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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 2 402-406
Copyright © 1997 by The Endocrine Society

Pediatric Endocrinology

Insulin Resistance in Short Children with Intrauterine Growth Retardation1

Paul L. Hofman, Wayne S. Cutfield, Elizabeth M. Robinson, Richard N. Bergman, Ram K. Menon, Mark A. Sperling and Peter D. Gluckman

Department of Pediatrics (P.L.H., W.S.C., P.D.G.) and the Health Research Council Biostatistics Unit, Department of Community Health (E.M.R.), University of Auckland, Auckland, New Zealand; the Department of Physiology and Biophysics, University of Southern California (R.N.B.), Los Angeles, California 90089; and the Department of Endocrinology, Children’s Hospital of Pittsburgh (R.K.M., M.A.S.), Pittsburgh, Pennsylvania 15260

Address all correspondence and requests for reprints to: Dr. Wayne Cutfield, Department of Pediatrics, University of Auckland, Private Bag 92019, Auckland, New Zealand.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Epidemiological studies have demonstrated an association between intrauterine growth retardation and an increased risk of adult diseases that include essential hypertension, noninsulin-dependent diabetes mellitus, and ischemic heart disease. A common feature of these diseases is insulin resistance.

To investigate whether abnormal insulin sensitivity was a characteristic of subjects with intrauterine growth retardation (IUGR), we compared two groups of short prepubertal children: a group with IUGR (birth weight less than the tenth percentile; n = 15) and a normal birth weight group (n = 12). Subjects underwent a modified frequently sampled iv glucose tolerance test that permitted calculation of the acute insulin response, insulin sensitivity index, and glucose effectiveness.

A marked difference in the insulin sensitivity index was noted between groups, with the IUGR group being less insulin sensitive [6.9 vs. 16.9 10-4 min-1·(µU/mL); P = 0.0048]. The acute insulin response was also significantly different between groups, with IUGR subjects having higher insulin levels (445 vs. 174 µU/mL; P = 0.005). There was no difference in glucose effectiveness between groups.

Short prepubertal IUGR children have a specific impairment in insulin sensitivity compared to their normal birth weight peers. In short IUGR children, impaired insulin sensitivity is a potential marker for the early identification and intervention in the development of late adult-onset noninsulin-dependent diabetes mellitus.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INTRAUTERINE growth retardation (IUGR) is a common condition associated with sequelae during childhood that include both short stature and a higher incidence of learning and behavioral difficulties (1, 2, 3, 4, 5, 6, 7, 8). The possibility that adverse intrauterine or early postnatal events could influence diseases in later life is a relatively new concept. In 1985, a correlation was shown between higher systolic blood pressures in adult men and low birth weight (9). Subsequently, Barker et al. extended these observations, exploring the relationship between birth weight and adult morbidity and mortality (10, 11, 12, 13). Significant relationships were observed between indexes of abnormal fetal growth and the development of a variety of adult diseases, including essential hypertension, noninsulin-dependent diabetes mellitus (NIDDM), and ischemic heart disease. Reduced insulin sensitivity is a feature shared by all of these diseases and is present before overt disease is apparent (14, 15, 16).

The increased risk of these adult-onset diseases in individuals born with evidence of disordered fetal growth suggests that early life events may have profound and long lasting effects. It has been postulated that fetal adaptation to an adverse intrauterine environment involves altered programming of endocrine pathways, leading to permanent metabolic changes, including reduced insulin sensitivity (10). Many of the later adult sequelae could be explained as a consequence of this change in insulin sensitivity. The aim of this study was to determine whether a difference in insulin sensitivity was present during childhood between short children with IUGR and short children of normal birth weight.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
All subjects were recruited from the Endocrine Clinics of Starship Children’s Hospital and were being evaluated for short stature. Enrollment criteria for study entry included height less than the fifth percentile (17), prepubertal sexual development, normal GH response to clonidine stimulation (defined as a GH level >7 µg/L), absence of acute or chronic illness, and absence of both islet cell antibodies (<=10 Juvenile Diabetes Foundation units), and insulin autoantibodies to exclude type 1 prediabetes. Subjects were excluded if a chromosomal, intrauterine infection or syndromal cause for intrauterine growth retardation was identified (with the exception of Russell Silver syndrome), a first degree relative had NIDDM, or medical therapy known to influence insulin sensitivity was being used. IUGR was defined as a birth weight less than the 10th percentile for gestational age (17). Birth weight and height were converted into SD scores to adjust for age and sex. Midparental height was calculated and similarly converted to a SD score. The weight for length index (18, 19) was used to provide an age-adjusted evaluation of relative obesity. Ideal body weight was defined as a weight for length index of 100% (normal range, 80–120%), with obesity above 120% and extreme thinness below 80%.

