Diabetic Embryopathy and Fuel-Mediated Organ Teratogenesis: Lessons from Animal Models

Summary

The growing recognition that faulty maternal metabolism during early organogenesis may be implicated in the increased incidence of birth defects in pregnancies complicated by diabetes has prompted worldwide efforts to institute improved preconceptional metabolic regulation. However, the failure to identify the periods of greatest risk for diabetic embryopathy, the mediating teratogen(s), and the underlying mechanisms have complicated attempts to establish precise therapeutic guidelines and targets. Some of the reported in vivo and in vitro experiences with rodent models have been reviewed to derive relevant insights.

Substantial literature indicates that diabetes (experimental as well as spontaneous) in pregnant rats and mice is attended by retardation of growth and developmental delay during embryogenesis, and a variable incidence of birth defects. Poor metabolic regulation of the diabetic mother during early organogenesis may also be followed by subsequent resorption of the conceptus at the site of implantation. Vulnerability to diabetes-related resorptions and all other forms of embryopathy appears to begin during the early postimplantation period and is greatest near the onset of neurolation. Overall susceptibility is markedly influenced by genetic factors and may be modified by the antecedent metabolic exposures of the conceptus (“carryover effects”).

Mediation for the anomalous embryo development in pregnancies of diabetic rodents appears to be multifactorial; all the aberrant fuels and fuel-related components of “the diabetic state” (e.g. high glucose; ketones; somatomedin inhibitor(s); osmolality, etc.) which have been tested to date display dysmorphogenic potential (“fuel-mediated organ terato-genesis”) in vitro. All tissues in the conceptus appear to be at risk. Dose-response relationships for the individual metabolic teratogens may be influenced by additive and synergistic inter-actions so that the integrated possibilities cannot be assessed fully by measurements confined to a single fuel or fuel-related component. In the context of the day-to-day variability in diabetes “control” of the poorly regulated mother, and the relatively longer duration of organogenesis, these multifactorial possibilities may account for the multiple birth defects that can occur in individual offspring, and the seemingly non-specific pattern of diabetic embryopathy.

Insulin therapy diminishes the dysmorphogenic effects of “the diabetic state” in rodents with experimental or spontaneous diabetes. The literature differs with regard to the degree of metabolic normalization that must be achieved. Some of the variation may be due to differences in the timing of therapy, and in the genetic susceptibility to metabolic teratogens. Overall experiences with insulin therapy appear to indicate that complete metabolic rectification may not be necessary. Moreover, hypoglycemia itself may be teratogenic during the phase of organogenesis in which the postimplantation rodent embryo is wholly dependent upon glycolysis (i.e. a period in development corresponding to ˜day 16-18 to day 24-25 of human pregnancy). These considerations have prompted the provisional clinical recommendation that near normalization rather than full normalization of maternal metabolism may be the most prudent therapeutic target for the intensification of diabetes management during the first four weeks of pregnancy.

It has been suggested that possibilities for similar “fuel-mediated teratogenesis” may obtain in all pregnancies. Thus, diabetic embryopathy may serve as a developmental paradigm with general relevance for many other hitherto unexplained birth defects in non-diabetic pregnancies.

Diabetic Embryopathy - Fuel-Mediated Teratogenesis - Animal Models - Experimental Diabetes in Rodents - Embryo Culture - Organogenesis - Normal and Diabetic Early Pregnancy - Glucose - Ketones - Somatomedin Inhibitor(s) - Birth Defects