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Endocrinology, doi:10.1210/en.2006-0653
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Endocrinology Vol. 148, No. 3 1350-1358
Copyright © 2007 by The Endocrine Society

Placental Restriction of Fetal Growth Increases Insulin Action, Growth, and Adiposity in the Young Lamb

Miles J. De Blasio, Kathryn L. Gatford, I. Caroline McMillen, Jeffrey S. Robinson and Julie A. Owens

Research Centre for Reproductive Health (M.J.D., K.L.G., J.S.R., J.A.O.), Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, and Discipline of Physiology (I.C.M.), School of Molecular Biosciences, University of Adelaide, Adelaide, South Australia 5005, Australia

Address all correspondence and requests for reprints to: Professor Julie A Owens, Research Centre for Reproductive Health, Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia 5005, Australia. E-mail: julie.owens{at}adelaide.edu.au.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Most children who are short or light at birth due to intrauterine growth restriction (IUGR) exhibit accelerated growth in infancy, termed "catch-up" growth, which together with IUGR, predicts increased risk of type 2 diabetes and obesity later in life. Placental restriction (PR) in sheep reduces size at birth, and also causes catch-up growth and increased adiposity at 6 wk of age. The physiological mechanisms responsible for catch-up growth after IUGR and its links to these adverse sequelae are unknown. Because insulin is a major anabolic hormone of infancy and its actions are commonly perturbed in these related disorders, we hypothesized that restriction of fetal growth would alter insulin secretion and sensitivity in the juvenile sheep at 1 month, which would be related to their altered growth and adiposity. We show that PR impairs glucose-stimulated insulin production, but not fasting insulin abundance or production in the young sheep. However, PR increases insulin sensitivity of circulating free fatty acids (FFAs), and insulin disposition indices for glucose and FFAs. Catch-up growth is predicted by the insulin disposition indices for amino acids and FFAs, and adiposity by that for FFAs. This suggests that catch-up growth and early-onset visceral obesity after IUGR may have a common underlying cause, that of increased insulin action due primarily to enhanced insulin sensitivity, which could account in part for their links to adverse metabolic and related outcomes in later life.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
EARLY LIFE FACTORS, reflected in patterns of prenatal and postnatal growth, can account for a significant proportion of the metabolic or insulin resistance syndrome in adults (1). Thus, intrauterine growth restriction (IUGR), evident as reduced weight, reduced length, and/or increased thinness at birth for gestational age is common, and predicts an increased risk of insulin resistance, type 2 diabetes, obesity, and related disorders in adult life (2, 3, 4). Most IUGR infants (57–84%) also exhibit accelerated growth in the first few months of life, termed "catch-up" growth (5). This catch-up growth independently predicts a greater risk of subsequently developing type 2 diabetes and cardiovascular disease (6, 7, 8, 9), and it has been suggested that this may be mediated in part via early development of increased adiposity, which catch-up growth also predicts (7, 8). The mechanisms linking catch-up growth after IUGR and its adverse metabolic sequelae including increased adiposity are unknown, however.

In infancy, insulin is essential for growth, and acute post-prandial increases in insulin, and its stimulation of amino acid uptake and protein synthesis and inhibition of protein breakdown can account for much of the increased protein accretion responsible for soft tissue growth in the neonate (10). Insulin also promotes triglyceride synthesis and storage in adipose tissue, as well as long bone growth through chondrocyte proliferation and hypertrophy (10, 11). In the IUGR infant, plasma insulin concentrations are low at birth and remain so for the first 6 months of life, compared with those of infants of average size at birth (12, 13, 14, 15, 16, 17). However, those IUGR infants undergoing catch-up growth have increased insulin secretion in response to glucose at 6 months of age, suggesting that catch-up growth is influenced and perhaps limited by insulin abundance (12). Alternatively, this apparent increase in stimulated insulin secretory response could reflect insulin resistance, although this would be unlikely to contribute to catch-up growth. Therefore, we suggest that increased sensitivity to, rather than increased production of insulin, accelerates neonatal growth after IUGR. Consistent with this, two studies report that IUGR infants display evidence of increased insulin sensitivity in the first few days or weeks of life (17, 18). If increased insulin action on glucose metabolism in liver and skeletal muscle occurs in IUGR infants and extends to amino acid and protein metabolism in these tissues and to glucose and lipid metabolism in adipose tissue, this may increase adiposity, as well as growth, and initiate the progression to later metabolic disease.