Study protocol

The study was reviewed and approved by the North Health Ethics Committee, and informed consent was obtained from parents. After an overnight fast, a modified frequently sampled iv glucose tolerance test (FSIGT) with tolbutamide was performed on all subjects (20). Subjects were admitted to the Daystay Unit at the Starship Children’s Hospital, where two iv catheters were inserted, one for sampling and the other for drug administration. Three baseline samples were drawn at -20, -10, and 0 min. An iv rapid infusion of 25% dextrose (0.3 g/kg) was administered over 30 s at time zero, with further samples being drawn at 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 19 min. An iv rapid infusion of tolbutamide (5 mg/kg) was administered over 30 s at 20 min. Further samples were drawn at 22, 23, 24, 25, 27, 30, 35, 40, 50, 60, 70, 80, and 90 min. The blood volume was 1.5 mL/sample.

Blood was collected in chilled tubes containing sodium heparin. After completion of the study, the blood samples were centrifuged, and the plasma was separated and frozen for later analysis. Plasma glucose and insulin levels were measured in all samples. Magnesium and potassium were measured at 0, 19, 40, and 90 min, and cholesterol, triglyceride, and fructosamine were measured at baseline.

Assays

Plasma glucose, fructosamine, magnesium, potassium, cholesterol, and triglyceride were measured using a Hitachi 911 automated random access analyzer (Tokyo, Japan) (21, 22, 23). The interassay coefficient of variation was 1.2–3% for all analytes. Insulin was determined by an established double antibody RIA technique (interassay coefficient of variation, 10.5%). Islet cell antibodies were measured by indirect immunofluorescence (24), and insulin autoantibodies were determined by a competitive RIA (25).

Calculations

Glucose and insulin measurements were analyzed using Bergman’s MINMOD software to determine the insulin sensitivity index (SI) and glucose effectiveness. Insulin sensitivity reflects the ability of insulin to increase net glucose disposal, whereas glucose effectiveness is a measure of glucose’s ability to enhance its own disposal and suppress its production at basal insulin levels. The model has been well described previously and validated extensively for both SI and glucose effectiveness (26, 29, 30). In the abbreviated FSIGT protocol, the 180 min value was replaced by the time zero value, as validated in children by Cutfield et al. (20).

The acute insulin response, an estimation of first phase insulin release, was calculated as the total insulin response during the first 10 min after the dextrose bolus corrected for the baseline insulin value (31). The glucose disappearance coefficient was calculated from the slope of the natural logarithm of glucose concentration between 10 and 19 min (32). To determine potential factors influencing SI, the original data collected from a previous study that we had performed investigating SI in normal prepubertal subjects were reanalyzed to investigate associations with height SD score, weight for length index, age, and sex (20).

Statistical analysis

Analyses were carried out using the statistical package SAS (version 10) for personal computers. Multiple analyses of covariance were performed, using transformations where appropriate, to investigate the differences in SI, glucose effectiveness, the glucose disappearance coefficient, and the acute insulin response between the two subject groups. Age, gender, gestational age, height SD score, weight for length index, and midparental height SD score were used as covariates. A separate repeated measures analysis was carried out on both potassium and magnesium levels to investigate differences between groups throughout the FSIGT. The acute insulin response was included as a covariate in the analysis. P < 0.05 was defined as significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The study consisted of 27 children, 15 IUGR subjects, and 12 normal birth weight subjects who fulfilled the enrollment criteria. Table 1Go describes the IUGR and normal birth weight control groups. Height SD score, weight for length index, midparental height SD score, race, and sex distributions were remarkably similar between groups. Although not significant, the IUGR group were slightly older. The older age of this group should not have influenced insulin sensitivity measurements, which have previously been shown to be unaffected by age in the prepubertal range 5–12 yr (20).


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  		Table 1. Clinical characteristics of the study groups

 
Using multiple analyses of covariance, the IUGR group were far less insulin sensitive than their normal birth weight peers (P = 0.0048; see Table 2Go). Throughout the FSIGT, the plasma glucose profiles were very similar between the two groups (see Fig. 1aGo); however, there was a striking difference in plasma insulin profiles, as shown in Fig. 1bGo. No differences were seen between groups for either glucose effectiveness or the glucose disappearance coefficient. As SI and the acute insulin response are inversely related, the acute insulin response was predictably different between groups (P = 0.005), with the IUGR group having larger values.


