TERATOGENIC EFFECTS OF ORAL HYPOGLYCEMIC AGENTS

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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.