Fetal adaptations in insulin secretion result from high catecholamines during placental insufficiency

Abstract

Placental insufficiency and intrauterine growth restriction (IUGR) of the fetus affects approximately 8% of all pregnancies and is associated with short- and long-term disturbances in metabolism. In pregnant sheep, experimental models with a small, defective placenta that restricts delivery of nutrients and oxygen to the fetus result in IUGR. Low blood oxygen concentrations increase fetal plasma catecholamine concentrations, which lower fetal insulin concentrations. All of these observations in sheep models with placental insufficiency are consistent with cases of human IUGR. We propose that sustained high catecholamine concentrations observed in the IUGR fetus produce developmental adaptations in pancreatic β-cells that impair fetal insulin secretion. Experimental evidence supporting this hypothesis shows that chronic elevation in circulating catecholamines in IUGR fetuses persistently inhibits insulin concentrations and secretion. Elevated catecholamines also allow for maintenance of a normal fetal basal metabolic rate despite low fetal insulin and glucose concentrations while suppressing fetal growth. Importantly, a compensatory augmentation in insulin secretion occurs following inhibition or cessation of catecholamine signalling in IUGR fetuses. This finding has been replicated in normally grown sheep fetuses following a 7-day noradrenaline (norepinephrine) infusion. Together, these programmed effects will potentially create an imbalance between insulin secretion and insulin-stimulated glucose utilization in the neonate which probably explains the transient hyperinsulinism and hypoglycaemia in some IUGR infants.

Postnatal undernutrition alters adult female mouse cardiac structure and function leading to limited exercise capacity

“…; Aljunaidy et al . ; Limesand & Rozance, ). Less is known about the consequences of postnatal undernutrition and growth retardation during the later stages of cardiac maturation, and if deficiencies incurred during this time are recoverable.…”

“…Numerous studies in animal models have focused on the long-term cardiovascular effects of IUGR (reviewed in Kuo et al 2017). In utero, however, factors in addition to nutrient supply are likely to contribute to the outcomes, such as hypoxia, high catecholamine levels or other stress hormones, and adverse changes to maternal and feto-placental physiology (Morrison et al 2007;Bjarnegard et al 2013;Cohen et al 2016;Aljunaidy et al 2017;Limesand & Rozance, 2017). Less is known about the consequences of postnatal undernutrition and growth retardation during the later stages of cardiac maturation, and if deficiencies incurred during this time are recoverable.…”

Postnatal β2 adrenergic treatment improves insulin sensitivity in lambs with IUGR but not persistent defects in pancreatic islets or skeletal muscle

“…; Danielson et al . ; Limesand & Rozance, ). We found that when placental insufficiency was produced by maternal hyperthermia in sheep, the resulting fetal hypercatecholaminaemia inhibited insulin secretion and independently slowed growth (Leos et al .…”

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).…”