Human placental growth hormone causes severe insulin resistance in transgenic mice

Barbour, Linda A.; Shao, Jianhua; Qiao, Liang; Pulawa, Leslie K.; Jensen, Dalan R.; Bartke, Andrzej; Garrity, Maureen; Draznin, Boris; Friedman, Jacob E.

doi:10.1067/mob.2002.121256

Cited by 187 publications

(141 citation statements)

References 19 publications

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“…Among the known effects of hGH are increased lipolysis, increased hepatic output of glucose, and increased peripheral resistance to insulin. hPGH elicits similar effects in experimental systems [40,41]. Thus, hPGH may act in concert with other placental hormones to augment the supply of fatty acids and glucose to the placenta.…”

Section: Primatesmentioning

confidence: 79%

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Placental Growth Hormone-Related Proteins and Prolactin-Related Proteins

Haig

2008

Placenta

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Section: Primatesmentioning

confidence: 79%

“…These PRLRs are targets for hPL produced by extravillous trophoblast [41] and hPRL produced by the decidual stroma [12]. Synctiotrophoblast is the source of hPL released into the general maternal circulation [44].…”

Section: Primatesmentioning

confidence: 99%

Placental Growth Hormone-Related Proteins and Prolactin-Related Proteins

Haig

2008

Placenta

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“…This location strongly argues for the maternal circulation as the sole insulin source regulating PGH secretion. PGH can cause insulin resistance by changing the subunit composition of phosphatidylinositol 3-kinase17 (11). The contribution of PGH to maternal insulin resistance makes it tempting to hypothesize a maternalplacental feedforward-feedback loop as proposed recently (28).…”

Section: Discussionmentioning

confidence: 99%

“…In vivo experiments have demonstrated that growth hormone, when infused into pregnant ewes late in gestation, can increase fetal growth (10). Transgenic mice overexpressing the human PGH gene become larger than their normal littermates and are hyperinsulinemic and insulin resistant (11). The relationship between fetal growth and PGH raises the possibility that PGH could be involved in the development of insulin resistance in pregnancy and might play an important role in gestational diabetes mellitus (GDM) and pregestational diabetes (12,13).…”

mentioning

confidence: 99%

Regulation of Placental Growth Hormone Secretion in a Human Trophoblast Model—The Effects of Hormones and Adipokines

et al. 2008

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Placental growth hormone (PGH) is secreted from the human placental syncytiotrophoblast into the maternal circulation. PGH levels in pregnant women correlate with the birth weight of their offspring. We hypothesized that metabolic regulators may alter PGH secretion. BeWo cells as human trophoblast models were treated for 24, 48, and 72 h with insulin, insulin-like growth factor (IGF)-1, cortisol, ghrelin, leptin and visfatin. P lacental growth hormone (PGH) is synthesized in and secreted from the human placental syncytiotrophoblast (1) into the maternal circulation in a nonpulsatile manner, detectable in the maternal circulation from gestational week 5, and gradually increases in concentration throughout pregnancy. It has a short half-life and is undetectable 3 h after parturition (2). It is only found in the maternal, but not fetal circulation. Its maternal levels rise profoundly between weeks 20 and 30 of gestation, thus progressively replacing pituitary growth hormone in the human maternal circulation from midgestation onward (3-5). PGH has somatotropic effects, acting on liver and adipose tissue to influence gluconeogenesis and lipolysis to help ensure an adequate nutrient supply for the fetoplacental unit (6).Previously, our group and others have shown a positive correlation between PGH levels in pregnant women and the birth weight of their offspring, stimulating discussions about its possible impact on fetal growth (2,7). Understanding the regulation of fetal growth is important. According to the "Fetal Origins of Disease" hypothesis, it is well recognized that Type 2 diabetes mellitus (T2DM) and features of the metabolic syndrome are associated with birth weights at the extreme of the growth continuum (either small or large for gestational age) (8). The physiologic role of PGH in pregnancy is not completely understood, but its continuous secretion at high levels during pregnancy sparked speculation that it may be an important placental hormone affecting both mother and, indirectly, fetus (9). In vivo experiments have demonstrated that growth hormone, when infused into pregnant ewes late in gestation, can increase fetal growth (10). Transgenic mice overexpressing the human PGH gene become larger than their normal littermates and are hyperinsulinemic and insulin resistant (11). The relationship between fetal growth and PGH raises the possibility that PGH could be involved in the development of insulin resistance in pregnancy and might play an important role in gestational diabetes mellitus (GDM) and pregestational diabetes (12,13).The regulation of PGH secretion is very different from that of pituitary growth hormone (GH) as growth-hormone-releasing hormone does not modulate PGH in vivo. Furthermore, in vitro and in vivo studies have revealed that alterations in maternal nutrient (glucose) availability may alter PGH secretion (14). However, two decades have passed since the discovery of PGH, and still little is known about the regulation of its secretion.We hypothesized that PGH secretion is regul...