To examine this possibility, IUGR was induced in the sheep by restricting placental growth and function. Placental insufficiency is a major cause of IUGR in human beings (19), and placental restriction (PR) causes similar metabolic, endocrine, and growth consequences for the fetal sheep to those commonly observed in human IUGR and other species (19, 20). Furthermore, we have recently reported that PR reduces size at birth, and causes catch-up growth and increased adiposity following birth in the sheep (21). Therefore, we hypothesized that PR of fetal growth and small size at birth increase insulin sensitivity and action on glucose, amino acid, and lipid metabolism in the sheep following birth. Furthermore, we hypothesized that these determinants of insulin action on circulating amino acids and free fatty acids (FFAs) would correlate with growth and adiposity, respectively, in early postnatal life. To investigate this we have independently measured insulin sensitivity and secretion in placentally restricted and control lambs, together with growth rates and body composition.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and surgery
The Adelaide University Animal Ethics Committee (Animal Ethics Approval Number: M/1/97A) approved all procedures. Placental growth was restricted in 45 Merino ewes by removal of the majority of visible endometrial caruncles (range 65–148) from the nonpregnant uterus, leaving either three to eight caruncles in each horn of the bicornuate uterus (PR) (22). This reduces the number of placentomes formed in the subsequent pregnancy, and, hence, placental size and function. After a 10-wk recovery period, the restricted ewes were mated, together with 24 unoperated control ewes, with ultrasound confirming pregnancies. Ewes were housed in individual pens in animal holding rooms from approximately a week before giving birth, with a 12-h light/12-h dark cycle, and fed lucerne chaff twice daily ad libitum, with water ad libitum. Control ewes delivered 27 singleton lambs (17 males, 10 females), and the placentally restricted delivered 25 singleton lambs (11 males, 14 females). Lambs were housed in the pens with their mothers from birth and throughout the study. At approximately 5 d of age, catheters were inserted into the lamb’s femoral artery and vein under general anesthesia, induced and maintained by halothane inhalation anesthetic. All lambs received an im injection of Ilium Penstrep (procaine penicillin 250 mg/ml, dihydrostreptomycin 250 mg/ml, and procaine hydrochloride 20 mg/ml; Troy Laboratories Pty Ltd., Smithfield, New South Wales, Australia) before surgery and then at 7 d after surgery. Patency of the catheters in the lambs was maintained by flushing the catheters with 3 ml heparinized saline (500 U/ml) daily for 3 d after surgery and then every second day.

Measurement of growth
At birth (d 0) and at 5-d intervals up to 45 d of age, size at birth in terms of body weight, crown-rump length (CRL), tibia and metatarsal lengths, shoulder height, and abdominal (measured around the trunk and in line with the umbilicus of the lamb) and hind limb (measured equidistant between the proximal end of the fibula and lateral malleolus of the tibia) circumferences were measured. Body mass index (BMI) was calculated as weight/CRL2 (kg/m2), and ponderal index (PI), as weight/CRL3 (kg/m3). The absolute growth rates (AGRs) for all parameters were linear for 45 ± 3 d after birth and were determined by linear regression analysis within individual sheep. Neonatal fractional growth rate (NFGR) was calculated as the AGR from birth to 45 d of age for each parameter relative to the size of that parameter at birth. Subscript indicates the growth rate for a parameter (e.g. NFGR in terms of weight is designated as NFGRweight). In addition, current fractional growth rate at 1 month of age was calculated as the AGR of a parameter relative to its size at that age.

