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Rina Balducci Center of Pediatric Endocrinology, Tor Vergata University, 00133-Rome, Italy
Address all correspondence and requests for reprints to: Prof. Stefano Cianfarani, M.D., Rina Balducci Center of Pediatric Endocrinology, Tor Vergata University—Faculty of Medicine, Via Montpellier 1, 00133-Rome, Italy. E-mail: stefano.cianfarani{at}uniroma2.it.
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Abstract |
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Introduction |
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Short stature is another major feature of SGA children, 10–20% achieving a final height lower than their genetic potential (12, 13). To date, the mechanisms that allow catch-up growth (CG) or (on the contrary) negatively affect postnatal growth are still unknown (14, 15).
In an attempt to integrate the two major clinical characteristics of SGA subjects, we hypothesized that CG itself might increase the risk of developing insulin resistance, especially when other risk factors, such as genetic predisposition and obesity, coexist (16). Epidemiological and clinical observations seem consistent with our hypothesis, suggesting that SGA children with CG in height and/or weight are at high risk of developing type 2 diabetes in later life (11, 17, 18, 19).
The aim of the present study was to investigate insulin sensitivity, lipid profile, and endocrine status in SGA children, compared with that in children born appropriate for gestational age (AGA), strictly matched for age, sex, pubertal status, body mass index (BMI), and height. Furthermore, within the SGA group, we aimed to relate postnatal growth to anthropometric, biochemical, and endocrine parameters.
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Subjects and Methods |
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We studied 82 children (mean age, 8.6 ± 3.5 yr; 44 females and 38 males) born small for gestational age (SGA) and 53 short normal children (mean age, 9.3 ± 3.3 yr; 25 females and 28 males) born AGA (short-AGA), attending the Outpatient Growth Clinic of the Rina Balducci Center of Pediatric Endocrinology (Tor Vergata University, Rome, Italy). SGA was defined as a birth weight less than the 10th centile, corrected for gestational age. AGA was defined as a birth weight above the 10th centile (20). Subjects with malformations or genetic disorders and those with family history of type 2 diabetes were excluded. In the SGA group (n = 82), 58 children were at pubertal stage 1, 8 at pubertal stage 2, 6 at stage 3, 7 at stage 4, and 3 at stage 5. In the short-AGA group (n = 53), 46 children were at pubertal stage 1, and 7 were at stage 2.
Short-AGA children were referred to our center for short stature and had normal GH peak responses (GH peak above 10 µg/liter for clonidine test, and above 20 µg/liter for GHRH + arginine test). In all children, endomysial and transglutaminase antibody testing was performed to exclude celiac disease. Free T4 and TSH assessment was carried out to rule out hypothyroidism. Karyotype was normal in all girls. The investigation was approved by the Ethical Committee of Tor Vergata University, and informed consent was obtained from all the parents.
A case-control study was carried out in 26 SGA (13 males and 13 females) and 26 AGA subjects. The 52 children included in the case-control study were a subset of the total 135 subjects enrolled in the study. For each patient (SGA), we selected a control (short-AGA) that was matched for sex, age (within 1 yr), pubertal status, BMI (within 0.5 kg/m2), and height (within 0.25 z-score). Among the 52 case-control subjects, 48 were at pubertal stage 1, and 4 were at stage 2.
Anthropometry
All children underwent anthropometric measurements using the growth standards of Tanner and Whitehouse (21). Height was expressed as z-score for chronological age and sex, according to the following formula: z-score = (x - average x)/SD, where x is the actual height, average x is the mean of the height at that age and for that sex, and SD is the SD from the mean. Midparental height (MPH) was used as an indicator of genetic growth potential: MPH for boys (cm) = father height + (mother height + 13)/2; MPH for girls (cm) = mother height + (father height - 13)/2. Both parents of each child were measured in our clinic. Children’s statures were corrected for their MPH according to the formula: corrected height (z-score) = actual height (z-score) - MPH (z-score). SGA children were subdivided into two groups according to their corrected height: CG group, children with corrected height of at least 0 z-score; and non-CG (NCG) group, subjects with corrected height less than 0 z-score. In all subjects with actual or corrected height of no more than 2 z-score, GH deficiency was ruled out by clonidine (100 µg/m2 orally) or GHRH (1 µg/kg iv) + arginine (0.5 g/kg iv) stimulation tests.
