![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
The Journal of Nutrition Vol. 128 No. 2 February 1998,
pp. 342S-346S
Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202
 |
ABSTRACT |
|---|
Abstract
References
|
|---|
Insulin is regarded as the primary fetal growth-promoting hormone, but direct in vivo experimental data supporting this conjecture are sparse. Data obtained from studies in in vivo, chronically catheterized fetal lambs under a variety of experimental circumstances demonstrate that glucose availability is the primary modulator of fetal protein accretion, via its ability to diminish amino acid catabolism. The ovine fetus is shown to be resistant to insulin-induced suppression of proteolysis, relative to the adult. Data from studies in the human premature infant show that the findings in the ovine fetus are similar to those in the ex utero premature human.
KEY WORDS: insulin · ovine fetus · leucine · tracer kinetics · human premature infant
Insulin has long been regarded as the primary fetal growth factor (McCormick et al. 1979
The first study (Liechty et al. 1991
In the first study, the insulin response to altered glucose was variable. Because the insulin and glucose concentrations were highly correlated, it was not possible to delineate effects as specific to glucose or insulin. Therefore, two additional studies were performed. In the first, insulin was "clamped" by fetal somatostatin infusion while glucose concentration was varied (Liechty et al. 1993 In the converse study, clamping glucose at basal levels while infusing insulin resulted in 44 and 100% increases of GUR (fed and fasted, respectively), with no change in glucose concentration. Insulin concentration was increased four- and sevenfold, respectively. Again, no change in leucine Ra was observed, but a large decrease in fetal leucine oxidation was observed in the fasted state only (Fig. 2C).
These three studies can be summarized as follows:
We have also compared protein metabolism in the ovine fetus with that in human premature infants by conducting a similar set of studies examining the effect of glucose and insulin on proteolysis in extremely premature newborns. Clinically stable, minimally stressed, extremely premature infants (approximately 26 wk gestation) were studied by using two glucose infusions [6.2 and 9.5 mg/(kg·min)] to determine whether an increase in glucose delivery suppresses proteolysis (as reflected by the rates of appearance of the essential amino acids phenylalanine and leucine) (Hertz et al. 1993
In summary, the results of our investigations suggest that proteolysis in the ovine fetus is remarkably resistant to suppression by insulin. This conclusion is supported by data from other investigators. In addition, this conclusion appears to be compatible with data obtained in postnatal premature human infants of similar gestational age, suggesting that this phenomenon is not unique to ruminants, nor simply a feature of in utero life, but a developmental feature of immature, growing organisms.
EVIDENCE OF INSULIN ACTION IN THE FETUS
, Susa et al. 1979). This belief has been based largely on circumstantial evidence such as large-for-gestational-age, hyperinsulinemic fetuses seen in maternal diabetes and Beckwith Weideman syndrome. In addition, the occasional infant born with pancreatic agenesis and hypoinsulinemia is uniformly small for gestational age (Lemons et al. 1979), and fetal pancreatectomy leads to intrauterine growth retardation (Fowden et al. 1989). Furthermore, growth hormone, a primary regulator of postnatal growth, is not believed to be important, because there is a paucity of growth hormone receptors in the fetus (Arosio et al. 1995, Gluckman 1995).
demonstrated decreased arterial concentration and increased fetal uptake of 
-amino nitrogen when the late-gestation ovine fetus was infused with exogenous insulin. The increased fetal amino acid uptake resulted in increased tissue synthesis, expansion of intracellular amino acid pools and increased catabolism, but the partitioning among these fates remains to be determined. They were not, however, able to document increased birth weight in fetal lambs infused chronically with insulin. Similarly, neither Stagenberg et al. (1981) nor Angervall et al. (1981) were able to show any increase in body or protein mass in rat fetuses injected with insulin during late gestation. Fetal pigs failed to show any significant growth response to insulin (Spencer et al. 1983). In contrast, Picon (1967) found a 10% increase in total body nitrogen in insulin-injected rat fetuses. Susa et al. (1979) found that chronic insulin infusion in the fetal rhesus monkey resulted in a significant 33% increase in body mass. Although chemical analysis of the carcasses was not performed, it can be presumed that the total body nitrogen was increased, although not likely to the same degree as body mass. The protein/DNA ratio was not changed, implying that any increase in lean body mass was mainly the result of tissue hyperplasia rather than hypertrophy.
). The placentas of these pups have diminished rates of protein breakdown but normal synthetic rates, with placentomegaly as the net result (Robinson et al. 1988). These findings are intriguing because it is generally held that fetal tissue responds to hyperinsulinemia by hypertrophy or hyperplasia (or both), whereas the placenta is generally not thought to be an insulin-sensitive organ. Further investigation is warranted to determine if these effects found in the rat can be demonstrated in other species.
, Shangraw et al. 1988, Fukagawa et al. 1989, Denne et al. 1991). Insulin-induced increases in protein synthesis are less consistent and appear to be highly dependent on experimental conditions (Castellino et al. 1987, Gelfand and Barrett 1987).
), as well as that of others (Van Veen et al. 1987), has demonstrated large increases in amino acid catabolism during fasting of the mother, a condition of hypoglycemia and hypoinsulinemia. Our overall hypothesis was that insulin would increase fetal protein accretion primarily by suppression of proteolysis, and secondarily by a decrease in amino acid catabolism, thereby indirectly increasing protein synthesis.
View larger version (22K):
[in a new window]
Fig 1.
