Intrauterine growth restriction and accelerated postnatal growth predict increased risk of diabetes. Uteroplacental insufficiency in the rat restricts fetal growth, but also impairs mammary development and postnatal growth. We used cross-fostering to compare the influence of prenatal and postnatal nutritional restraint on adult glucose tolerance, insulin secretion, insulin sensitivity and hypothalamic NPY content in WKY rats at 6 months of age. Bilateral uterine vessel ligation (Restricted) to induce uteroplacental insufficiency or sham surgery (Control) was performed on day 18 of gestation. Control, Restricted and Reduced (reducing litter size of Controls to match Restricted) pups were cross-fostered onto a Control or Restricted mother 1 day after birth. Restricted pups were born small compared to Controls. Restricted males, but not females, remained lighter up to 6 months, irrespective of postnatal environment. By 10 weeks, Restricted-on-Restricted males ate more than Controls. At 6 months Restricted-on-Restricted males had increased hypothalamic NPY content compared to other groups and together with Reduced-on-Restricted males had increased retroperitoneal fat weight (% body weight) compared to Control-on-Controls. Restricted-on-Restricted males had impaired glucose tolerance, reduced first-phase insulin secretion, but unaltered insulin sensitivity, compared to Control-on-Controls. In males, being born small and exposed to an impaired lactational environment adversely affects adult glucose tolerance and first-phase insulin secretion, but improving lactation partially ameliorates this condition. This study identifies early life as a target for intervention to prevent later diabetes following prenatal restraint. ; Andrew L Siebel, Amy Mibus, Miles J De Blasio, Kerryn T Westcott, Margaret J Morris, Larissa Prior, Julie A Owens, and Mary E Wlodek