Chronic fetal hyperinsulinemia and hyperglycemia cause intrauterine hypoxia, increasing fetal iron demand for erythropoiesis by 30-40%. The hypoxic fetus has two potential sources of iron: endogenous iron stores and increased maternal-fetal iron transport mediated by TfR located on the syncytiotrophoblast. TfR protein expression is increased in diabetic pregnancies characterized by low fetal iron stores and is inversely related to those stores, suggesting regulation by fetal iron status (Petry et al., AJP 1994). In cell culture, TfR protein expression is regulated by coordinate stabilization of TfR mRNA and destabilization of ferritin mRNA by IRPs which bind iron-responsive elements on the respective mRNAs. We hypothesized that placental IRP and TfR mRNA concentrations are increased in irondeficient diabetic placentas, related to the degree of iron deficiency. IRP1&2 and TfR mRNA were isolated from 5 diabetic placentas with evidence of iron deficiency (cord serum [ferritin] <5th percentile; low placental nonheme [Fe]) and 6 diabetic placentae with normal iron status. TfR protein expression was assessed by Scatchard analysis of competitive binding of 125Itransferrin following isolation of syncytiotrophoblastic membranes. IRPs were measured using RNA gel shift assays. Identities of IRP1&2 were confirmed in supershift assays and Western blots using specific antibodies. TfR mRNA was detected by Northern blot. Optical density of gels and blots was measured using Image1. IRP1, but not IRP2, was detected in the samples. IRP1 content was greater in the irondeficient than in the ironsufficient group(mean ± SD optical density units: 8.9 ± 4.3 v 4.2± 1.2; p=0.03), and was inversely correlated with calculated storage iron (r=0.66; p<0.05). IRP1 content was directly correlated with TfR mRNA(r=0.80; p=0.01). The increased TfR number seen in lowiron diabetic placentas is likely due to increased IRP binding and thus stabilization of TfR mRNA.