Prevention of Placental Insufficiency Improves Beta-Cells Function

预防胎盘功能不全可改善 β 细胞功能

基本信息

批准号：
10578797
负责人：
SEAN W LIMESAND
金额：
$ 45.48万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10578797
关键词：
Adult Affect Barker Hypothesis Beta Cell Cell Proliferation Cell physiology Chronic Cues DNA Data Defect Depressed mood Development Diabetes Mellitus Disease Disease Progression Elderly Environment Epigenetic Process Exposure to Failure Fetal Growth Retardation Fetal Reduction Fetal Sheep Fetus Functional disorder Future Genes Glucose Goals Heterogeneity Human Hypoglycemia Hypoxemia Hypoxia Impairment Incidence Individual Infant Inflammatory Insulin Islet Cell Islets of Langerhans Knowledge Longitudinal Studies MALAT1 gene Maintenance Medical Metabolic Metabolic Diseases Metabolism Modeling Modification Morbidity - disease rate NF-kappa B Newborn Infant Non-Insulin-Dependent Diabetes Mellitus Norepinephrine Nutrient Outcome Oxygen Pathogenesis Pathology Pathology Report Pathway interactions Perinatal Physiological Placental Insufficiency Predisposition Prevention Process Production RNA Binding Regulation Research Role Stimulus Supplementation Testing Untranslated RNA Work biological adaptation to stress cell type clinically relevant comparison control cytokine diabetes risk effective therapy endocrine pancreas development experimental study extracellular fetal fetus nutrition functional loss improved in utero innovation insight insulin secretion islet negative affect neonate nutrient deprivation offspring overexpression perinatal health prenatal exposure prenatal stress preservation prevent response restoration sheep model side effect stem supplemental oxygen

项目摘要

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.

抽象的胰岛功能障碍是2型糖尿病发病机理中的签名特征，可以源自对位置不足（PI）和胎儿生长限制（FGR）的发展适应。我们已经确定了胰岛素产生和分泌的大幅减少，这些胰岛素的生产和分泌持续存在于FGR。我们阐明的努力 FGR胰岛中的编程机制表明，正常的构成核因子Kappa B的减少（NFκB）活性对胰岛素分泌产生负面影响。此外，我们的初步发现抑郁症 NFκB活性具有缺氧诱导的MALAT1表达，因为这种长的基因间非编码（LINC）RNA 结合NFκB以防止激活。该项目的指导前提是低胎儿氧和葡萄糖 PI的浓度在发育过程中引起β细胞功能障碍。因此，我们计划纠正氧气和 PI期间FGR胎儿中的葡萄糖浓度，并显示出胰岛素分泌和β细胞的改善增殖。基础实验表明，将氧气和葡萄糖的补充合并为具有PI诱导的FGR的胎儿可改善胰岛素的分泌，但引起持续β细胞的潜在提示失败未被发现。我们假设PI-FGR中氧气和葡萄糖浓度的校正胎儿达到正常，对照胎儿值将通过增强β细胞增殖和胰岛素来预防β细胞功能障碍通过恢复组成型和物理NFκB活性的分泌。此外，胎儿氧和葡萄糖校正将解决FGR羔羊β细胞中编程的缺陷。我们已经适应了胎儿 Pi-Fgr的绵羊模型，以在子宫内在受控的子宫内测试氧气和葡萄糖的补充混合物环境。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，胰岛素增加，并恢复胰岛中的葡萄糖刺激的胰岛素分泌（GSIS），证明其适合性作为测试反向PI的能力是否可以改善β细胞衰竭的模型。在AIM 1中，我们将评估氧和葡萄糖校正的联合作用，以改善胎儿和新生儿的β细胞功能诱导的FGR。在AIM 2中，我们将确定较低的构成NFκB活性导致的GSI的局限性到FGR胰岛中的Malat1过表达。通过减轻低氧血症并提供葡萄糖，这是一种主要营养素 β细胞的响应能力，我们期望胰岛素分泌和β细胞增殖会增加和编程引起β细胞功能障碍的机制将恢复正常。这些实验的影响将很高，因为它们将提供有关PI诱导的胎儿中β细胞功能障碍可逆性的基本知识 FGR。此外，我们的实验将定义FGR胎儿中NFκB调节的独特作用这会导致持续降低胰岛素分泌的发育适应。我们还将获得新的见解当胎儿氧和麸质正确时，独特的胰岛编程机制的可逆性是正确的预计将改善FGR患者的短期和长期结局。