Vitamin D and Developmental Origins of Insulin Resistance

摘要 2型糖尿病（T2 DM）是全球死亡和残疾的主要原因。近四分之一的退伍军人 2型糖尿病的患病率估计到2025年将增加到36%。生活方式干预， 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 被认为是不可持续的。更有趣的是，即使在糖尿病发生后， 成功减肥，表明其他决定因素在疾病易感性中发挥作用。多项研究 为子宫内环境因素影响胎儿和婴儿生长模式的假说提供了证据 导致在以后的生活中对胰岛素抵抗（IR）和代谢紊乱的易感性增加。 大约有100万退伍军人是育龄妇女，其中一半缺乏维生素D。维生素D 怀孕期间缺乏胰岛素与青春期前儿童的胰岛素抵抗有关。然而，没有先前的干预 对人类的研究已经评估了产前补充维生素D对后代IR的影响， 代谢并发症在啮齿动物中，母体维生素D缺乏导致促炎免疫细胞 计划在后代和增加水平的全身炎症细胞因子之前的发展， 红外光谱出生后补充维生素D不会逆转任何这些免疫或代谢变化， 这表明免疫细胞的持续表观遗传编程也参与其中。初步数据显示， 这是第一次IR可以移植。来自接受维生素D的胎儿的造血干细胞（HSC） 子宫内缺乏可导致永久性IR并使骨髓（BM）造血向更大的祖细胞转移 和骨髓细胞中的维生素D充足的成年小鼠，这意味着表观遗传免疫重编程。甲基化 对来自维生素D缺乏与维生素D充足的HSC的受体的BM的分析鉴定了多个差异 甲基化区域。该项目的重点是Jarid 2启动子中的高甲基化区域， 已知甲基转移酶被活性维生素D上调。相应基因表达分析 数据表明，Jarid 2对Mef 2-PGC 1 α-miR 106 b网络的调节可能是一个潜在的途径， 介导免疫代谢表型。因此，我们假设Jarid 2抑制和PGC 1 α 在胚胎发生过程中，HSC的上调使髓样细胞促进IR， 这一过程可以通过母亲产前补充维生素D来逆转。为了测试这种表观遗传 在体内的免疫程序，我们建议，以确定改变骨髓表达的影响， Jarid 2/PGC 1 α/miR 106 b通路在IR发生中的作用。 有机会从多中心维生素D治疗哮喘减少中获得人体样本和数据 确定产前维生素D补充剂（4000 IU/d vs.安慰剂）在 后代IR和以后生活中的代谢结果。这些研究的结果可能会描述新的 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 在怀孕前和怀孕早期的维生素D水平，以及更积极的常规补充。 . !

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. . !