Insulin secretion in response to an iv glucose tolerance test (IVGTT)
At 35 ± 2 d of age, an IVGTT was performed on a subset of lambs (16 controls, 13 PRs). Lambs were fasted for 3 h before the experiment but were allowed water ad libitum. Arterial blood samples (2 ml) were taken at –5, –3, 0, 2, 5, 10, 15, 20, 25, 30, 40, 60, 70, 80, 90, 100, 120, 140, 160, 180, and 210 min. At 0 min, 0.25 g glucose per kg live weight was rapidly infused iv over 30 sec. Blood glucose concentration at each time was measured using a HemoCue glucometer (HemoCue AB, Ángelgolm, Sweden). The remaining blood was centrifuged, and plasma collected for subsequent measurement of plasma glucose and insulin concentrations. Fasting plasma glucose and insulin concentrations are the mean of the concentrations at the first three time points before glucose administration. Insulin secretion during the IVGTT was calculated as the area under the insulin concentration curve vs. time (23). Areas under the glucose and insulin curves, with the mean of the fasting concentrations as the baseline, were calculated using the Sigma Scan Pro version 4 image analysis software package (Jandel Scientific Software, San Rafael, CA).

Analysis of plasma glucose and insulin concentrations
The quantitative determination of plasma glucose was performed with a COBAS MIRA automated sample system using the Glucose HK assay kit (Roche Diagnostics, Castle Hill, New South Wales, Australia), with the calibrator for automated systems (C.f.a.s.), and quality controls Precinorm U and Precipath U (Roche Diagnostics). Plasma insulin was measured using a commercially available RIA kit for human insulin (Phadeseph; Pharmacia-Upjohn Diagnostics AB, Uppsala, Sweden).

Hyperinsulinemic euglycemic clamp (HEC) and insulin sensitivity of glucose metabolism
At 32 ± 2 d of age, a HEC was performed on the same subset of lambs as the IVGTT (16 controls, 13 PRs). Lambs were fasted for 3 h before the experiment but were allowed water ad libitum throughout. Arterial blood was sampled (2 ml) at –10, –5, and 0 min, and human insulin (Actrapid; Novo Nordisk A/S, Bagsvaerd, Denmark) was then continuously infused iv (2 mU/kg/min) and blood sampled (0.2 ml) every 5 min for 120 min. Blood glucose at each time point was measured using a HemoCue glucometer (HemoCue AB). At 15 min after the start of the insulin infusion, glucose (25%) was infused iv initially at 2 mg/kg/min. The glucose infusion rate (GIR) was then adjusted each 5 min after the measurement of blood glucose to maintain euglycemia at the fasting blood glucose concentration, using a modification of a previously published algorithm (24). The mean coefficient of variation in blood glucose during the second hour of the clamp was 2.6%. Plasma insulin was measured before the start of (–10, –5, and 0 min) and during the second hour of the HEC (60, 75, 90, 105, and 120 min) to determine the fasting plasma insulin concentration and the plateau plasma insulin concentration achieved, respectively. The insulin sensitivity of whole body glucose metabolism was determined as the mean GIR from 60–120 min (GIR60–120) during the HEC, divided by the mean plasma insulin concentration in the second hour of infusion measured every 15 min (23). The mean coefficient of variation for GIR60–120 in each lamb during the HEC was less than 8.3%.

Insulin sensitivity of circulating amino acids
Plasma {alpha}-amino nitrogen concentration was measured before and during the second hour of the HEC (–10, –5, 0, 60, 75, 90, 105, and 120 min) by colorimetric assay on these lambs (16 controls, 13 PRs) (25). Briefly, 100 µl plasma was deproteinized with 800 µl 0.04 M H2SO4 and 100 µl 0.3 M sodium tungstate. These were centrifuged for 15 min at 3000 x g, and the 100 µl supernatant collected and placed into a 96-well plate. To this, 24 µl sodium tetraborate (saturated, pH 9.6 with 5 M NaOH) and 20 µl 0.02 M ß-Naphthoquinone sulfonate was added, and the plate was incubated in a dry oven for 20 min at 80 C, then cooled in a –20 C freezer for 5 min. Water (120 µl), 36 µl acid formaldehyde (0.6 M HCl, 0.045 M HCHO), and 20 µl 0.05 M sodium thiosulfate were added and incubated again at room temperature for 30 min. The absorbance was read at 490 and 690 nm on an ELISA plate reader. The insulin sensitivity of circulating amino acids was calculated as the percentage change from fasting plasma {alpha}-amino nitrogen concentrations to those during the second hour of the HEC, corrected for the plateau plasma insulin concentration ({alpha}-aN60–120').

