The results from previous animal studies have shown that nutritional insults during pregnancy and lactation are linked to glucose intolerance via either hyperinsulinemia/insulin resistance, or decreased insulin secretory capacity, depending on the type and timing of the prenatal nutritional insult. Maternal low-protein diets during pregnancy followed by control diets post weaning [2, 5], in addition to energy restricted prenatal diets during the latter half of pregnancy followed by control diets post weaning [6, 7] are associated with insulin-sensitive offspring, but with reduced insulin secretory capacity. The findings reported here for F1 animals are consistent with the maternal protein malnutrition animal model that are linked with impaired glucose tolerance among the mature offspring – but without accompanying hyperinsulinemia/insulin resistance. In contrast, other previous single-generation animal studies have shown that maternal energy-restricted diets fed throughout pregnancy lead to hyperinsulinemia/insulin resistance in adult offspring when followed by adequate and hypercaloric diets post weaning [8, 9]. Similarly, we report here that reduced insulin sensitivity and hyperinsulinemia are also evident in (F2) animals whose mothers were fed energy-restricted diets throughout pregnancy/lactation and are then maintained on the same energy restricted diet post weaning. Why insulin sensitivity normalizes in the F3 offspring of such developmentally-programmed insulin resistant F2 females, however, even though they were exposed to the same prenatal and post weaning dietary protocols as their mothers (energy-restricted/energy-restricted) remains to be determined. This is especially puzzling given that insulin resistance is generally characterized as an 'adaptive' phenotypic trait in nutrient poor environments [10]. Based on the results presented here, it is possible that the insulin sensitivity of the mother fed an energy-restricted diet during pregnancy is a critical variable (i.e., offspring of insulin-resistant mothers fed energy-restricted diets develop normal insulin sensitivity, while the offspring of insulin-sensitive mothers fed energy-restricted diets during pregnancy become insulin resistant). In the current study, the reason for this may be that the maternal insulin resistance of pregnant dams fed an energy-restricted diet increases the availability of nutrients for the fetus – in effect normalizing fetal nutrition and development – while the relative insulin sensitivity of pregnant dams fed an energy-restricted diet makes fewer nutrients available for the developing fetus and programs for insulin resistance in the offspring. For F3 animals whose (F2) mothers were fed energy-restricted diets during pregnancy/lactation, but that were fed adequate diets ad libitum post weaning (F3.2), their improved insulin sensitivity, despite significant (p < 0.05) increases in adult body weight, suggests that maternal diet during gestation/lactation, and not post weaning diet or body weight is the critical variable determining relative insulin sensitivity/resistance. This is of particular interest, given that our group has previously shown that the adequately-nourished grand-offspring (F3) of (F1) rats malnourished during gestation and perinatal life remain significantly less insulin sensitive than control animals [2], suggesting that it is the energy-restriction during pregnancy and lactation in the current study that results in the improved insulin sensitivity of F3 animals. Sex differences are evident in the data in that changes in glucose-insulin metabolism were more pronounced, and more often reached the level of statistical significance, among females than among males. The overall pattern of intergenerational change in glucose-metabolism is similar for both F1 – F3 males and females, however, and among both sexes, insulin resistance (as measured by HOMA), along with fasting insulin and glucose levels, peak in the F2 generation. This leaves the extent of the reduction of insulin resistance between F3.1 (energy restricted post weaning diet) and F3.2 (ad libitum post weaning diet) male and female animals as the only other significant sex-based difference. Here, among both males and females, insulin sensitivity improves dramatically among all F3 animals (whose mothers were fed an energy restricted diet during pregnancy), but among females the larger improvement is among the F3.2 (ad libitum) post weaning diet; whereas among males, insulin sensitivity is most improved among animals fed the F2.1 (energy-restricted post weaning) diet. These sex-based differences should be interpreted with caution, however, because while differences exist in the degree of improved insulin sensitivity between F3 males and females by post weaning diet, among F3.1 and F3.2 females HOMA values do not differ significantly from female controls; and HOMA values of F3.1 and F3.2 males do not differ significantly from each other.