The impact of IUGR on pancreatic islet development and β-cell function

Abstract

Placental insufficiency is a primary cause of intrauterine growth restriction (IUGR). IUGR increases the risk of developing type 2 diabetes mellitus (T2DM) throughout life, which indicates that insults from placental insufficiency impair β-cell development during the perinatal period because β-cells have a central role in the regulation of glucose tolerance. The severely IUGR fetal pancreas is characterized by smaller islets, less β-cells, and lower insulin secretion. Because of the important associations among impaired islet growth, β-cell dysfunction, impaired fetal growth, and the propensity for T2DM, significant progress has been made in understanding the pathophysiology of IUGR and programing events in the fetal endocrine pancreas. Animal models of IUGR replicate many of the observations in severe cases of human IUGR and allow us to refine our understanding of the pathophysiology of developmental and functional defects in islet from IUGR fetuses. Almost all models demonstrate a phenotype of progressive loss of β-cell mass and impaired β-cell function. This review will first provide evidence of impaired human islet development and β-cell function associated with IUGR and the impact on glucose homeostasis including the development of glucose intolerance and diabetes in adulthood. We then discuss evidence for the mechanisms regulating β-cell mass and insulin secretion in the IUGR fetus, including the role of hypoxia, catecholamines, nutrients, growth factors, and pancreatic vascularity. We focus on recent evidence from experimental interventions in established models of IUGR to understand better the pathophysiological mechanisms linking placental insufficiency with impaired islet development and β-cell function.

A 1 week IGF-1 infusion decreases arterial insulin concentrations but increases pancreatic insulin content and islet vascularity in fetal sheep

“…; Boehmer et al. ; Limesand and Rozance ). For example, fetuses from pregnancies complicated by placental insufficiency and severe intrauterine growth restriction (IUGR) are characterized by lower circulating IGF‐1 and lower β ‐cell mass (Van Assche et al.…”

“…While these studies show important effects of IGF-1 on b-cell mass and insulin production, the physiological endocrine regulation of fetal islet development and b-cell mass are largely unexplored. Understanding this regulation is important because common complications of pregnancy result in abnormal b-cell mass and islet development with implications for fetal insulin concentrations and the regulation of fetal growth (Green et al 2010;Boehmer et al 2017;Limesand and Rozance 2017). For example, fetuses from pregnancies complicated by placental insufficiency and severe intrauterine growth restriction (IUGR) are characterized by lower circulating IGF-1 and lower b-cell mass (Van Assche et al 1977;Ostlund et al 1997).…”

Classic solutions to a modern problem: exercise training improves metabolic disorders in offspring from fathers on a high fat diet

“…The specific epigenetic mechanisms of paternal high fat diet are not yet clear. However, the severity of β-cell loss in these rats is comparable to losses seen in severe maternal disorders such as placental insufficiency with pathological fetal growth restriction, and extends the fetal programming field beyond traditional maternal complications (Boehmer et al 2017). A remarkable aspect of the current investigation was the finding that moderate exercise training of offspring early in life restored insulin sensitivity in adult progeny from paternal high fat diet.…”

“…However, the severity of β‐cell loss in these rats is comparable to losses seen in severe maternal disorders such as placental insufficiency with pathological fetal growth restriction, and extends the fetal programming field beyond traditional maternal complications (Boehmer et al . ).…”

Dietary Leucine Supplementation Restores Serum Glucose Levels, and Modifying Hepatic Gene Expression Related to the Insulin Signal Pathway in IUGR Piglets

“…Intrauterine growth restriction/retardation (IUGR), as characterized by lower birth weight, is one of the most common complications during pregnancy and is associated with high morbidity and mortality in neonatal humans and livestock, especially in multiparous animals (e.g., pigs) [1,2]. IUGR impairs the organ development, compromises the size and structure of organs, and leads to dysfunction of the corresponding organs [3].…”