Insulin sensitivity of circulating FFAs
Plasma FFA concentration was measured before and during the second hour of the HEC (–10, –5, 0, 60, 75, 90, 105, and 120 min) by enzymatic colorimetric analysis using a commercially available kit (Wako Pure Chemical Industries, Osaka, Japan) (intraassay coefficient of variation, 4%). The insulin sensitivity of circulating FFA was calculated as the percentage change from fasting FFA concentrations to those during the second hour of the HEC, corrected for the plateau plasma insulin concentration (FFA 60–120).

Insulin clearance and post-hepatic insulin secretory rate
Insulin clearance was calculated as the rate of insulin infusion during the HEC divided by the plateau plasma insulin concentration achieved in the second hour of the clamp (23). Post-hepatic insulin secretory rate in the fasting state was calculated as the fasting plasma insulin concentration before the IVGTT multiplied by the insulin clearance rate (23). Post-hepatic insulin secretory rate in the stimulated state was calculated as the maximal plasma insulin concentration after glucose administration during the IVGTT, multiplied by the insulin clearance rate (23).

Disposition index
The disposition index is a measure of insulin action reflecting both insulin abundance and sensitivity, and was calculated for glucose, amino acid, and FFA metabolism as the post-hepatic insulin delivery rate in the fasting or stimulated state multiplied by the insulin sensitivity of glucose metabolism, or circulating amino acids or FFA (23). The insulin disposition index provides a more accurate and unbiased assessment of insulin secretory capacity than fasting or glucose-stimulated plasma insulin concentrations alone because it provides a measure of whether insulin secretion is appropriate given the individual’s insulin sensitivity (26).

Postmortem
At approximately 43 ± 2 d of age, a subset of the lambs (9 controls and 7 PRs) was killed by iv administration of an overdose of barbiturates (Pentobarbitone, Lethabarb; Virbac Pty. Ltd, Peakhurst, New South Wales, Australia). All organs were removed, and weighed and measured. Fat depots that could be accurately dissected were weighed (retroperitoneal, perirenal, and omental). Visceral fat weight was calculated as the sum of these three fat depots.

Statistical analysis
Data are expressed as mean ± SEM, unless otherwise stated. The effects of PR and gender were assessed by two between factor ANOVA (SPSS 13 software package for Windows; SPSS, Inc., Chicago, IL). One-sided Pearson correlation analyses (SPSS 13 software package for Windows) were used to test the following a priori hypotheses: 1) small size at birth would positively predict insulin sensitivity and action on glucose, amino acid, and lipid metabolism in the neonatal lamb; 2) insulin action on amino acid metabolism would predict neonatal growth rate; and 3) insulin action on lipid metabolism would predict adiposity in the young lamb. Multiple linear regression analysis (SPSS 13 software package for Windows) was used to test the a priori hypothesis that small size at birth and rapid neonatal growth would independently and positively predict adiposity. Hyperbolic decay (2 parameter) curves and overall mean with bidirectional error bars were fitted to the relationships between insulin sensitivity and fasting or stimulated post-hepatic insulin secretion rates (shown in Fig. 2Go), with the equation of the hyperbolic curve in the form y = a * b/(b + x) (Sigmaplot 9 for Windows; SPSS, Inc.). Statistical significance was assumed at P < 0.05.


