Biochemical basis of islet beta-cell compensation and failure in normal pregnancy and gestational diabetes mellitus

正常妊娠和妊娠糖尿病中胰岛β细胞代偿和失败的生化基础

• 批准号: nhmrc : 418077
• 负责人: Prof Christopher Nolan
• 金额: $ 32.06万
• 依托单位: Australian National University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/biochemical-basis-islet-diabetes-mellitus/96610
• 关键词: Biochemical; basis; islet; beta; cell

The factors causing the current world-wide crisis of rapidly rising diabetes prevalence remain poorly understood. Of potential major importance, however, is the hypothesis that abnormalities in the maternal metabolic environment, as occur in gestational diabetes (GDM) (diabetes that develops in pregnancy), result in abnormal development of metabolic systems in the baby resulting in higher risk of adult onset diabetes in the babies. Therefore, it is of importance to understand the mechanisms causing GDM, such that effective measures can be developed to counter this passing on of diabetes risk from mother to baby. It is known that a key factor causing GDM is failure of maternal pancreatic islet beta-cells to compensate for increased demands for insulin production in pregnancy. Poorly understood, however, are the cellular mechanisms of islet beta-cell compensation in normal pregnancy and failure of this compensation in GDM pregnancy. We have recently shown that there is a pathway of fat metabolism (triglyceride- free fatty acid cycle) within the islet beta-cell that has an important role in amplyfing insulin secretion necessary to maintain normal blood glucose and protecting the islets from failure in obese rats. The major focus of this project is to test the hypothesis that this pathway has a key role in the adaptation of pancreatic islets to normal pregnancy and its dysfunction contributes to the causation of GDM. Of great interest from preliminary findings is that a master regulator of glucose and fat metabolism, PGC1alpha, is markedly reduced in islets during normal pregnancy. Studies will also be directed to PGC1alpha's role in islet adaptation to pregnancy and failure in GDM. We expect that successful completion of this project will lead to the development of highly targeted counter measures to prevent GDM and to slow and reverse the current epidemic of diabetes.

导致当前糖尿病患病率迅速上升的全球危机的因素仍然知之甚少。然而，一个潜在的重要假设是，母体代谢环境的异常，如妊娠期糖尿病（GDM）（妊娠期发展的糖尿病），会导致婴儿代谢系统的异常发育，从而增加婴儿成人发病糖尿病的风险。因此，了解导致GDM的机制是很重要的，这样可以制定有效的措施来对抗这种糖尿病风险从母亲传递给婴儿。众所周知，导致GDM的一个关键因素是母体胰岛β细胞无法补偿妊娠期胰岛素产生需求的增加。然而，对正常妊娠中胰岛β细胞代偿和GDM妊娠中这种代偿失败的细胞机制了解甚少。我们最近发现，在肥胖大鼠中，胰岛β细胞内存在一种脂肪代谢途径（无甘油三酯脂肪酸循环），它在放大胰岛素分泌以维持正常血糖和保护胰岛免于衰竭方面发挥重要作用。本项目的主要重点是验证该通路在胰岛适应正常妊娠中起关键作用，其功能障碍导致GDM的假设。初步研究结果显示，在正常妊娠期间，胰岛中葡萄糖和脂肪代谢的主要调节因子pgc1 - α显著减少。研究还将针对pgc1 α在胰岛对妊娠的适应和GDM失败中的作用。我们预计，该项目的成功完成将导致制定高度针对性的对策，以预防GDM，减缓和扭转目前糖尿病的流行。