Ponderal index [weight (g)/length (cm)3 x 100] was used as anthropometric measurement to discriminate between proportionate and nonproportionate SGA newborns (22).
Hormone and biochemical assays
Blood samples for base-line hormone assessments were collected between 0800 and 0900 h, in fasting conditions.
Fasting insulin, fasting glucose insulin ratio, homeostasis assessment model (HOMA) for insulin resistance [HOMA-IR = (fasting insulin in mU/liter) x (fasting glucose in mM)/22.5], and HOMA-ß-cell function [(fasting insulin in mU/liter x 20)/(fasting glucose in mM - 3.5)] were chosen as measures of insulin sensitivity. A glucose insulin ratio less than 6 (23) and a HOMA-IR value more than 3 (24) were chosen as indicators of reduced insulin sensitivity.
Serum insulin was measured by immunoradiometric assay (IRMA) (RADIM, Rome, Italy). The intra-assay CV was 2.2–3.9%, the interassay CV was 4.7–12.2%, and the sensitivity limit was 1.2 mU/liter. Serum cortisol was measured by RIA (BYK-Sangtec Diagnostica, Dietzebach, Germany). The intra-assay CV was 3.6–4.8%, the interassay CV was 6.0–7.3%, and the sensitivity limit was 0.9 µg/dl. Serum GH was measured by IRMA (Diagnostic Systems Laboratories, Inc., Webster, TX). The intra-assay CV was 3.1–5.4%, the interassay CV was 5.9–11.5%, and the sensitivity limit was 0.01 µg/liter. Serum IGF-I was measured by IRMA (Nichols Institute Diagnostics, San Juan Capistrano, CA). The intra-assay CV was 3.3–4.6%, the interassay CV was 9.3–15.8%, and the sensitivity limit was 6 µg/liter. Serum IGF-binding protein-3 was measured by IRMA (Diagnostic Systems Laboratories, Inc.). The intra-assay CV was 1.8–3.9%, the interassay CV was 0.5–1.9%, and the sensitivity limit was 0.2 mg/liter. Serum TSH was measured by IRMA (Cambridge Life Sciences plc, Ely, UK). The intra-assay CV was 2.0–7.7%, the interassay CV was 6.3–9.8%, and the sensitivity limit was 0.02 mU/liter. Free T4 was measured by RIA (BYK-Sangtec Diagnostica). The intra-assay CV was 2.0–4.6%, the interassay CV was 4.9–7.8%, and the sensitivity limit was 0.1 ng/dl.
Blood glucose was measured immediately, by the glucose oxidase method, using a glucose analyzer (YSI, Inc., Yellow Springs, OH). Plasma total and high-density-lipoprotein (HDL) cholesterol were measured enzymatically by an automatic photometric method (Roche Molecular Biochemicals, Mannheim, Germany). Plasma triglycerides were analyzed enzymatically (Roche Molecular Biochemicals). Low-density-lipoprotein (LDL) cholesterol concentrations were calculated by the Friedewald-Fredrickson formula [LDL cholesterol = total cholesterol - (HDL cholesterol + triglycerides/2.2)] (25).
Alanine aminotransferase (ALT), aspartate aminotransferase, and 
-glutamyltransferase (GGT) were measured by spot photometry (Olympus Corp. System Reagents, Hamburg, Germany).