Figure 2
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  		FIG. 2. The effect of PR on plasma glucose and insulin secretion in response to an IVGTT in young lambs. Mean plasma glucose (A) and plasma insulin (B) concentration curves from IVGTTs (0.25 g/kg glucose bolus) are shown for controls (open circles) and placentally restricted (solid circles) from baseline (–5, –3, and 0 min) to 210 min, with the glucose bolus administered at 0 min. Data are presented as mean ± SEM, determined by addition of time as a repeated measure factor (22 levels) by ANOVA. Individual contrasts are shown: *, P < 0.05 for control compared with placentally restricted.

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effect of PR on size at birth, postnatal growth, and adiposity
PR reduced weight (–21%, P < 0.001), abdominal circumference (–10%; P < 0.001), hind limb circumference (–13%; P < 0.001), and CRL (–9%; P < 0.001) at birth (Table 1Go). PR also reduced the length of long bones at birth (–5% for all), as well as skull width and length (P < 0.05 for both). At 30 d of age, the placentally restricted lambs were smaller than controls in terms of weight, abdominal and hind limb circumference, CRL, shoulder height, and skull width than controls (P < 0.05 for all) (Table 1Go) but had caught up in terms of all size parameters, with the exception of skull width, by 45 d of age (Fig. 1Go). PR increased AGR for skull length (+43%) and increased neonatal FGR for weight (+29%), abdominal circumference (+18%), CRL (+17%), skull length (+48%), and current FGR for weight (+9%), abdominal circumference (+13%) and skull length (+46%) (P < 0.05 for all) (Table 2Go). PR did not affect the AGR, FGR, and current FGR for all other parameters of growth. Weight, CRL, skull width, shoulder height, tibia and metatarsal length, and abdominal circumference at birth were greater in males than females (P < 0.05 for all; data not shown).


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  		TABLE 1. The effect of experimentally induced PR on size at birth and at 1 month of age in sheep

 

Figure 1
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  		FIG. 1. The effect of PR on postnatal growth in lambs. Controls shown as open circles, placentally restricted shown as closed circles. Data shown as mean ± SEM. *, P < 0.05.

 

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  		TABLE 2. Effect of PR on postnatal growth of lambs

 
Effect of PR on fasting and plateau plasma metabolites and glucose tolerance
PR increased fasting plasma {alpha}-amino nitrogen concentrations (P < 0.05) but did not alter fasting plasma glucose or FFAs concentrations in lambs at 30 d of age (Table 3Go). It did not alter the plateau plasma glucose or FFAs but increased the plateau plasma {alpha}-amino nitrogen (P < 0.05). PR did not alter the change in glucose FFAs or {alpha}-amino nitrogen concentrations (Table 3Go). It reduced the maximum plasma glucose concentration and reduced the rate of glucose clearance from 30–50 min after the glucose bolus (Fig. 2Go). PR did not alter the area under the glucose curve during IVGTT (Fig. 2Go).


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  		TABLE 3. Effect of PR on plasma insulin and metabolite concentrations, and insulin sensitivity in the young lamb

 
Effect of PR on insulin abundance, sensitivity, and action
PR did not alter fasting plasma insulin concentrations but reduced glucose stimulated insulin secretion for the first 15 min after administration of the glucose bolus during the IVGTT (Fig. 2Go and Table 3Go). PR did not alter fasting post-hepatic insulin secretory rate but reduced the stimulated post-hepatic insulin secretory rate (Table 3Go). It did not alter the insulin sensitivities of glucose metabolism and circulating amino acids but increased that of circulating FFAs (+21%; P < 0.05). PR also increased the fasting insulin disposition indices for glucose and FFAs (P < 0.05), and tended to reduce the stimulated disposition indices for glucose and amino acids.

The fasting post-hepatic insulin delivery rate was negatively correlated with insulin sensitivity of glucose metabolism in a hyperbolic fashion, particularly in PR lambs (r = 0.62; P = 0.006) (Fig. 3AGo), as was the stimulated post-hepatic insulin delivery rate (controls: r = 0.90, P = 0.01; PR: r = 0.93, P = 0.001) (Fig. 3BGo).


