Intrauterine growth retardation (IUGR) is a common complication of pregnancy and is associated with increased morbidity and mortality in the newborn. Epidemologic studies of humans have suggested that intrauterine growth restriction is associated with an increased risk of glucose intolerance and diabetes later in life. The mechanisms responsible for this phenomenon are unknown. We used a model of intrauterine growth retardation in the rat to determine if decreased insulin and glucose availability to the fetus leads to glucose intolerance and diabetes after birth. We ligated maternal uterine arteries in pregnant rats (n=15) on day 19 of gestation (term = 21.5 d). Sham operated pregnant rats served as controls (n=14). The animals were allowed to spontaneously deliver. Litters were culled to 6 on day 1 of life. Pancreatic islets were harvested from newborns (d 4), juveniles (d 30), young adults (d 67) and older adults (6 months), and periperfusion studies of the islets performed (Ramp studies). Glucose concentrations were increased in the perfusate every 2 minutes up to a maximum of 50 mM. Insulin concentrations were measured by RIA. OGTT's were measured on day of life 21, 67, 100, and 6 months. Fasting insulin and glucose concentrations were also measured at these ages. On d4, ramp studies were abnormal in IUGR animals. Maximal insulin secretion at glucose concentrations between 30-50 mM was 35% lower in islets of IUGR newborns compared to - controls (p<0.05). In older animals first and second phase insulin secretion were lower in IUGR animals compared to controls (p<0.01). OGTT's demonstrated mild glucose intolerance at age 21 days and by age 100 days, were markedly abnormal. At age 21, days fasting glucose and insulin concentrations did not differ between IUGR and control animals. However, after a 2 g/kg glucose bolus, glucose and insulin concentrations in IUGR's were nearly double those of controls (p<0.01). By age 100 days, fasting glucose and insulin levels were significantly higher in IUGR's than in controls (p<0.001) indicating that these animals had developed overt diabetes. Urine was also positive for glucose. IUGR animals were markedly obese. After the glucose bolus, it took the IUGR animals at least twice as long to return to baseline compared to controls. We conclude that the variables in the intrauterine milieu associated with IUGR, such as decreased glucose and insulin availability to the fetus, lead to a permanent B-cell defect resulting in glucose intolerance and the development of diabetes later in life.