Boehmer Brit H, Limesand Sean W, Rozance Paul J
Department of PediatricsPerinatal Research Center, University of Colorado School of Medicine, Aurora, Colorado, USA.
School of Animal and Comparative Biomedical SciencesUniversity of Arizona, Tucson, Arizona, USA.
J Endocrinol. 2017 Nov;235(2):R63-R76. doi: 10.1530/JOE-17-0076. Epub 2017 Aug 14.
Placental insufficiency is a primary cause of intrauterine growth restriction (IUGR). IUGR increases the risk of developing type 2 diabetes mellitus (T2DM) throughout life, which indicates that insults from placental insufficiency impair β-cell development during the perinatal period because β-cells have a central role in the regulation of glucose tolerance. The severely IUGR fetal pancreas is characterized by smaller islets, less β-cells, and lower insulin secretion. Because of the important associations among impaired islet growth, β-cell dysfunction, impaired fetal growth, and the propensity for T2DM, significant progress has been made in understanding the pathophysiology of IUGR and programing events in the fetal endocrine pancreas. Animal models of IUGR replicate many of the observations in severe cases of human IUGR and allow us to refine our understanding of the pathophysiology of developmental and functional defects in islet from IUGR fetuses. Almost all models demonstrate a phenotype of progressive loss of β-cell mass and impaired β-cell function. This review will first provide evidence of impaired human islet development and β-cell function associated with IUGR and the impact on glucose homeostasis including the development of glucose intolerance and diabetes in adulthood. We then discuss evidence for the mechanisms regulating β-cell mass and insulin secretion in the IUGR fetus, including the role of hypoxia, catecholamines, nutrients, growth factors, and pancreatic vascularity. We focus on recent evidence from experimental interventions in established models of IUGR to understand better the pathophysiological mechanisms linking placental insufficiency with impaired islet development and β-cell function.
胎盘功能不全是宫内生长受限（IUGR）的主要原因。IUGR会增加一生中患2型糖尿病（T2DM）的风险，这表明胎盘功能不全造成的损害会在围产期损害β细胞的发育，因为β细胞在葡萄糖耐量调节中起核心作用。严重IUGR胎儿的胰腺特征为胰岛较小、β细胞较少且胰岛素分泌较低。由于胰岛生长受损、β细胞功能障碍、胎儿生长受限与T2DM易感性之间存在重要关联，因此在理解IUGR的病理生理学以及胎儿内分泌胰腺的程序化事件方面已取得重大进展。IUGR动物模型重现了人类严重IUGR病例中的许多观察结果，并使我们能够更深入地了解IUGR胎儿胰岛发育和功能缺陷的病理生理学。几乎所有模型都表现出β细胞数量逐渐减少和β细胞功能受损的表型。本综述首先将提供与IUGR相关的人类胰岛发育和β细胞功能受损的证据，以及对葡萄糖稳态的影响，包括成年期葡萄糖耐量异常和糖尿病的发展。然后，我们将讨论调节IUGR胎儿β细胞数量和胰岛素分泌的机制的证据，包括缺氧、儿茶酚胺、营养物质、生长因子和胰腺血管的作用。我们重点关注来自IUGR既定模型实验干预的最新证据，以更好地理解将胎盘功能不全与胰岛发育受损和β细胞功能障碍联系起来的病理生理机制。
