Prevention of Placental Insufficiency Improves Beta-Cells Function

摘要 胰岛功能障碍是2型糖尿病发病机制的标志性特征，可源于 胎盘功能不全(PI)和胎儿生长受限(FGR)的发育适应我们已经确定了 患有FGR的后代胰岛素产生和分泌显著减少，这种现象持续存在。我们努力澄清 FGR胰岛的编程机制表明，正常、组成性核因子kappaB的减少 核因子κB的活性对胰岛素的分泌有负面影响。此外，我们的初步发现与抑郁有关 核因子κB的活性与缺氧诱导的MALAT1表达有关，因为这种长的基因间非编码(LINC)RNAs 结合核因子κB以防止激活。这个项目的指导前提是低胎儿的氧气和血糖 在发育过程中，PI的浓度会导致β细胞功能障碍。因此，我们计划纠正氧气和 妊娠期胎儿血糖浓度及胰岛素分泌和β细胞的改善 扩散。基础实验表明，氧和葡萄糖的联合补充对 PI诱导的FGR胎儿胰岛素分泌增加，但导致持续性β细胞的潜在线索 失败是未被发现的。我们假设PI-FGR中氧和葡萄糖浓度的校正 胎儿恢复正常，控制胎儿值将通过促进β细胞增殖和胰岛素来预防β细胞功能障碍 分泌通过恢复结构性和生理性的NFκB活性。此外，胎儿的氧气和 葡萄糖校正将解决FGR羔羊β细胞的程序性缺陷。我们已经调整了我们的胎儿 绵羊PI-FGR模型在受控的子宫内测试补充氧和葡萄糖混合物 环境。五天的氧气和葡萄糖校正的初步实验降低了去甲肾上腺素， 增加胰岛素，恢复葡萄糖刺激的胰岛胰岛素分泌(GSIS)，证明其适宜性 作为一个模型来测试反转PI的能力是否改善了β单元故障。在目标1中，我们将评估 氧、糖联合纠正改善PI-1胎儿和新生儿β细胞功能的研究 诱导FGR。在目标2中，我们将确定由于较低的结构性NFκB活性而导致的GSI的局限性 MALAT1在FGR胰岛中的过表达。通过缓解低氧血症和提供葡萄糖，葡萄糖是 β-细胞的反应性，我们预计胰岛素的分泌和β-细胞的增殖将增加并编程 导致β细胞功能障碍的机制将恢复正常。这些实验的影响将是很大的，因为它们 将为PI诱导的胎儿β细胞功能障碍的可逆性提供基本的新知识 FGR。此外，我们的实验将确定NFκB在胎儿生长受限的β细胞中的独特作用 这会导致持续降低胰岛素分泌的发育适应。我们还将对以下问题有新的认识 当胎儿的氧气和葡萄糖被纠正时，独特的胰岛编程机制的可逆性，这是 预计将改善FGR患者的短期和长期结果。

Abstract Pancreatic islet dysfunction is a signature feature in the pathogenesis of Type 2 Diabetes and can stem from developmental adaptations to placental insufficiency (PI) and fetal growth restriction (FGR). We have identified significant reductions in insulin production and secretion that persist in offspring with FGR. Our efforts to elucidate programming mechanisms in FGR islets indicate that reductions in normal, constitutive nuclear factor kappa B (NFκB) activity negatively affects insulin secretion. Additionally, our preliminary findings associate depressed NFκB activity with hypoxia-induced MALAT1 expression because this long intergenic non-coding (linc) RNA binds NFκB to prevent activation. The guiding premise of this project is that low fetal oxygen and glucose concentrations from PI cause β-cell dysfunction during development. Therefore, we plan to correct oxygen and glucose concentrations in FGR fetuses during PI and show improvements in insulin secretion and β-cell proliferation. Foundational experiments demonstrate that combined supplementation of oxygen and glucose to the fetus with PI-induced FGR improves insulin secretion, but the underlying cues that cause persistent β-cell failure are undiscovered. We hypothesize that correction of oxygen and glucose concentrations in the PI-FGR fetus to normal, control fetal values will prevent β-cell dysfunction by enhancing β-cell proliferation and insulin secretion through the restoration of constitutive and physiological NFκB activity. Furthermore, fetal oxygen and glucose correction will resolve programmed deficiencies in β-cells of FGR lambs. We have adapted our fetal sheep model of PI-FGR to test a supplemental mixture of oxygen and glucose in a controlled, in utero environment. Preliminary experiments with five days of oxygen and glucose correction lowered norepinephrine, increased insulin, and restored glucose-stimulated insulin secretion (GSIS) in islets, demonstrating its suitability as a model to test whether the capacity to reverse PI ameliorates β-cell failure. In Aim 1, we will evaluate the combined effect of oxygen and glucose correction to improve β-cell function in fetuses and neonates with PI- induced FGR. In Aim 2, we will determine limitations in GSIS that result from lower constitutive NFκB activity due to MALAT1 overexpression in FGR islets. By alleviating hypoxemia and providing glucose, a major nutrient for β-cell responsiveness, we expect that insulin secretion and β-cell proliferation will increase and programming mechanisms causing β-cell dysfunction will return to normal. Impact of these experiments will be high, as they will provide fundamental new knowledge about the reversibility of β-cell dysfunction in fetuses with PI-induced FGR. In addition, our experiments will define the unique roles for NFκB regulation in β-cells from FGR fetuses that cause developmental adaptations that persistently lower insulin secretion. We also will gain new insight on the reversibility of a distinct islet-programming mechanism when fetal oxygen and glucose is corrected, which is expected to improved short- and long-term outcomes in individuals with FGR.