Prevention of Placental Insufficiency Improves Beta-Cells Function

Abstract Pancreatic islet dysfunction is a signature feature in the pathogenesis of Type 2 Diabetes and can stem from developmental adaptations to placental insufficiency (PI) and fetal growth restriction (FGR). We have identified significant reductions in insulin production and secretion that persist in offspring with FGR. Our efforts to elucidate

programming mechanisms in FGR islets indicate that reductions in normal, constitutive nuclear factor kappa B (NFκB) activity negatively affects insulin secretion. Additionally, our preliminary findings associate depressed NFκB activity with hypoxia-induced MALAT1 expression because this long intergenic non-coding (linc) RNA

binds NFκB to prevent activation. The guiding premise of this project is that low fetal oxygen and glucose concentrations from PI cause β-cell dysfunction during development. Therefore, we plan to correct oxygen and glucose concentrations in FGR fetuses during PI and show improvements in insulin secretion and β-cell

proliferation. Foundational experiments demonstrate that combined supplementation of oxygen and glucose to the fetus with PI-induced FGR improves insulin secretion, but the underlying cues that cause persistent β-cell failure are undiscovered. We hypothesize that correction of oxygen and glucose concentrations in the PI-FGR

fetus to normal, control fetal values will prevent β-cell dysfunction by enhancing β-cell proliferation and insulin secretion through the restoration of constitutive and physiological NFκB activity. Furthermore, fetal oxygen and glucose correction will resolve programmed deficiencies in β-cells of FGR lambs. We have adapted our fetal

sheep model of PI-FGR to test a supplemental mixture of oxygen and glucose in a controlled, in utero environment. Preliminary experiments with five days of oxygen and glucose correction lowered norepinephrine, increased insulin, and restored glucose-stimulated insulin secretion (GSIS) in islets, demonstrating its suitability

as a model to test whether the capacity to reverse PI ameliorates β-cell failure. In Aim 1, we will evaluate the combined effect of oxygen and glucose correction to improve β-cell function in fetuses and neonates with PI- induced FGR. In Aim 2, we will determine limitations in GSIS that result from lower constitutive NFκB activity due

to MALAT1 overexpression in FGR islets. By alleviating hypoxemia and providing glucose, a major nutrient for β-cell responsiveness, we expect that insulin secretion and β-cell proliferation will increase and programming mechanisms causing β-cell dysfunction will return to normal. Impact of these experiments will be high, as they

will provide fundamental new knowledge about the reversibility of β-cell dysfunction in fetuses with PI-induced FGR. In addition, our experiments will define the unique roles for NFκB regulation in β-cells from FGR fetuses that cause developmental adaptations that persistently lower insulin secretion. We also will gain new insight on

the reversibility of a distinct islet-programming mechanism when fetal oxygen and glucose is corrected, which is expected to improved short- and long-term outcomes in individuals with FGR.