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  		Table 2. Characteristics of glucose and insulin regulation in the study groups

 


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  		Figure 1. Glucose (a) and insulin (b) profiles during the FSIGT for normal (closed boxes) and IUGR (open circles) children, expressed as the mean ± SEM.

 
As previously demonstrated by Bergman et al. (33), the relationship between SI and acute insulin response was hyperbolic (1/acute insulin response vs. SI; r = 0.78; P = 0.0001) (3). The relationship between birth weight SD score and SI appeared nonlinear (Fig. 2Go), but was not obviously reciprocal or logarithmic. A marked increase in SI was noted with increasing birth weight above -1.3 SD from the mean.



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  		Figure 2. Relationship between birth weight SD score (SDS) and SI for all subjects studied. Closed boxes, Normal children; open circles, IUGR children.

 
Although no difference was noted between groups for the glucose disappearance coefficient, there was considerable individual variability, with one IUGR subject verging on glucose intolerance with a value of 0.7% (a value <0.5% is indicative of glucose intolerance). This low glucose disappearance coefficient reflected a significant decrease in SI combined with low glucose effectiveness. The subject’s fructosamine level, however, was normal, indicating normoglycemia over the 3 weeks before the testing. No difference existed between groups for either plasma cholesterol or triglyceride levels.

Both potassium (P = 0.001) and magnesium (P = 0.0001) had a significant reduction in levels during the FSIGT. No effect was seen between groups, although potassium and magnesium levels were slightly higher in the IUGR birth weight group at baseline and remained elevated above the normal birth weight levels throughout the study.

On further analysis of our previous normal prepubertal subject data (n = 29), an association was found between weight for length index and the log of SI (P = 0.05; r = 0.36). No relationship was apparent between SI and height SD score, sex, or age.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study is the first to formally examine insulin sensitivity in children born with IUGR and has demonstrated a marked difference in SI between IUGR and normal birth weight subjects. The lower SI values in the IUGR subjects confirm that an abnormality in insulin sensitivity, i.e. insulin resistance, exists during childhood in otherwise asymptomatic individuals. Asymptomatic first degree relatives of patients with NIDDM or essential hypertension have demonstrated impaired insulin sensitivity before the onset of overt NIDDM (14, 15, 16, 34). During 25 yr of follow-up of first degree relatives with NIDDM, the cummulative risk for developing diabetes with an isolated defect in SI was as high as 40% (34). As with first degree relatives of NIDDM patients, there are limited data to suggest that those with IUGR have a high risk of developing NIDDM in late adult life (10). Therefore, it is conceivable that impaired SI is an important early marker that might permit the identification in childhood of those with IUGR and short stature who are more likely to develop NIDDM and associated disorders such as hypertension, dyslipidemia, and ischemic heart disease in late adult life. The long interval between impaired SI and onset of NIDDM provides an opportunity to develop intervention strategies to delay or prevent the onset of later disease.

The definition of IUGR as a birth weight less than the tenth percentile for gestational age is commonly used (4, 6, 35, 36). However, it is a poorly defined term, with birth weight less than the third or fifth percentile or birth length employed by some researchers (2, 3, 8, 37). Regardless of the definition used, IUGR is a frequent occurrence. Approximately 10–20% of IUGR children do not exhibit catch-up growth in infancy and become short adults (17, 38, 39). From our observation of insulin resistance in short IUGR children, it would appear that approximately 1–2% of the general population are at risk of significant insulin resistance and associated disorders in adulthood. It is possible that these insulin-resistant short IUGR children are representative of the entire IUGR group. This would indicate that insulin resistance may be a problem of far greater magnitude than we have initially identified.

To maintain normoglycemia, a commensurate increase in insulin release is required to compensate for a reduction in insulin sensitivity (29, 33). The hyperbolic relationship between insulin sensitivity and ß-cell function was shown in this study, with reduced insulin sensitivity in IUGR children being compensated for by the release of twice as much insulin during the study. The greater demand placed on pancreatic ß-cells to produce larger amounts of insulin to achieve normoglycemia puts the IUGR group at risk of eventual ß-cell exhaustion. The sequence of insulin resistance followed by ß-cell failure may be important mechanisms leading to NIDDM in those with IUGR. That an isolated defect in insulin sensitivity was present in the IUGR group was reinforced by the normal glucose disappearance coefficient, a measure of glucose utilization, which reflects the combined actions of SI, Sg, and ß-cell function.

