AbstractPancreatic islet dysfunction is a signature feature in the pathogenesis of Type 2 Diabetes and can stem fromdevelopmental adaptations to placental insufficiency (PI) and fetal growth restriction (FGR). We have identifiedsignificant reductions in insulin production and secretion that persist in offspring with FGR. Our efforts to elucidateprogramming mechanisms in FGR islets indicate that reductions in normal constitutive nuclear factor kappa B(NFB) activity negatively affects insulin secretion. Additionally our preliminary findings associate depressedNFB activity with hypoxia-induced MALAT1 expression because this long intergenic non-coding (linc) RNAbinds NFB to prevent activation. The guiding premise of this project is that low fetal oxygen and glucoseconcentrations from PI cause -cell dysfunction during development. Therefore we plan to correct oxygen andglucose concentrations in FGR fetuses during PI and show improvements in insulin secretion and -cellproliferation. Foundational experiments demonstrate that combined supplementation of oxygen and glucose tothe fetus with PI-induced FGR improves insulin secretion but the underlying cues that cause persistent -cellfailure are undiscovered. We hypothesize that correction of oxygen and glucose concentrations in the PI-FGRfetus to normal control fetal values will prevent -cell dysfunction by enhancing -cell proliferation and insulinsecretion through the restoration of constitutive and physiological NFB activity. Furthermore fetal oxygen andglucose correction will resolve programmed deficiencies in -cells of FGR lambs. We have adapted our fetalsheep model of PI-FGR to test a supplemental mixture of oxygen and glucose in a controlled in uteroenvironment. Preliminary experiments with five days of oxygen and glucose correction lowered norepinephrineincreased insulin and restored glucose-stimulated insulin secretion (GSIS) in islets demonstrating its suitabilityas a model to test whether the capacity to reverse PI ameliorates -cell failure. In Aim 1 we will evaluate thecombined effect of oxygen and glucose correction to improve -cell function in fetuses and neonates with PI-induced FGR. In Aim 2 we will determine limitations in GSIS that result from lower constitutive NFB activity dueto MALAT1 overexpression in FGR islets. By alleviating hypoxemia and providing glucose a major nutrient for-cell responsiveness we expect that insulin secretion and -cell proliferation will increase and programmingmechanisms causing -cell dysfunction will return to normal. Impact of these experiments will be high as theywill provide fundamental new knowledge about the reversibility of -cell dysfunction in fetuses with PI-inducedFGR. In addition our experiments will define the unique roles for NFB regulation in -cells from FGR fetusesthat cause developmental adaptations that persistently lower insulin secretion. We also will gain new insight onthe reversibility of a distinct islet-programming mechanism when fetal oxygen and glucose is corrected which isexpected to improved short- and long-term outcomes in individuals with FGR.