Investigating Fetal Pancreatic β-cell NFκB Signaling as a Novel Pathway Linking Early Metabolic Dysfunction to Type 2 Diabetes Later in Life

Intrauterine growth restriction (IUGR) increases perinatal morbidity and mortality and results in long-term metabolic consequences, including premature β-cell failure and type 2 diabetes. IUGR fetuses have β-cells that fail to sense intrauterine nutrients properly thereby leading to impaired oxidative metabolism, reduced insulin secretion, and decreased β-cell mass. Oxidative metabolism increases cytoplasmic calcium leading to insulin secretion, suggesting impaired calcium handling within the IUGR β-cell. NFκB is a calcium-sensitive transcription factor that promotes β-cell mass by regulating β-cell replication and apoptosis and is activated in adult β-cells during nutrient stimulation and insulin secretion. Therefore, we propose that evaluating fetal β-cell-specific NFκB activation will uncover a novel mechanism linking intrauterine β-cell failure, lower β-cell mass, and the later development of type 2 diabetes. This will be tested with in vivo and in vitro nutrient and calcium stimulation in chronically catheterized late gestation normally grown fetal sheep for eventual comparison to fetal sheep subjected to experimental IUGR with similar characteristics and complications to human IUGR pregnancies.