Protein anabolic effects of insulin and IGF-I  in the ovine fetus

Shen, Weihua; Wisniowski, Paul; Ahmed, Lasker S.; Boyle, David W.; Denne, Scott C.; Liechty, Edward A.

doi:10.1152/ajpendo.00399.2002

Cited by 44 publications

(34 citation statements)

References 54 publications

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“…The anabolic hormones insulin and IGF-I likely affect the fetal response to a direct amino acid infusion and have been shown to promote fetal protein synthesis and accretion (22,(37)(38)(39). Insulin promotes fetal amino acid utilization, oxidation, and protein synthesis in a variety of animal models, both independently and synergistically with supplemental amino acids (5,9,30,40).…”

Section: Discussionmentioning

confidence: 99%

Prolonged infusion of amino acids increases leucine oxidation in fetal sheep

Maliszewski

Gadhia

O'Meara

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Maliszewski AM, Gadhia MM, O'Meara MC, Thorn SR, Rozance PJ, Brown LD. Prolonged infusion of amino acids increases leucine oxidation in fetal sheep. Am J Physiol Endocrinol Metab 302: E1483-E1492, 2012. First published March 27, 2012 doi:10.1152/ajpendo.00026.2012.-Maternal high-protein supplements designed to increase birth weight have not been successful. We recently showed that maternal amino acid infusion into pregnant sheep resulted in competitive inhibition of amino acid transport across the placenta and did not increase fetal protein accretion rates. To bypass placental transport, singleton fetal sheep were intravenously infused with an amino acid mixture (AA, n ϭ 8) or saline [control (Con), n ϭ 10] for ϳ12 days during late gestation. Fetal leucine oxidation rate increased in the AA group (3.1 Ϯ 0.5 vs. 1.4 Ϯ 0.6 mol·min Ϫ1 ·kg Ϫ1 , P Ͻ 0.05). Fetal protein accretion (2.6 Ϯ 0.5 and 2.2 Ϯ 0.6 mol·min Ϫ1 ·kg Ϫ1 in AA and Con, respectively), synthesis (6.2 Ϯ 0.8 and 7.0 Ϯ 0.9 mol·min Ϫ1 ·kg Ϫ1 in AA and Con, respectively), and degradation (3.6 Ϯ 0.6 and 4.5 Ϯ 1.0 mol·min Ϫ1 ·kg Ϫ1in AA and Con, respectively) rates were similar between groups. Net fetal glucose uptake decreased in the AA group (2.8 Ϯ 0.4 vs. 3.9 Ϯ 0.1 mg·kg Ϫ1 ·min Ϫ1 , P Ͻ 0.05). The glucose-O2 quotient also decreased over time in the AA group (P Ͻ 0.05). Fetal insulin and IGF-I concentrations did not change. Fetal glucagon increased in the AA group (119 Ϯ 24 vs. 59 Ϯ 9 pg/ml, P Ͻ 0.05), and norepinephrine (NE) also tended to increase in the AA group (785 Ϯ 181 vs. 419 Ϯ 76 pg/ml, P ϭ 0.06). Net fetal glucose uptake rates were inversely proportional to fetal glucagon (r 2 ϭ 0.38, P Ͻ 0.05), cortisol (r 2 ϭ 0.31, P Ͻ 0.05), and NE (r 2 ϭ 0.59, P Ͻ 0.05) concentrations. Expressions of components in the mammalian target of rapamycin signaling pathway in fetal skeletal muscle were similar between groups. In summary, prolonged infusion of amino acids directly into normally growing fetal sheep increased leucine oxidation. Amino acid-stimulated increases in fetal glucagon, cortisol, and NE may contribute to a shift in substrate oxidation by the fetus from glucose to amino acids. pregnancy; insulin; fetal protein metabolism; fetal growth PREVIOUS ATTEMPTS TO IMPROVE fetal outcomes with use of maternal high-protein supplementation have actually increased the risk for small-for-gestational-age birth and infant mortality (26,36). Similarly, supplementation of pregnant sheep with intravenous amino acids for several days at the end of gestation demonstrated adverse fetal effects, including hypoxia and respiratory and metabolic acidosis (34). The mechanisms that explain poor fetal outcomes in response to maternal protein supplementation during pregnancy are unknown.Experiments using normal pregnant sheep have led to some testable explanations for how high-protein supplementation during pregnancy might adversely affect fetal outcomes (4). Short-and long-term maternal amino acid infusions using mixtures of amino acids with a higher essential-nonessential ...

