TERATOGENIC EFFECTS OF ORAL HYPOGLYCEMIC AGENTS

口服降糖药的致畸作用

• 批准号: 2201861
• 负责人: IDA M. WASHINGTON
• 金额: $ 9.97万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2201861
• 关键词: congenital skeletal disorder; drug interactions; embryo /fetus drug adverse effect; embryo /fetus tissue /cell culture; glucose metabolism; high performance liquid chromatography; hypoglycemic agents; laboratory mouse; laboratory rat; light microscopy; mammalian embryology; noninsulin dependent diabetes mellitus; oral administration; placental transfer; potassium channel; scanning electron microscopy; superoxide dismutase; teratogens; tolbutamide; voltage /patch clamp

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.

口服降糖药（OHA），包括磺酰脲类和双胍类， 广泛用于治疗非胰岛素依赖型糖尿病 mellitus (NIDDM)，但这些药物的致畸作用和机制 人们对药物知之甚少。 OHA 已被认为具有致畸性 人类并在实验动物体内得到证实，但这些发现 由于先天性畸形的风险增加，情况变得更加复杂 一般来说，糖尿病患者的后代，以及无法 区分化合物本身的体内致畸作用和 母体系统代谢变化的影响。 本实验室的前期工作采用全体外方法 胚胎培养和神经化小鼠胚胎作为模型 证明了两种广泛使用的磺酰脲类药物的胚胎病变作用， 甲苯磺丁脲和氯磺丙脲，以及双胍、二甲双胍。 最 磺脲类药物治疗的一个重要副作用是低血糖，但这 发现该因素与观察到的胚胎病无关 影响。 该提案的假设是致畸产生 甲苯磺丁脲、氯磺丙脲和二甲双胍引起的胎盘转移 以及这些药物在敏感阶段对胚胎的直接影响 的器官发生。甲苯磺丁脲和氯磺丙脲的作用是 阻断 ATP 依赖性 K+ (KATP) 通道和/或葡萄糖的改变 摄取和代谢。而二甲双胍建议通过改变 葡萄糖摄取和代谢。本研究的具体目标将 通过确定是否磺酰脲类药物来解决这一假设， 甲苯磺丁脲和氯磺丙脲，1) 在器官发生过程中穿过胎盘 使用 HPLC 检测母体血清、胚胎液和组织 母亲给药后； 2) 在器官发生过程中阻断 KATP 通道和 通过膜片钳单通道 KATP 通道开放剂抵消 胚胎细胞； 3）改变体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， OHA 暴露后的掺入和糖酵解代谢，并且是 在体外被超氧化物歧化酶（SOD）抵消。 二甲双胍将 进行调查以确定该药物是否 1) 穿过胎盘 在器官发生过程中； 2）改变葡萄糖的摄取和代谢 胚胎经历器官发生，并在体外被 SOD 抵消。这 这项工作的目标是更好地定义致畸风险和机制 OHA 旨在提供对治疗至关重要的信息 妊娠 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 正常和异常胚胎发育。