General experimental protocol for ovine fetal studies described in this paper. Experimental procedures included fetal glucose infusion, fetal euglycemic hyperinsulinemia and normoinsulinemic hyperglycemia. Identical studies were performed under fed and maternal fasting conditions. Basal period measurements were compared with experimental period, and fed studies compared with fasted measurements by three-factor ANOVA.
View this table:
Table 1.
Experimental conditions of studies to delineate the independent effects of insulin and glucose on ovine fetal amino acid kinetics1
GLUCOSE EFFECTS ON FETAL
AMINO ACID KINETICS
) was designed to study the effect of substrate replacement in the fasted catabolic fetus, contrasted with the effect in fetuses of well-fed ewes. After obtaining basal kinetic measurements, glucose was infused into the fetus at 15 mg/min, a rate chosen to duplicate normal fetal umbilical glucose uptake. In the fed animals, glucose concentration increased by 30%, insulin by 22% and total glucose intake (umbilical + infused) by 30%. There was no effect on leucine Ra or on leucine oxidation. In the fasted state, glucose concentration doubled, and insulin increased by 72%, but total glucose intake was not significantly increased. Again, no change in leucine Ra was seen, but leucine oxidation, which was 1.3-fold higher in the fasted basal state compared with the fed state, decreased by 50%, returning to a rate similar to the fed basal state. These data are depicted in Figure 2A. This decline in oxidation resulted in a change from net catabolism to net accretion of leucine during the glucose infusion.
View larger version (30K):
[in a new window]
Fig 2.
Composite of data from three experiments in fetal lambs. Leucine rate of appearance (Ra) is depicted on the left and leucine oxidation is depicted on the right. The basal conditions are shown by open bars, experimental by solid bars (panel B, medium glucose infusion by hatched bars, high glucose infusion by solid bars).
EFFECT OF GLUCOSE INDEPENDENT
OF INSULIN
), whereas in the second, euglycemia was maintained while hyperinsulinemia was induced by fetal insulin infusion (Liechty et al. 1992).
EFFECT OF INSULIN INDEPENDENT
OF GLUCOSE
SUMMARY OF STUDIES IN EWES
).
). The kinetic model employed accounted for disposal of leucine tracer from the fetus to the placenta, which was not done in the previously mentioned experiments. This investigator was able to demonstrate a small decrease in leucine appearance from protein breakdown, in spite of a lack of significant change in total plasma leucine Ra. These data are contrasted with those from our comparable study in Figure 3. It is unclear whether the differences in the conclusions between these studies are the result of the model for analysis or differences in experimental protocols, or simply lack of adequate statistical power in our study. However, it is clear that any suppressive effect insulin may have on fetal proteolysis is not of the magnitude of that seen in postnatal subjects, in which suppression of proteolysis by 30% is commonly demonstrated.
View larger version (38K):
[in a new window]
Fig 3.
Comparison of data from experiments utilizing the euglycemic hyperinsulinemia protocol in ovine fetal lambs. The data of Milley (1994) were converted from µmol/(kg·min) to µmol/min by multiplying by the mean fetal weight reported in that study.
View larger version (20K):
[in a new window]
Fig 4.
Relative effects of insulin concentration or glucose concentration on ovine fetal leucine oxidation. Data are aggregated from a series of four studies (Liechty et al. 1991 , 1992, 1993 and 1996). There is no correlation between insulin and leucine oxidation, whereas a significant correlation exists between glucose concentration and leucine oxidation.
HUMAN STUDIES
). Although increases in glucose delivery resulted in clear increases in glucose utilization, substantial reductions in endogenous glucose production and threefold increases in insulin concentration, there was no change in whole-body proteolysis in these extremely premature infants (Fig. 5). Additional studies conducted in full-term newborns in the first few days of life have demonstrated that two- to threefold increases in insulin concentration produced by intravenous infusions of glucose and/or lipid result in no change in whole-body proteolysis (Denne et al. 1995). Changes in insulin concentration of this magnitude have consistently produced reductions in whole-body proteolysis in adult subjects (Flakoll et al. 1989, Shangraw et al. 1988, Tessari et al. 1986). Thus, human premature and term newborns, like the ovine fetus, appear to be resistant to the antiproteolytic effects of insulin, at least at low-to-moderate insulin concentrations.
View larger version (15K):
[in a new window]
Fig 5.
Rates of appearance of leucine and phenylalanine in extremely premature human infants during exogenous glucose infusion; increment in insulin concentration is also depicted.
). The rates of appearance of leucine and phenylalanine were measured in premature infants (26-wk gestation) before and during euglycemic hyperinsulinemia. Insulin concentrations were increased 11-fold during exogenous insulin infusion, and whole-body proteolysis was reduced by 18%. Thus, as in the ovine fetus, supraphysiologic concentrations of insulin may reduce proteolysis in extremely premature infants, although perhaps not to the same degree as that observed in adult subjects (Tessari et al. 1986).
CONCLUSIONS
| |
FOOTNOTES |
|---|
| |
LITERATURE CITED |
|---|
Abstract
References
|
|---|
This article has been cited by other articles:
|
|
 |
|
  W. Shen, P. Wisniowski, S. C. Denne, D. W. Boyle, and E. A. Liechty Anabolic effects of insulin and IGF-I in the ovine fetus are reduced by prolonged maternal fasting Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E907 - E913. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Shen, P. Wisniowski, L. Ahmed, D. W. Boyle, S. C. Denne, and E. A. Liechty Protein anabolic effects of insulin and IGF-I in the ovine fetus Am J Physiol Endocrinol Metab, April 1, 2003; 284(4): E748 - E756. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