Figure 3
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  		FIG. 3. Relationship between fasting and stimulated post-hepatic insulin secretory rate, and insulin sensitivity of glucose metabolism in control and placentally restricted lambs. Individual values and mean ± SEM shown for controls (open circles, dashed line) and placentally restricted (closed circles, solid line). The following predictive models were obtained by regression analysis. A, Controls: post-hepatic insulin delivery rate x (0.13 + insulin sensitivity of glucose metabolism) = 64.8, r = 0.44, P = 0.076. Placentally restricted: post-hepatic insulin delivery rate x (0.066 + insulin sensitivity of glucose metabolism) = 51.4, r = 0.62, P = 0.006. B, Controls: stimulated post-hepatic insulin delivery rate x (0.27 + insulin sensitivity of glucose metabolism) = 1348, r = 0.90, P = 0.01. Placentally restricted: stimulated post-hepatic insulin delivery rate x (0.46 + insulin sensitivity of glucose metabolism) = 1157, r = 0.93, P = 0.001.

 
Size at birth, insulin abundance, sensitivity, and disposition indices
Insulin sensitivity of glucose metabolism, circulating amino acids, and FFAs each correlated negatively with birth weight (r = –0.53, r = –0.58, r =–0.46, respectively; P < 0.001 for all).

The fasting insulin disposition index for glucose also correlated negatively with weight (r = –0.63; P = 0.001) and thinness (PI: r = –0.46, P = 0.006; BMI: r = –0.63, P = 0.001) at birth. The stimulated insulin disposition index for glucose similarly correlated negatively with thinness at birth (PI: r = –0.35, P = 0.04; BMI: r = –0.33, P = 0.05). The fasting insulin disposition index for amino acids correlated negatively with weight (r = –0.28; P = 0.05) and thinness (BMI: r = –0.28, P = 0.05) at birth.

Postnatal growth, adiposity and insulin abundance, sensitivity, and disposition indices
Neonatal and current FGR for weight each correlated positively with the insulin disposition indices for glucose (r = 0.58, n = 29, P < 0.001; r = 0.58, n = 29, P < 0.001, respectively), amino acids (r = 0.27, n = 28, P = 0.05; r = 0.28, n = 28, P < 0.05, respectively), and FFAs (r = 0.42, n = 28, P = 0.015; r = 0.42, n = 28, P < 0.05, respectively).

PR did not alter weight, CRL, or BMI at 45 d of age (Table 4Go). It increased total perirenal fat in absolute terms and relative to body weight at 45 d of age (P < 0.05 for both). PR also increased omental fat weight relative to body weight (P < 0.05) (Table 4Go). It increased visceral fat (perirenal, retroperitoneal, and omental fat) in absolute, and relative, terms (P < 0.05 for both).


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  		TABLE 4. Effect of PR on body size and fat mass at 45 d of age in the young lamb

