，一个 活性维生素D上调甲基转移酶基因表达分析 研究表明，Jarid2对Mef2-PGC1miR106b网络的调节可能是一条潜在的途径 调节免疫代谢表型。因此，我们假设Jarid2抑制和Pgc1α 胚胎发生期间HSCs上调编程髓系细胞以促进IR，这 这一过程可以通过孕妇产前补充维生素D来逆转。为了测试这种表观遗传学 免疫程序在体内，我们建议确定改变髓系表达的影响 Jarid2/PGC1miR106b途径在小鼠胰岛素抵抗发生发展中的作用。此外，我们还将利用唯一的 从多中心维生素D产前哮喘减少中心获得人体样本和数据的机会 试验(VDAART)确定产前补充维生素D(4000IU/d与安慰剂)在 后代胰岛素抵抗和生命后期的代谢结果。这些研究的发现很可能描绘出小说 免疫细胞被编程以诱导IR的概念，并可为早期筛查提供基础 怀孕前和怀孕早期维生素D水平的变化，以及更积极的常规补充。 。 好了！

Abstract Type 2 diabetes (T2DM) is the leading cause of death and disability worldwide. Nearly one in four veterans have T2DM and this prevalence is estimated to increase to 36% by 2025. Lifestyle interventions aiming at weight loss are successful at reducing risk of diabetes but long-term weight-maintenance strategies have been found to be unsustainable. More interestingly, substantial diabetes risk (~40-50%) remains even after successful weight loss, suggesting that other determinants play a role in disease susceptibility. Multiple studies provide evidence for the hypothesis that environmental factors in utero affect patterns of fetal and infant growth that result in increased susceptibility to insulin resistance (IR) and metabolic disorders later in life. Approximately one million veterans are women of childbearing age and half are vitamin D-deficient. Vitamin D deficiency during pregnancy has been linked to IR in prepubertal children. However, no prior interventional studies in humans have evaluated the effects of antenatal vitamin D supplementation on offspring IR and metabolic complications. In rodents, maternal vitamin D deficiency results in a pro-inflammatory immune cell program in the offspring and increased levels of systemic inflammatory cytokines prior to the development of IR. Postnatal vitamin D supplementation does not reverse any of these immune or metabolic changes, suggesting that persistent epigenetic programming of immune cells is involved. Our preliminary data shows for the first time that IR is transplantable. Hematopoietic stem cells (HSCs) from fetuses subjected to vitamin D deficiency in utero confer permanent IR and shift bone marrow (BM) hematopoiesis toward greater progenitors and myeloid cells in vitamin D-sufficient adult mice, implying epigenetic immune reprogramming. Methylation analysis of BM from recipients of vitamin D-deficient vs. –sufficient HSCs identified multiple differentially methylated regions. This project focuses on a hypermethylated region in the promoter of Jarid2, a methyltransferase known to be upregulated by active vitamin D. Analysis of corresponding gene expression data identified that regulation of the Mef2-PGC1α-miR106b network by Jarid2 could be a potential pathway mediating the immunometabolic phenotype. Thus, we hypothesize that Jarid2 suppression and PGC1α upregulation in HSCs during embryogenesis program myeloid cells to promote IR, and that this process can be reversed with maternal antenatal vitamin D supplementation. To test this epigenetic immune program in vivo, we propose to determine the influence of altering myeloid expression of the Jarid2/PGC1α/miR106b pathway in mice on the development of IR. Additionally, we will utilize a unique opportunity to obtain human samples and data from the multicenter Vitamin D Antenatal Asthma Reduction Trial (VDAART) to determine the role of antenatal vitamin D supplementation (4000 IU/d vs. placebo) in offspring IR and metabolic outcomes later in life. Findings from these studies are likely to delineate novel concepts by which immune cells are programmed to induce IR, and could provide the basis for early screening of vitamin D levels before and early in pregnancy, as well as more aggressive routine supplementation. . !