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“…Historically, placental hormones including placental growth hormone (HPGH), human placental lactogen (hPL), progesterone, and cortisol have been implicated, and an association between placental hormones and insulin resistance has been demonstrated (3,4,12,20,27,31,32). However, more recent evidence is conflicting (reviewed in Ref.…”

mentioning

confidence: 99%

Accretion of visceral fat and hepatic insulin resistance in pregnant rats

Einstein

Fishman

Muzumdar

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Insulin resistance (IR) is a hallmark of pregnancy. Because increased visceral fat (VF) is associated with IR in nonpregnant states, we reasoned that fat accretion might be important in the development of IR during pregnancy. To determine whether VF depots increase in pregnancy and whether VF contributes to IR, we studied three groups of 6-mo-old female Sprague-Dawley rats: 1) nonpregnant sham-operated rats (Nonpreg; n = 6), 2) pregnant sham-operated rats (Preg; n = 6), and 3) pregnant rats in which VF was surgically removed 1 mo before mating (PVF−; n = 6). VF doubled by day 19 of pregnancy (Nonpreg 5.1 ± 0.3, Preg 10.0 ± 1.0 g, P < 0.01), and PVF− had similar amounts of VF compared with Nonpreg (PVF− 4.6 ± 0.8 g). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp in late gestation in chronically catheterized unstressed rats. Glucose IR (mg·kg−1·min−1) was highest in Nonpreg (19.4 ± 2.0), lowest in Preg (11.1 ± 1.4), and intermediate in PVF− (14.7 ± 0.6; P < 0.001 between all groups). During the clamp, Nonpreg had greater hepatic insulin sensitivity than Preg [hepatic glucose production (HGP): Nonpreg 4.5 ± 1.3, Preg 9.3 ± 0.5 mg·kg−1·min−1; P < 0.001]. With decreased VF, hepatic insulin sensitivity was similar to nonpregnant levels in PVF− (HGP 4.9 ± 0.8 mg·kg−1·min−1). Both pregnant groups had lower peripheral glucose uptake compared with Nonpreg. In parallel with hepatic insulin sensitivity, hepatic triglyceride content was increased in pregnancy (Nonpreg 1.9 ± 0.4 vs. Preg 3.2 ± 0.3 mg/g) and decreased with removal of VF (PVF− 1.3 ± 0.4 mg/g; P < 0.05). Accretion of visceral fat is an important component in the development of hepatic IR in pregnancy, and accumulation of hepatic triglycerides is a mechanism by which visceral fat may modulate insulin action in pregnancy.

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Human placental growth hormone causes severe insulin resistance in transgenic mice

Cited by 187 publications

References 19 publications

Placental Growth Hormone-Related Proteins and Prolactin-Related Proteins

Placental Growth Hormone-Related Proteins and Prolactin-Related Proteins

Regulation of Placental Growth Hormone Secretion in a Human Trophoblast Model—The Effects of Hormones and Adipokines

Accretion of visceral fat and hepatic insulin resistance in pregnant rats

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