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

造成目前全球糖尿病流行率迅速上升的危机的因素仍然知之甚少。然而，潜在的主要重要性是这样一种假设，即母体代谢环境的异常，如发生在妊娠糖尿病（GDM）（妊娠期发展的糖尿病）中，导致婴儿代谢系统的异常发育，从而导致婴儿成人发病糖尿病的风险更高。因此，重要的是要了解导致GDM的机制，以便制定有效的措施来对抗这种糖尿病风险从母亲传给婴儿。众所周知，导致GDM的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，人们对正常妊娠中胰岛β细胞代偿的细胞机制以及妊娠期糖尿病患者胰岛β细胞代偿失败的细胞机制还知之甚少。我们最近已经表明，在胰岛β细胞内存在脂肪代谢途径（不含甘油三酯的脂肪酸循环），其在放大维持正常血糖所必需的胰岛素分泌和保护肥胖大鼠的胰岛免于衰竭中具有重要作用。本项目的主要重点是验证这一假设，即该途径在胰岛适应正常妊娠中起关键作用，其功能障碍导致GDM的发生。从初步研究结果中可以看出，葡萄糖和脂肪代谢的主要调节因子PGC1 α在正常妊娠期间的胰岛中明显减少。研究还将针对PGC1 α在胰岛适应妊娠和GDM失败中的作用。我们希望，该项目的成功完成将导致制定高度针对性的应对措施，以预防GDM，减缓和扭转目前糖尿病的流行。

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.