TERATOGENIC EFFECTS OF ORAL HYPOGLYCEMIC AGENTS

口服降糖药(OHAs)，包括磺脲类和双胍类， 被广泛用于治疗非胰岛素依赖型糖尿病 糖尿病(NIDDM)，但其致畸作用及其机制 人们对毒品知之甚少。OHA的致畸作用已在 并在活体实验动物身上进行了演示，但这些发现 因先天畸形风险增加而变得复杂 糖尿病患者的后代，以及无法 在体内区分化合物本身的致畸作用和 母体系统中产生的代谢变化的影响。 本实验室采用体外全细胞培养方法进行的初步工作 以胚胎培养和神经发育的小鼠胚胎为模型 展示了两种广泛使用的磺脲类药物的胚胎致病作用， 甲苯丁胺和氯丙胺，以及双胍和二甲双胍。最多的 磺脲类药物的重要副作用是低血糖，但这 发现因素不是观察到的胚胎病变的原因 效果。这一建议的假设是，畸形产生了 由甲苯丁胺、氯丙胺和二甲双胍引起的胎盘转移 这些药物对敏感期胚胎的直接影响 器官发生的基因。甲苯丁胺和氯丙胺的作用方式是 阻断ATP依赖的K(KATP)通道和/或葡萄糖的改变 吸收和新陈代谢。鉴于二甲双胍被提议通过改变 葡萄糖的摄取和代谢。这项研究的具体目的是 通过确定磺脲类化合物是否， 甲苯丁胺和氯丙胺，1)在器官发生过程中穿过胎盘 用高效液相色谱法测定母体血清和胚胎液及组织 母体给药后；2)在器官发生过程中阻断KATP通道并 可被KATP通道开放剂通过膜片钳单次阻断 胚胎细胞；3)改变细胞内葡萄糖的摄取和代谢。 通过测量葡萄糖摄取来进行器官发生的胚胎， 与OHA接触后的糖酵解代谢，以及 在体外被超氧化物歧化酶(SOD)中和。二甲双胍将成为 被调查以确定该药物是否穿过胎盘 在器官发生过程中；2)改变葡萄糖的吸收和代谢 进行器官发生的胚胎，并在体外被超氧化物歧化酶中和。这个 这项工作的目标是更好地定义致畸风险和机制 OHAS，以便提供对治疗至关重要的信息 妊娠期NIDDM患者的管理。此外，这些实验 将提供有关KATP通道潜在作用的新信息 在正常和异常的胚胎发育中。

Oral hypoglycemic agents (OHAs), including sulfonylureas and biguanides, are widely used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), but the teratogenic effects and mechanisms of these drugs are poorly understood. OHA teratogenicity has been suggested in humans and demonstrated in laboratory animals in vivo, but these findings are complicated by an increased risk of congenital malformations in the offspring of diabetics, in general, as well as the inability to distinguish in vivo between teratogenic effects of a compound, per se, and the influence of metabolic changes produced in the maternal system. Preliminary work in this laboratory using the in vitro method of whole- embryo culture and the neurulating mouse embryo as a model has demonstrated embryopathic effects of two widely-used sulfonylureas, tolbutamide and chlorpropamide, and the biguanide, metformin. The most important side-effect of sulfonylurea therapy is hypoglycemia, but this factor was found not to be responsible for the observed embryopathic effects. The hypothesis of this proposal is that teratogenesis produced by tolbutamide, chlorpropamide, and metformin is due to placenta transfer and direct effect of these agents on the embryo during the sensitive stage of organogenesis. Tolbutamide and chlorpropamide are proposed to act by blocking ATP-dependent K+ (KATP) channels and/or alteration of glucose uptake and metabolism. whereas metformin is proposed to act by altering glucose uptake and metabolism. The specific aims of this research will address this hypothesis by determining whether or not the sulfonylureas, tolbutamide and chlorpropamide, 1) cross the placenta during organogenesis using HPLC assays of maternal serum and embryonic fluid and tissues following maternal dosing; 2) block KATP channels during organogenesis and are counteracted by KATP channel openers by patch-clamping single embryonic cells; and 3) alter glucose uptake and metabolism within the embryo undergoing organogenesis by measuring glucose uptake, incorporation, and glycolytic metabolism following OHA exposure, and are counteracted in vitro by superoxide dismutase (SOD). Metformin will be investigated to determine whether or not this drug 1) crosses the placenta during organogenesis; and 2) alters glucose uptake and metabolism in embryos undergoing organogenesis, and is counteracted in vitro by SOD. The goal of this work is to better define teratogenic risks and mechanisms of OHAs in order to provide information critical to the therapeutic management of pregnant NIDDM patients. In addition, these experiments will provide new information regarding the potential role of KATP channels in normal and abnormal embryonic development.