The Placental Variant of Human Growth Hormone Reduces Maternal Insulin Sensitivity in a Dose-Dependent Manner in C57BL/6J Mice

Abstract

The human placental GH variant (GH-V) is secreted continuously from the syncytiotrophoblast layer of the placenta during pregnancy and is thought to play a key role in the maternal adaptation to pregnancy. Maternal GH-V concentrations are closely related to fetal growth in humans. GH-V has also been proposed as a potential candidate to mediate insulin resistance observed later in pregnancy. To determine the effect of maternal GH-V administration on maternal and fetal growth and metabolic outcomes during pregnancy, we examined the dose-response relationship for GH-V administration in a mouse model of normal pregnancy. Pregnant C57BL/6J mice were randomized to receive vehicle or GH-V (0.25, 1, 2, or 5 mg/kg · d) by osmotic pump from gestational days 12.5 to 18.5. Fetal linear growth was slightly reduced in the 5 mg/kg dose compared with vehicle and the 0.25 mg/kg groups, respectively, whereas placental weight was not affected. GH-V treatment did not affect maternal body weights or food intake. However, treatment with 5 mg/kg · d significantly increased maternal fasting plasma insulin concentrations with impaired insulin sensitivity observed at day 18.5 as assessed by homeostasis model assessment. At 5 mg/kg · d, there was also an increase in maternal hepatic GH receptor/binding protein (Ghr/Ghbp) and IGF binding protein 3 (Igfbp3) mRNA levels, but GH-V did not alter maternal plasma IGF-1 concentrations or hepatic Igf-1 mRNA expression. Our findings suggest that at higher doses, GH-V treatment can cause hyperinsulinemia and is a likely mediator of the insulin resistance associated with late pregnancy.

Maternal serum placental growth hormone, insulin-like growth factors and their binding proteins at 20 weeks’ gestation in pregnancies complicated by gestational diabetes mellitus

“…6,9 We and others have demonstrated that transgenic expression or administration of exogenous GH-V causes insulin resistance in mice. [10][11][12] A positive association between maternal GH-V and foetal growth has been found in previous studies. [13][14][15] Increased maternal GH-V concentrations were also observed in large for gestational age (lGA) pregnancies.…”

“…10,17 Previously we treated both pregnant and non-pregnant female mice with recombinant GH-V and found that GH-V reduced maternal insulin sensitivity in a dose-dependent manner. 11,12 We therefore hypothesized that the maternal serum GH-V would also be altered in GDM pregnancies. However, a direct diabetogenic effect…”

The Role of Placental Hormones in Mediating Maternal Adaptations to Support Pregnancy and Lactation

“…GH may also be important for modulating pancreatic insulin production (Billestrup and Nielsen, 1991 ; Brelje et al, 1993 ). However, GH from the placenta appears to be primarily important in the acquisition of insulin resistance and shifting metabolic fuel use from glucose to lipid in the mother during pregnancy (Table 1 ; PRL/PL/GH; Horber and Haymond, 1990 ; Goodman et al, 1991 ; Galosy and Talamantes, 1995 ; Barbour et al, 2002 ; Dominici et al, 2005 ; Boparai et al, 2010 ; Liao et al, 2016b ; Sairenji et al, 2017 ). Placental GH reduces insulin receptor expression and signaling, as well as, diminishes the abundance of the insulin-sensitive glucose-transporter, GLUT-4, in the skeletal muscle (Barbour et al, 2004 ; Kirwan et al, 2004 ).…”

Central growth hormone action regulates metabolism during pregnancy

“…Although growth hormone (GH) has not been generally associated with the metabolic changes during pregnancy, several studies suggest that GH signaling is capable of affecting the maternal organism (7,32,50,51). First, GH and prolactin share a similar intracellular signaling cascade, which is largely dependent on the activation of signal transducer and activator of transcription 5 (STAT5) proteins (19,30,75).…”