From our previous work, it appears that fetal development in the abnormal intrauterine milieu of a mother with diabetes results in impaired glucose tolerance in adult life. In adult Wistar rats that were the offspring of mildly or severely diabetic mothers, in vitro islet stimulation and in vivo insulin uptake studies were undertaken to distinguish between alterations in glucose sensitivity and insulin secretion at the B cell level and alterations in insulin sensitivity and uptake at the level of the peripheral tissues. Insulin output after glucose stimulation by isolated islets was lower than normal in the rats of mothers with mild diabetes and higher than normal in the animals of severely diabetic mothers, confirming the results of previous in vivo studies. Insulin binding by the liver was normal in both groups. Insulin uptake by the kidney was normal in rats with mildly diabetic mothers but was increased in rats of severely diabetic mothers, suggesting decreased uptake of insulin by the peripheral tissues. Impaired glucose tolerance in rats of mildly diabetic mothers, resulting from decreased responsiveness to glucose, is interpreted as a consequence of hyperactivity of these B cells during the intrauterine life. Impaired glucose tolerance in rats of severely diabetic mothers, associated with insulin hypersecretion and decreased insulin uptake by the peripheral tissues might result from intrauterine alterations of the peripheral receptor or postreceptor system induced by the abnormal intrauterine milieu. These data on experimental diabetes in the rat demonstrate that the maternal diabetic environment exerts a diabetogenic influence on the offspring.