Our observation of a far greater acute insulin response in IUGR children challenges the previously proposed "thrifty phenotype" hypothesis, which suggests that the increased incidence of NIDDM in those born small is due to a combination of ß-cell hypoplasia and insulin resistance. We propose an alternative hypothesis to explain the insulin resistance seen in those born with IUGR, termed the fetal salvage hypothesis. The malnourished fetus receives inadequate nutrition for optimal growth. To ensure that adequate amounts of glucose are delivered to essential organs such as the brain, peripheral insulin resistance occurs, which allows for a redistribution of nutrient supply within the fetus. In this critical phase of development, inadequate nutrition leads to a permanent reduction in insulin-responsive skeletal muscle glucose transporter number or function. Support for such a hypothesis comes from IUGR studies in rats (27, 28). In this model, insulin-mediated glucose uptake and glucose transporter (Glut-1) protein levels are reduced in skeletal muscle of IUGR fetuses. However, no changes are seen in glucose transport or Glut-1 protein levels in the IUGR fetal brain.

Peripheral glucose uptake is determined by the triad of insulin sensitivity, ß-cell function, and glucose effectiveness (29). An impairment of at least 80% in two of these factors is required before glucose intolerance occurs, and in most patients with NIDDM, Sg, SI, and ß-cell function are all impaired. In the present study, no difference was seen between groups for Sg, indicating that a defect in Sg is not an early characteristic of the metabolic abnormality seen in IUGR children. If the evolution of NIDDM is similar in IUGR subjects and those with NIDDM, it is likely that the initial defect involves reduced insulin sensitivity, with a defect in insulin release or Sg occurring later, but before the onset of overt disease in predisposed individuals.

Both the IUGR and normal birth weight groups used in this study were short. It was hypothesized that if children born with IUGR had failed to show catch-up growth, they may have suffered a greater intrauterine metabolic insult and were more likely to demonstrate a defect in insulin sensitivity. Short children are generally thin, as demonstrated in this study. Consequently, a group of short, normal birth weight children was used as controls to adjust for this variable. Insulin sensitivity can be influenced by a number of factors, including relative obesity and ethnic origin. In the largest population of prepubertal children studied with the minimal model, the only factor associated with SI was relative obesity (20). Our further analysis of these data demonstrated a positive correlation between weight for length index and SI, with thinner children being more insulin sensitive. In the same study, height was shown to have no correlation with SI, implying that short, normal birth weight subjects are representative of a normal population. In adults, the relationship between relative obesity and SI is also nonlinear, with increasing leanness associated with dramatic increases in SI (33). Therefore, the high SI obtained in this study probably reflects the thinness of the subjects, emphasizing the need to use groups of similar size and nutritional status.

Although the IUGR subjects in this study did not manifest a decrease in insulin sensitivity to a degree associated with severe insulin-resistant states, this may occur in later life. Puberty is associated with a marked reduction in insulin sensitivity. In early adulthood, insulin sensitivity improves, but remains lower than prepubertal levels (20, 40, 41), whereas during later adult life, insulin sensitivity continues to gradually decrease. Obesity (especially abdominal) is also known to play an important role in the development of insulin resistance. Increasing adiposity in these subjects, who were very thin, could reduce their insulin sensitivity. Several studies have suggested that both maternal malnutrition and lower birth weight are risk factors for the later development of abdominal or truncal obesity (42, 43, 44). If insulin sensitivity is lower than normal during childhood, it would seem probable that, given the changes known to occur physiologically with age and the likelihood of increasing adiposity, significant insulin resistance could well ensue.

The relationship between SI and birth weight SD score appeared complex and nonlinear, with a trend to lower SI with lower birth weight. By using a birth weight below the tenth percentile to define IUGR, a small number of normal birth weight subjects, by definition, were included. Therefore, in this study, it was unlikely that these arbitrarily divided groups were completely representative of either IUGR or normal birth weight.