 
Total visceral fat weight was not related to birth weight (partial correlation: r = –0.088, P = 0.104) but was positively predicted by NFGRweight (partial correlation, r = 0.411; P = 0.034) in control and placentally restricted lambs combined (overall, r = 0.595; P = 0.091; n = 14). The basal insulin disposition index for FFAs predicted total visceral fat (r = 0.90; n = 7; P = 0.003).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study has demonstrated that experimentally restricting placental growth in the sheep, which reduces size at birth and increases early postnatal growth rate, also increases adiposity, at 6 wk of age, consistent with observations in human infants with IUGR (8). PR did not alter BMI of the young sheep, probably reflecting the decrease in muscle mass that occurred concomitant with increased adiposity (21). Furthermore, PR increases insulin action on glucose and FFA metabolism in the young lamb. This is due primarily to increases in insulin sensitivity after PR and small size at birth, rather than enhanced insulin production, also consistent with previous observations in infants that were IUGR (17, 18). Notably, it was insulin sensitivity and insulin action on circulating FFAs that were most enhanced by PR in the young lamb, and the latter was predictive of increased visceral fat. Although circulating FFAs were not clamped during the insulin infusion, the positive relationship between fat deposition and insulin action to suppress circulating FFAs also suggests that the FFA response to insulin reflects primarily increased fatty acid uptake, rather than decreased production. This enhanced insulin action on FFA metabolism in the young lambs after PR may directly contribute to the observed increase in their visceral adiposity. The latter has been observed in IUGR children, in lambs small-at-birth due to multiple pregnancies, and in juvenile offspring in other species that were small at birth (7, 8, 27, 28, 29, 30, 31, 32). If this excess accretion and storage of fat persists, as is evident in adult human beings who are IUGR (8), it may partly account for their adverse metabolic and cardiovascular outcomes (33, 34, 35, 36). Catch-up growth, but not size at birth, independently predicted adiposity in the juvenile lamb. This is consistent with observations for children and adults who were IUGR, in whom both small size at birth is predictive of reduced lean tissue mass, while catch-up growth is predictive of overall obesity in later life (37, 38). In the present study, in placentally restricted lambs only, both small size at birth and catch-up growth were associated with heavier fat depot weights (data not shown). The mechanistic basis of this link between catch-up growth in infancy and later obesity has not been determined, but our observations suggest a common basis in enhanced insulin sensitivity of skeletal muscle, which accounts for much of body mass, and adipose tissue. Thus, catch-up growth in terms of soft tissues after IUGR was substantially predicted by insulin action on amino acid metabolism. This suggests that both components of insulin action, metabolic insulin sensitivity and insulin abundance, are important determinants of catch-up growth because the latter may limit the extent to which it can occur. Despite accelerated growth after birth, the placentally restricted young sheep still has reduced skeletal muscle mass (21), suggesting incomplete catch-up possibly due to limitations of insulin abundance or the intrinsic capacity of the tissue itself. The association between catch-up growth in infancy and later obesity and metabolic disease may, therefore, reflect a common underlying cause, that of a generalized enhancement of sensitivity to insulin in adipose tissue and those tissues accounting for much of body weight in early life.

PR did not affect the fasting plasma insulin and fasting post-hepatic insulin secretory rate in the young lamb; however, insulin secretion, as assessed from the response to a glucose load or stimulated post-hepatic insulin secretory rate, was reduced in the placentally restricted lamb. This is consistent with observations in human IUGR infants (12, 18) and suggests that increased insulin abundance in the fasting state at least was not contributing to increased insulin action and catch-up growth or increased adiposity. This finding implies that in the sheep, as shown in the rat and observed in human beings, prenatal restriction impairs ß-cell responsiveness to glucose stimulation or secretory capacity and, hence, insulin secretion in the post-prandial state in early postnatal life (12, 18, 39). However, the accurate assessment of insulin secretion requires concomitant independent estimates of insulin sensitivity. Here we show that insulin production in the fasting state is related to insulin sensitivity of glucose metabolism in a hyperbolic fashion in the young lamb, with insulin secretion increasing as insulin sensitivity decreases (Fig. 3AGo), as we have previously reported in the adult sheep (23) and as occurs in human beings (40, 41, 42). This relationship was present in both control and placentally restricted lambs, suggesting little or no impairment of insulin production in the latter in the fasted state. In contrast, at any given level of insulin sensitivity, glucose-stimulated insulin secretion appeared to be lower in placentally restricted than in control lambs (Fig. 3BGo), resulting in a tendency for a lower insulin disposition index for glucose metabolism in the stimulated state. Therefore, PR induces a defect in nutrient-stimulated insulin secretion in early postnatal life, consistent with the placentally restricted juvenile rat, and IUGR infants and young adults (12, 18, 39, 43). Furthermore, this defect in insulin secretion after PR has emerged before any onset of insulin resistance, as has been described in young adults with IUGR (44). It has also been long recognized that impairment of the first phase glucose-stimulated insulin secretion is associated with an early sign of ß-cell dysfunction in type 2 diabetic patients (45, 46, 47). Nevertheless, PR did not alter glucose tolerance in the juvenile lamb, suggesting that the onset of insulin resistance will be required before impairment of glucose control becomes evident.