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Section: Discussionmentioning

confidence: 99%

Prolonged infusion of amino acids increases leucine oxidation in fetal sheep

Maliszewski

Gadhia

O'Meara

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…Nonetheless, such mechanism is biologically plausible. Insulin is an anabolic hormone in utero (21,27), whereas GC treatment caused proteolysis in sheep fetuses (13). Also, IR explained a large part of the GC-induced proteolytic response in human adults (14).…”

Section: Discussionmentioning

confidence: 99%

Transient Catabolic State with Reduced IGF-I after Antenatal Glucocorticoids

et al. 2007

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Glucocorticoid (GC) administration before preterm birth reduces neonatal morbidity but may restrain growth. Here we explored the effect of antenatal GC on nutrient substrates [glucose, FFA, amino acids (AA)], and on IGF-I and IGF-binding protein-1 (IGFBP-1). We analyzed umbilical vein (UV) plasma obtained at birth from 91 preterm newborns that received one course of GC (last exposure 1-1358 h before birth) and 49 newborns that did not. We found that recent GC exposure (Յ48 h) raised glucose, FFA, and AA concentrations, and the homeostasis model assessment of insulin resistance (HOMA-IR) index, but lowered IGF-I concentrations. The AA surge was greater in newborns with a birth weight z score Ͻ0 than in those with a z score Ͼ0. Although all AA were transiently increased, the increment was most robust for glutamine and alanine. Shorter duration since GC administration and lower IGF-I concentrations independently predicted AA levels. In conclusion, an antenatal course of GC elicited a transient catabolic state encompassing all nutrient substrates, and a temporary drop in IGF-I concentrations. These changes may explain the growth-inhibitory effects of repeated antenatal GC administration. Future research should clarify the role of IGF-I in the protein-catabolic response to GC. (Pediatr Res 62: 295-300, 2007)

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“…The biologic meaning of the inhibitory effect of arginine on whole-body protein turnover is as yet unexplained. Arginine suppressed protein synthesis despite increased insulin concentrations, which would be expected to stimulate protein synthesis (42). A possible explanation may lie in the organ-specific actions of arginine.…”

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confidence: 99%

Arginine and Mixed Amino Acids Increase Protein Accretion in the Growth-Restricted and Normal Ovine Fetus by Different Mechanisms

et al. 2005

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Protein metabolism may be perturbed in intrauterine growth restriction (IUGR). Arginine is indispensable for growth and nitrogen balance in young mammals. Fetuses with IUGR therefore may benefit from arginine supplementation. The purpose of this study was to determine 1) the effects of IUGR on protein metabolism in the ovine fetus and 2) the effects of arginine or mixed amino acid (AA) infusion on protein metabolism in these fetuses. Pregnant ewes and their fetuses were catheterized at 110 d gestation and randomly assigned to control or IUGR groups. IUGR was induced by repetitive placental embolization. Parameters of fetal protein metabolism were determined from [ring-2 H 5 ]phenylalanine kinetics at baseline and in response to a 4-h infusion of either arginine or an isonitrogenous AA mixture. There were no differences in protein metabolism between control and IUGR groups either at baseline or in response to arginine or AA treatment. Both arginine and AA infusion increased fetal protein accretion in both groups. Arginine did this by decreasing protein turnover, synthesis, and breakdown. AAs increased protein turnover and synthesis while decreasing protein breakdown. AA infusion resulted in a significantly higher increase in protein accretion than arginine infusion. Thus, in the ovine fetus, placental embolization has no clear effect on protein metabolism. Arginine and AAs both stimulate protein accretion but do so in distinctly different ways. Mixed AA infusion has a greater effect on protein accretion than arginine alone and therefore may be a better strategy for stimulating fetal growth. Intrauterine growth restriction (IUGR) is a major cause of perinatal mortality and morbidity (1,2). Although there are many possible causes, the key feature of IUGR is impaired fetal growth and, hence, by inference, impaired protein accretion. However, there are few data describing the alterations in protein metabolism that must underlie IUGR.In the IUGR human neonate, the few studies available are conflicting (3-5). Protein accretion rates are reported to be normal, although both increased (3,4) and reduced (5) protein synthesis and turnover have been reported. A previous study on protein kinetics in the ovine fetus in which growth was restricted by heat stress showed no significant changes in protein synthesis, breakdown, or accretion (6). However, a number of reports provide indirect evidence of altered protein metabolism in human fetuses with IUGR. In human pregnancies that are complicated with IUGR, fetal plasma AA concentrations are reduced (7,8), and this persists after birth (9). Concentrations of most essential AAs are lower, particularly those of the branched-chain AAs valine, isoleucine, and leucine (7,9). The maternal plasma AA concentrations are higher than in uncomplicated pregnancies and often not significantly different from nonpregnant controls (8).There is also indirect evidence of impaired urea production in association with IUGR. Plasma and urinary urea levels are

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Protein anabolic effects of insulin and IGF-I in the ovine fetus

Cited by 44 publications

References 54 publications

Prolonged infusion of amino acids increases leucine oxidation in fetal sheep

Prolonged infusion of amino acids increases leucine oxidation in fetal sheep

Transient Catabolic State with Reduced IGF-I after Antenatal Glucocorticoids

Arginine and Mixed Amino Acids Increase Protein Accretion in the Growth-Restricted and Normal Ovine Fetus by Different Mechanisms

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