Pancreas Development and Insulin Secretion
Sponsored by the APS Endocrinology & Metabolism Section

It has been recognized for nearly 70 years that the early environment in which a child grows and develops can have long-term effects on subsequent health and survival. The mechanisms underlying the association between size at birth and impaired glucose tolerance or type 2 diabetes are unclear. There are now substantial data to suggest that intrauterine growth restriction (IUGR) has adverse affects on the development of the fetal endocrine pancreas. To address this general theme, the three speakers will focus on specific aspects of pancreatic development during normal and pathological pregnancies. David Hill will discuss the regulation and plasticity of pancreas development. He will provide a description of pancreatic embyrogenesis and the role of transcription and growth factors, addressing whether islets can be built from precursors. He also will consider the impact of nutrition, environment, and other limiting factors on the mechanisms involved in various models of islet regeneration, including the role of endothelial precursor cells, alpha cells, and the vasculature, finishing with a discussion of how plasticity mechanisms involved in pancreatic islet development are compromised by fetal programming. Sean Limesand will focus on how fetal insulin secretion is regulated in utero by nutrient supply and coordinated with fetal growth. He will specifically discuss ho disruption of the nutrient supply, as observed in most IUGR pregnancies, has been shown to decrease fetal insulin concentrations and disrupt fetal b-cell function, and provide evidence for dependence of islet under development on the type and duration of nutrient deficiency. Becky Simmons will discuss experimental data focused on a model of intrauterine growth retardation in the rat that leads to diabetes in later life. She will discuss how oxidative stress in the fetus is a major consequence of uteroplacental insufficiency and how decreased substrate supply alters the redox state in susceptible tissues leading to an imbalance between the production of ROS and antioxidant capacity which results in mitochondrial dysfunction and oxidative stress. She then will discuss how the ß-cell is particularly vulnerable to oxidative stress because of reduced expression of antioxidant enzymes in the pancreatic islets and the high oxidative energy requirement of the fetal pancreas.  She will provide data from studies demonstrating that oxidative stress induces aberrant methylation and chromatin remodeling in Pdx-1, a gene critical for ß-cell development, considering how this might indicate a potential mechanism by which IUGR leads to permanent defects in transcription regulation, leading to an abnormal phenotype of ß-cell failure.