To assess other aspects of insulin action, a variety of other biochemical parameters were assessed. Magnesium and potassium are cations transported into cells by insulin-dependent mechanisms (45, 46). As expected, a significant decrease in the plasma concentration of both cations occurred after dextrose- and tolbutamide-induced insulin release. There was, however, no difference between groups despite the relative hyperinsulinemia in the IUGR group, (approximately double that in the normal birth weight group). Although no difference was statistically found, a trend was apparent for higher potassium and magnesium plasma concentrations in the IUGR birth weight group, which almost reached significance for potassium (P = 0.07). This trend is the reverse of what would be expected if insulin sensitivity for potassium and magnesium transport was similar in both groups and suggests that along with an abnormality in insulin-dependent peripheral glucose uptake, an abnormality in the transport of these cations may also exist.

In summary, this study has demonstrated an impressive difference in insulin sensitivity between short IUGR and normal birth weight children. These findings indicate that in subjects with IUGR, reduced insulin sensitivity occurs in childhood, and this impaired insulin sensitivity may be a potential marker for the early identification and intervention in the development of late adult-onset NIDDM.


   Acknowledgments
 
Orinase was generously donated by Upjohn InterAmerican Corp.


   Footnotes
 
1 This work was supported by grants from the Auckland Medical Research Foundation and Pharmacia Peptide Hormones. Back

Received June 20, 1996.

Revised October 29, 1996.

Accepted November 7, 1996.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4489 - 4493.
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E. Nilsson, P. Poulsen, M. Sjogren, C. Ling, M. Ridderstrale, L. Groop, and A. Vaag
Regulation of skeletal muscle PPAR{delta} mRNA expression in twins
J. Physiol., November 1, 2007; 584(3): 1011 - 1017.
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 Diabetes CareHome page
V. Nobili, M. Marcellini, G. Marchesini, E. Vanni, M. Manco, A. Villani, and E. Bugianesi
Intrauterine Growth Retardation, Insulin Resistance, and Nonalcoholic Fatty Liver Disease in Children
Diabetes Care, October 1, 2007; 30(10): 2638 - 2640.
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 NEJMHome page
P. Hovi, S. Andersson, J. G. Eriksson, A.-L. Jarvenpaa, S. Strang-Karlsson, O. Makitie, and E. Kajantie
Glucose Regulation in Young Adults with Very Low Birth Weight
N. Engl. J. Med., May 17, 2007; 356(20): 2053 - 2063.
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 EndocrinologyHome page
N. M. Thompson, A. M. Norman, S. S. Donkin, R. R. Shankar, M. H. Vickers, J. L. Miles, and B. H. Breier
Prenatal and Postnatal Pathways to Obesity: Different Underlying Mechanisms, Different Metabolic Outcomes
Endocrinology, May 1, 2007; 148(5): 2345 - 2354.
[Abstract] [Full Text] [PDF]

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S. P. Ford, B. W. Hess, M. M. Schwope, M. J. Nijland, J. S. Gilbert, K. A. Vonnahme, W. J. Means, H. Han, and P. W. Nathanielsz
Maternal undernutrition during early to mid-gestation in the ewe results in altered growth, adiposity, and glucose tolerance in male offspring
J Anim Sci, May 1, 2007; 85(5): 1285 - 1294.
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P. Saenger, P. Czernichow, I. Hughes, and E. O. Reiter
Small for Gestational Age: Short Stature and Beyond
Endocr. Rev., April 1, 2007; 28(2): 219 - 251.
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K. Hultman, C. Alexanderson, L. Manneras, M. Sandberg, A. Holmang, and T. Jansson
Maternal taurine supplementation in the late pregnant rat stimulates postnatal growth and induces obesity and insulin resistance in adult offspring
J. Physiol., March 15, 2007; 579(3): 823 - 833.
[Abstract] [Full Text] [PDF]

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 Eur J EndocrinolHome page
E. N Evagelidou, V. I Giapros, A. S Challa, D. N Kiortsis, A. A Tsatsoulis, and S. K Andronikou
Serum adiponectin levels, insulin resistance, and lipid profile in children born small for gestational age are affected by the severity of growth retardation at birth
Eur. J. Endocrinol., February 1, 2007; 156(2): 271 - 277.
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M. van Dijk, E. M. N. Bannink, Y. K. van Pareren, P. G. H. Mulder, and A. C. S. Hokken-Koelega
Risk Factors for Diabetes Mellitus Type 2 and Metabolic Syndrome Are Comparable for Previously Growth Hormone-Treated Young Adults Born Small for Gestational Age (SGA) and Untreated Short SGA Controls
J. Clin. Endocrinol. Metab., January 1, 2007; 92(1): 160 - 165.
[Abstract] [Full Text] [PDF]

