Human Placental Growth Hormone Increases Expression of the P85 Regulatory Unit of Phosphatidylinositol 3-Kinase and Triggers Severe Insulin Resistance in Skeletal Muscle

Barbour, Linda A.; Shao, Jianhua; Qiao, Liang; Leitner, Wayne; Anderson, Marianne; Friedman, Jacob E.; Draznin, Boris

doi:10.1210/en.2003-1297

Cited by 175 publications

(135 citation statements)

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“…Recently, Barbour and colleagues (87,93) demonstrated that insulin resistance of pregnancy is likely due to increased expression of skeletal muscle p85 in response to increasing concentrations of human placental growth hor- mone. Furthermore, women remaining insulin resistant postpartum have been found to display higher levels of p85 in the muscle (94).…”

Section: Increased Expression Of P85〈mentioning

confidence: 99%

Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85α

2006

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Initial attempts to unravel the molecular mechanism of insulin resistance have strongly suggested that a defect responsible for insulin resistance in the majority of patients lies at the postreceptor level of insulin signaling. Subsequent studies in insulin-resistant animal models and humans have consistently demonstrated a reduced strength of insulin signaling via the insulin receptor substrate (IRS)-1/phosphatidylinositol (PI) 3-kinase pathway, resulting in diminished glucose uptake and utilization in insulin target tissues. However, the nature of the triggering event(s) remains largely enigmatic. Two separate, but likely, complementary mechanisms have recently emerged as a potential explanation. First, it became apparent that serine phosphorylation of IRS proteins can reduce their ability to attract PI 3-kinase, thereby minimizing its activation. A number of serine kinases that phosphorylate serine residues of IRS-1 and weaken insulin signal transduction have been identified. Additionally, mitochondrial dysfunction has been suggested to trigger activation of several serine kinases, leading to a serine phosphorylation of IRS-1. Second, a distinct mechanism involving increased expression of p85␣ has also been found to play an important role in the pathogenesis of insulin resistance. Conceivably, a combination of both increased expression of p85␣ and increased serine phosphorylation of IRS-1 is needed to induce clinically apparent insulin resistance. Diabetes 55: 2392-2397, 2006 E ven though insulin resistance has emerged as an enormous health care problem, trespassing the fields of obesity, diabetes, hypertension, and cardiovascular diseases (1,2), its molecular mechanism remains incompletely understood. Clinically, the term insulin resistance implies that higher-than-normal concentrations of insulin are required to maintain normoglycemia. On a cellular level, this term defines an inadequate strength of insulin signaling from the insulin receptor downstream to the final substrates of insulin action involved in multiple metabolic and mitogenic aspects of cellular function (3).Insulin action is initiated by an interaction of insulin with its cell surface receptor (4). The insulin receptor is a heterotetrameric protein that consists of two extracellular ␣ subunits and two transmembrane ␤ subunits connected by disulfide bridges (5-7). Insulin binding to the extracellular ␣ subunit induces conformational changes of the insulin receptor that activate the tyrosine kinase domain of the intracellular portion of the ␤ subunit (8 -11). Once the tyrosine kinase of insulin receptors is activated, it promotes autophosphorylation of the ␤ subunit itself, where phosphorylation of three tyrosine residues (Tyr-1158, Tyr-1162, and Tyr-1163) is required for amplification of the kinase activity (12,13). Activation of the tyrosine kinase of the insulin receptor also leads to a rapid phosphorylation of the so-called "docking proteins," such as insulin receptor substrate (IRS)-1, -2, -3, and -4, and several Shc proteins (52-, 46-, and...

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Section: Increased Expression Of P85〈mentioning

confidence: 99%

Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85α

2006

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“…Recently, Barbour et al [15] demonstrated that the insulin resistance of pregnancy is likely to be due to Fig. 3 Correlation between the p85α:p110 ratio and glucose infusion rate (GIR) (a) and changes in PI 3-kinase activity and changes in GIR (b) in eight lean women.…”

Section: Discussionmentioning

confidence: 99%

“…PI 3-kinase activity was determined in 1-3 μl of the immunoprecipitate by thin layer chromatography, as described previously [15].…”

Section: Determination Of Irs-1-associated Pi 3-kinase Activitymentioning

confidence: 99%

“…Because the monomer and the heterodimer compete for the same binding sites on the IRS proteins, an imbalance could cause either increased or decreased PI 3-kinase activity. This possibility has recently been supported by studies of the insulin-resistant states induced by human placental growth hormone [15], obesity and type 2 diabetes [16]. If the production of p85 can be enhanced nutritionally, the resulting changes in the ratio of p85 to p110 may be the earliest manifestation of the ensuing insulin resistance.…”

Section: Introductionmentioning

confidence: 97%

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Nutritional upregulation of p85α expression is an early molecular manifestation of insulin resistance

et al. 2006

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Aims/hypothesis: We sought to define early molecular alterations associated with nutritionally induced insulin resistance in humans. Methods: Insulin sensitivity was assessed using a hyperinsulinaemic-euglycaemic clamp in eight healthy women while on an isocaloric diet and after 3 days of overfeeding (50% above eucaloric diet). Expression of phosphatidylinositol (PI) 3-kinase subunits p85α and p110 was assessed and measurements were made of IRS-1-associated PI 3-kinase activity, tyrosine and serine phosphorylation of IRS-1, and serine and threonine phosphorylation of p70S6 kinase. Measurements were made in skeletal muscle biopsies obtained before and after overfeeding. Results: Three days of overfeeding resulted in a reduction of insulin sensitivity accompanied by: (1) increased expression of skeletal muscle p85α; (2) an alteration in the ratio of p85α to p110; (3) a decrease in the amount of IRS-1-associated p110; and (4) a decrease in PI 3-kinase activity. Increases in expression of p85α and in the p85α:p110 ratio demonstrated a highly significant inverse correlation with insulin sensitivity, and changes in PI 3-kinase activity correlated with changes in insulin sensitivity. Tyrosine and serine phosphorylation of IRS-1 and serine and threonine phosphorylation of p70S6 kinase were unaffected by 3 days of overfeeding. Conclusions/interpretation: We identified a novel mechanism of nutritionally induced insulin resistance in healthy women of normal weight. We conclude that increased expression of p85α may be one of the earliest molecular alterations in the mechanism of the insulin resistance associated with overfeeding.

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“…As speculation, this regulation may lead to changes in PGH secretion in conditions associated with altered levels of hormones and adipokines such as in diabetic pregnancies. Thus, we selected hormones and adipokines, which are known to be closely related to fetal growth and adiposity, and tested their potential to act as PGH secretagauges: insulin as a potent stimulator of fetal growth and lipogenesis (15); IGF-1, which is related to increased birth size in diabetic pregnancies (16), and cortisol, also linked to fetal growth (17). Among the adipokines, we choose leptin, which is closely associated with fetal overgrowth (18) and reflects the mother's body fat mass (19), ghrelin, which, in low levels, is associated with increased insulin resistance and inversely related to birth weight (20), and visfatin, which is altered in gestational diabetes (21).…”

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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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Human Placental Growth Hormone Increases Expression of the P85 Regulatory Unit of Phosphatidylinositol 3-Kinase and Triggers Severe Insulin Resistance in Skeletal Muscle

Cited by 175 publications

References 27 publications

Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85α

Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85α

Nutritional upregulation of p85α expression is an early molecular manifestation of insulin resistance

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

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