The factors responsible for this impaired insulin secretion coupled with enhanced insulin action in the young lamb after PR are unknown, but some aspect of the altered metabolic and endocrine environment before birth is presumably responsible. The placentally restricted fetal sheep is hypoxemic and hypoglycemic, with elevated circulating cortisol and reduced plasma concentrations of insulin, insulin-like growth factors I and II, thyroid hormones, and prolactin (48, 49, 50, 51, 52). Both cortisol and thyroid hormones have well-established roles in modulating the development of numerous tissues, including the pancreas, skeletal muscle, and liver before and after birth (53, 54, 55, 56). The impaired stimulated insulin secretory capacity evident in the placentally restricted lamb may be due to reduced ß-cell mass and ß-cell altered responsiveness to secretagogues. IGF-II is a ß-cell survival factor, and we have shown previously that the placentally restricted fetal sheep has reduced plasma levels and tissue expression of IGF-II (20, 49). This, together with the increased circulating cortisol of the placentally restricted fetus, would be expected to decrease proliferation and increase apoptosis of ß-cells and reduce ß-cell mass. Whether chronic PR persistently alters ß-cell functional capacity in the sheep is yet to be determined. Certainly, PR imposed late in gestation in the rat programs increased oxidative stress and mitochondrial dysfunction in islets from postnatal offspring, who go on to develop diabetes in adulthood (57). Glucocorticoids have also affected insulin stimulated GLUT4 recruitment to the surface of skeletal muscle cells and, hence, decreased glucose uptake in the rat (58). The increased exposure to cortisol prenatally in the placental restricted lamb may, therefore, increase the abundance of insulin targets and, hence, the response to insulin in late gestation, which might persist in early postnatal life. Another mechanism may be via effects on skeletal muscle development because both cortisol and thyroid hormones influence differentiation of myofibers. IUGR has altered the development and function of skeletal muscles in pigs at birth, increasing the proportion of type 1 muscle fibers (59), which are more insulin sensitive than type 2 fibers. If this pattern persists, it may partly underlie the increased metabolic sensitivity to insulin observed here in the young IUGR lamb.

In conclusion, this study has shown that experimental PR reduces size at birth, and increases the neonatal growth rate of soft and skeletal tissues and visceral adiposity in the young lamb. Furthermore, catch-up growth predicts increased visceral adiposity of the latter. PR impairs insulin production but increases insulin sensitivity of circulating FFAs and insulin’s metabolic actions more generally. Because insulin action on glucose and amino acid metabolism substantially predicted neonatal catch-up growth after fetal growth restriction, while insulin action on FFAs predicted visceral adiposity, increased insulin action in early postnatal life may be a common underlying cause and explain similar associations also observed in human IUGR. If the adverse sequelae of prenatal restriction, being increased visceral adiposity and impaired insulin secretion, persist, they may lead to and explain the links with adverse metabolic outcomes and diabetes in later life.


   Acknowledgments
 
We thank Simon Fielke, Frank Carbone, Dr. Tim Butler, Dr. Mike Adams, and Anne Jurisevic for the removal of endometrial caruncles from ewes, and Linda Mundy and Damian Adams for their help with assays.


   Footnotes
 
This project was funded by a National Health & Medical Research Council (NH&MRC) of Australia project grant and partially funded by an Australian Research Council small grant. K.L.G. was supported by a Peter Doherty Postdoctoral Fellowship from the NH&MRC and the Hilda Farmer Medical Research Associateship from the University of Adelaide.

Disclosure Statement: The authors have nothing to disclose.

First Published Online November 16, 2006

Abbreviations: AGR, Absolute growth rate; BMI, body mass index; CRL, crown-rump length; FFA, free fatty acid; GIR, glucose infusion rate; HEC, hyperinsulinemic euglycemic clamp; IUGR, intrauterine growth restriction; IVGTT, iv glucose tolerance test; NFGR, neonatal fractional growth rate; PI, ponderal index; PR, placental restriction.

Received May 16, 2006.

Accepted for publication November 8, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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