Increased insulin sensitivity and maintenance of glucose utilization rates in fetal sheep with placental insufficiency and intrauterine growth restriction

Abstract

In this study we determined body weight-specific fetal (umbilical) glucose uptake (UGU), utilization (GUR), and production rates (GPR) and insulin action in intrauterine growth-restricted (IUGR) fetal sheep. During basal conditions, UGU from the placenta was 33% lower in IUGR fetuses, but GUR was not different between IUGR and control fetuses. The difference between glucose utilization and UGU rates in the IUGR fetuses demonstrated the presence and rate of fetal GPR (41% of GUR). The mRNA concentrations of the gluconeogenic enzymes glucose-6-phophatase and PEPCK were higher in the livers of IUGR fetuses, perhaps in response to CREB activation, as phosphorylated CREB/total CREB was increased 4.2-fold. A hyperglycemic clamp resulted in similar rates of glucose uptake and utilization in IUGR and control fetuses. The nearly identical GURs in IUGR and control fetuses at both basal and high glucose concentrations occurred at mean plasma insulin concentrations in the IUGR fetuses that were approximately 70% lower than controls, indicating increased insulin sensitivity. Furthermore, under basal conditions, hepatic glycogen content was similar, skeletal muscle glycogen was increased 2.2-fold, the fraction of fetal GUR that was oxidized was 32% lower, and GLUT1 and GLUT4 concentrations in liver and skeletal muscle were the same in IUGR fetuses compared with controls. These results indicate that insulin-responsive fetal tissues (liver and skeletal muscle) adapt to the hypoglycemic-hypoinsulinemic IUGR environment with mechanisms that promote glucose utilization, particularly for glucose storage, including increased insulin action, glucose production, shunting of glucose utilization to glycogen production, and maintenance of glucose transporter concentrations.

Dietary melatonin supplementation alters uteroplacental amino acid flux during intrauterine growth restriction in ewes

“…Although we observed similar uterine uptake of glucose across treatment groups, uteroplacental uptake was increased in RES v. ADQ fed ewes. Several models of IUGR brought about by placental insufficiency or decreased placental mass, such as heat stress and maternal overnutrition, have decreased glucose uptake in IUGR v. control dams (Wallace et al, 2002;Limesand et al, 2007). In the hyperthermia ovine model, reduced glucose transport capacity occurs due to a smaller placenta size and reduced concentrations of glucose transporters per gram of placenta (Thureen et al, 1992;Limesand et al, 2007).…”

“…Several models of IUGR brought about by placental insufficiency or decreased placental mass, such as heat stress and maternal overnutrition, have decreased glucose uptake in IUGR v. control dams (Wallace et al, 2002;Limesand et al, 2007). In the hyperthermia ovine model, reduced glucose transport capacity occurs due to a smaller placenta size and reduced concentrations of glucose transporters per gram of placenta (Thureen et al, 1992;Limesand et al, 2007). In the overnutrition ovine model, reduced glucose transport capacity occurs primarily due to a decreased placental surface area and placental size, whereas glucose transporter density remains similar across treatment groups (Hay, 2006;Wallace et al, 2006).…”

Sensitivity to metabolic signals in late-gestation growth-restricted fetuses from rapidly growing adolescent sheep

“…In this model, growth-restricted pregnancies are generated by maternal exposure to hyperthermia (38), and preliminary data demonstrate increased insulin receptor protein coupled with decreased levels of insulin signal transduction inhibitors, such as glycogen synthesis kinase in liver and skeletal muscle, which would have the effect of enhancing insulin action to promote glycogen deposition. Indeed, preliminary studies document increased weight-specific glycogen concentrations in these organs in this ovine intrauterine growth restricted (IUGR) model (33) as well as higher GLUT1 protein in the fetal brain (22) and higher GLUT4 protein in the heart (1). Furthermore, previous studies of maternal insulin infusions leading to fetal hypoglycemia reported a decline in brain GLUT3, an increase in brain GLUT1, and a subsequent decline in liver GLUT1, but no significant reduction in insulin-sensitive myocardium, skeletal muscle, and adipose tissue GLUT1 or GLUT4 concentrations, compared with gestational age-matched sham controls (7).…”

Endocrine And Metabolic Adaptations Of Calves To Extra-Uterine Life

“…Newborns are normally exposed to very high levels of multiple vasoactive substances (catecholamines, angiotensin II and renin) that provoke increased blood pressure [37]. As far as infl uence of catecholamines on thermogenesis, both adrenalin and noradrenaline stimulate brown adipose tissue (BAT) thermogenesis by the activation of adenylate cyclase through binding of β-adrenergic receptors [38]. This binding leads to an increased activity of cAMP which stimulates hormone-sensitive lipase which in turn activates lipolysis to provide fatty acids for mitochondrial respiration.…”

“…In addition to their role in BAT thermogenesis, catecholamines are involved in long term modulation of BAT growth and development during cold stress. Therefore, catecholamines play critical roles both in the activation of BAT thermogenesis during acute periods of cold exposure and in the recruitment and proliferation of BAT during sustained periods of cold exposure [38].…”