Problem: Gestational obesity and insulin resistance pose a significant threat to the future health of our population. Mothers and children of these metabolically maladaptive pregnancies experience extensive morbidity and mortality. This study characterized postprandial insulin sensitivity in female Sprague Dawley rats at 5-days and 15-days gestation. Based on these findings, a model of gestational obesity was developed using 35% sucrose supplementation (SS). The efficacy of a preventative and a therapeutic intervention at modulating sucrose-induced gestational insulin resistance in Sprague Dawley rats was elucidated. Methods: Insulin sensitivity in the post-prandial state includes insulin-dependent and Hepatic Insulin Sensitizing Substance (HISS)-dependent components, and can be characterized with the Rapid Insulin Sensitivity Test (RIST). HISS is a putative hepatic factor released in the fed-state that selectively increases glucose uptake in skeletal muscle, kidney and heart. In the first phase of this study, the effects of insulin were assessed in pregnant animals (5 and 15-days gestation) and their virgin controls. Groups of 15-day gestation and virgin animals had SS for 8-weeks (with a 2-week recovery), 10-weeks or 22-weeks. Half of all of the 10-week SS animals were treated with either SAMEC (given chronically, containing S-adenosyl-methionine, vitamin C and vitamin E) or BENAC (given once the night before the acute study, containing bethanechol chloride and n-acetyl-l-cysteine). Body weight, weight gained over the gestational period, fat pad mass, post-prandial glycemia, plasma insulin and triglyceride concentrations were measured in all groups. Results: 5-days gestation was associated with preserved direct insulin action and increased HISS-dependent insulin action. 15-days gestation was associated with a mixed insulin resistance: both direct and HISS-dependent insulin action were reduced. SS in these pregnant and virgin rats eliminated HISS-dependent insulin action, associated with hyperinsulinemia, hypertriglyceridemia and obesity. In the SS group given 8-weeks of sucrose (then a 2-week recovery), virgins spontaneously partially recovered HISSdependent insulin action. At 15-days gestation, recovery was complete with reductions in plasma insulin and triglyceride concentrations, and normalization of body weight and fat pad mass. 10-week SS resulted in complete absence of HISS-dependent insulin action, and produced a model of gestational obesity. Prolonged (22-week) SS did not result in hyperglycemia or elevation of plasma insulin concentration above 10-week SS. SAMEC in 10-week SS 15-day pregnant and virgin rats prevented the loss of HISS-dependent insulin action, and normalized plasma insulin and triglyceride concentrations. BENAC given to 10-week SS virgin and 15-day pregnant rats normalized overall insulin responses secondary to restoration of HISS-dependent insulin action. This was accompanied by a reduction (for virgins) and normalization (at 15-days gestation) of plasma insulin and triglyceride concentrations. In 15-day pregnant controls (no sucrose), BENAC increased the HISS-dependent insulin action significantly above baseline and reduced plasma triglycerides and insulin below control levels. Conclusions: These results suggest an explanation for the insulin resistance occurring in pregnancy, whereby HISS may facilitate metabolic adaptation. HISS may represent a pathophysiological missing link in the insulin resistant disorders of pregnancy. These findings substantiate a series of unexplored treatments (including BENAC and SAMEC) for the epidemic of gestational obesity and diabetes in mothers-to-be and the deleterious metabolic programming occurring in the next generation.