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 PediatricsHome page
F. M. Regan, W. S. Cutfield, C. Jefferies, E. Robinson, and P. L. Hofman
The Impact of Early Nutrition in Premature Infants on Later Childhood Insulin Sensitivity and Growth
Pediatrics, November 1, 2006; 118(5): 1943 - 1949.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
T. Pfab, T. Slowinski, M. Godes, H. Halle, F. Priem;, and B. Hocher
Low Birth Weight, a Risk Factor for Cardiovascular Diseases in Later Life, Is Already Associated With Elevated Fetal Glycosylated Hemoglobin at Birth
Circulation, October 17, 2006; 114(16): 1687 - 1692.
[Abstract] [Full Text] [PDF]

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 Eur J EndocrinolHome page
R. Pasquali and A. Gambineri
Insulin-sensitizing agents in polycystic ovary syndrome.
Eur. J. Endocrinol., June 1, 2006; 154(6): 763 - 775.
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B. C. Galland, B. J. Taylor, D. P. G. Bolton, and R. M. Sayers
Heart rate variability and cardiac reflexes in small for gestational age infants
J Appl Physiol, March 1, 2006; 100(3): 933 - 939.
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C. A. Quigley, A. M. Gill, B. J. Crowe, K. Robling, J. J. Chipman, S. R. Rose, J. L. Ross, F. G. Cassorla, A. M. Wolka, J. M. Wit, et al.
Safety of Growth Hormone Treatment in Pediatric Patients with Idiopathic Short Stature
J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5188 - 5196.
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 Hum ReprodHome page
T. Sir-Petermann, C. Hitchsfeld, M. Maliqueo, E. Codner, B. Echiburu, R. Gazitua, S. Recabarren, and F. Cassorla
Birth weight in offspring of mothers with polycystic ovarian syndrome
Hum. Reprod., August 1, 2005; 20(8): 2122 - 2126.
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L. Ibanez, A. Fucci, C. Valls, K. Ong, D. Dunger, and F. de Zegher
Neutrophil Count in Small-for-Gestational Age Children: Contrasting Effects of Metformin and Growth Hormone Therapy
J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3435 - 3439.
[Abstract] [Full Text] [PDF]

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 NEJMHome page
R. A. Bazaes, V. Mericq, A. Plagemann, T. Harder, P. L. Hofman, and W. S. Cutfield
Premature Birth and Insulin Resistance
N. Engl. J. Med., March 3, 2005; 352(9): 939 - 940.
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 Eur J EndocrinolHome page
S. Tenhola, P. Halonen, J. Jaaskelainen, and R. Voutilainen
Serum markers of GH and insulin action in 12-year-old children born small for gestational age
Eur. J. Endocrinol., March 1, 2005; 152(3): 335 - 340.
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 DiabetesHome page
J. C. Jimenez-Chillaron, M. Hernandez-Valencia, C. Reamer, S. Fisher, A. Joszi, M. Hirshman, A. Oge, S. Walrond, R. Przybyla, C. Boozer, et al.
{beta}-Cell Secretory Dysfunction in the Pathogenesis of Low Birth Weight-Associated Diabetes: A Murine Model
Diabetes, March 1, 2005; 54(3): 702 - 711.
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 Arch. Dis. Child.Home page
K A Neville and J L Walker
Precocious pubarche is associated with SGA, prematurity, weight gain, and obesity
Arch. Dis. Child., March 1, 2005; 90(3): 258 - 261.
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 NEJMHome page
P. L. Hofman, F. Regan, W. E. Jackson, C. Jefferies, D. B. Knight, E. M. Robinson, and W. S. Cutfield
Premature Birth and Later Insulin Resistance
N. Engl. J. Med., November 18, 2004; 351(21): 2179 - 2186.
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 NEJMHome page
M. A. Sperling
Prematurity -- A Window of Opportunity?
N. Engl. J. Med., November 18, 2004; 351(21): 2229 - 2231.
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 ScienceHome page
P. D. Gluckman and M. A. Hanson
Living with the Past: Evolution, Development, and Patterns of Disease
Science, September 17, 2004; 305(5691): 1733 - 1736.
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 PediatricsHome page
N. J.T. Arends, V. H. Boonstra, and A. C.S. Hokken-Koelega
Head Circumference and Body Proportions Before and During Growth Hormone Treatment in Short Children Who Were Born Small for Gestational Age
Pediatrics, September 1, 2004; 114(3): 683 - 690.
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