Fetal undernutrition, placental insufficiency, and pancreatic β-cell development programming in utero

Abstract

The prevalence of obesity and type 2 (T2D) diabetes is a major health concern in the United States and around the world. T2D is a complex disease characterized by pancreatic β-cell failure in association with obesity and insulin resistance in peripheral tissues. Although several genes associated with T2D have been identified, it is speculated that genetic variants account for only <10% of the risk for this disease. A strong body of data from both human epidemiological and animal studies shows that fetal nutrient factors in utero confer significant susceptibility to T2D. Numerous studies done in animals have shown that suboptimal maternal environment or placental insufficiency causes intrauterine growth restriction (IUGR) in the fetus, a critical factor known to predispose offspring to obesity and T2D, in part by causing permanent consequences in total functional β-cell mass. This review will focus on the potential contribution of the placenta in fetal programming of obesity and TD and its likely impact on pancreatic β-cell development and growth.

Keywords: IUGR; diabetes; fetal programming; insulin secretion; islet.

Fig. 1.

Placental insufficiency programming of β-cell mass in the offspring. Fetal intrauterine growth restriction (IUGR) is a result of changes in suboptimal maternal intrauterine environment, which influences placental function. This includes several integrated factors, including but not limited to reduced activity of mechanistic target of rapamycin (mTOR) signaling pathways, specific hormones such as placental lactogen levels, and exosomal content (i.e., microRNAs). All of these factors may contribute to fetal IUGR and the development of pancreatic β-cell mass in the fetus. BCAA, branched chain amino acid.