Statistics
Results are reported as the mean ± SD. Differences between means were assessed using an unpaired two-tailed t test. Differences between SGA and short-AGA subjects in the case-control study were evaluated by the paired t test. After ascertaining that variables were normally distributed, the relationships among parameters were evaluated by Pearson correlation. All the relationships among anthropometric, metabolic, and endocrine variables within the SGA group (n = 82) were controlled for the effects of age, pubertal stage, and BMI. Multiple regression and forward stepwise regression analyses were used in the selection of predictors of height and corrected stature. The 
2 test, after Yates’ correction, was used to compare the prevalence of cases with reduced insulin sensitivity in SGA and short-AGA groups. Significance was assigned for P < 0.05. A computer program was used for all statistical calculations (BMPD Statistical Software, SOLO 3.0; BMPD, Los Angeles, CA).
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Results |
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The whole SGA and short-AGA populations were analyzed to investigate differences among anthropometric, biochemical, and endocrine variables (Table 1
). No significant differences in age, ponderal index, height, and BMI were found. SGA children showed significantly lower mean MPH (-0.89 ± 0.89 vs. -0.56 ± 0.78 z-score, P = 0.03) and higher mean corrected stature (-0.36 ± 1.4 vs. -1.13 ± 0.83 z-score, P = 0.0001).
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). Despite the fact that SGA subjects had a pubertal stage significantly more advanced, no difference in the insulin sensitivity parameters was found between the two groups. However, the different pubertal maturation might account for the slightly higher percentage of SGA children with insulin sensitivity indices out of the normal range. No significant differences in insulin sensitivity parameters and in the prevalence of subjects with abnormal G/I ratio and HOMA-IR were found after omitting the pubertal children. SGA children showed significantly reduced levels of glucose (4.4 ± 0.9 vs. 4.9 ± 0.6 mM, P < 0.0001), total cholesterol (160.1 ± 28.8 vs. 171.8 ± 28.5 mg/dl, P = 0.02), and HDL cholesterol (53.3 ± 12.1 vs. 58 ± 11.4 mg/dl, P = 0.02).
Finally, SGA subjects showed significantly lower levels of cortisol (12.7 ± 6.1 vs. 16 ± 5.8 µg/dl, P = 0.002) and higher concentrations of IGF-I (0.4 ± 2.4 vs. -0.82 ± 1.6 z-score, P = 0.001).
Case-control study
To further investigate the differences between SGA and short-AGA children, we carried out a case-control study in 26 SGA and 26 AGA subjects strictly matched for sex, age, pubertal status, BMI, and height (Table 2).
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). No significant difference in the prevalence of abnormal G/I ratio (SGA: 3/26 vs. short-AGA: 3/26) and HOMA-IR (SGA: 4/26 vs. short-AGA: 1/26) was observed in the case-control study groups.
The analysis of the subjects selected for the case-control study confirmed that SGA children showed significantly lower glucose levels (4.4 ± 0.7 vs. 4.9 ± 0.4 mM, P < 0.005, Table 2).
Comparisons between SGA children with and without CG
To identify the predictors of CG, we subsequently subdivided the SGA group into CG (n = 25) and NCG (n = 57) children. We found that CG children had significantly higher birth weight (2.3 ± 0.3 vs. 1.9 ± 0.4 kg, P = 0.0002), birth length (46.4 ± 2.9 vs. 44.4 ± 3.0 cm, P = 0.01), and actual BMI (18.3 ± 4.6 vs. 15.8 ± 3.9 kg/m2, P = 0.02). NCG children showed higher levels of TSH (2.5 ± 1.3 vs. 1.9 ± 0.6 mU/liter, P = 0.002), total cholesterol (164.4 ± 28 vs. 150.4 ± 28.8 mg/dl, P < 0.05), and LDL-cholesterol (101.2 ± 23.8 vs. 88.6 ± 21.6 mg/dl, P < 0.05) (Table 3). No significant difference in cortisol levels was found.
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All correlations were controlled for the effect of age, pubertal status, and BMI. Actual height was closely related to birth weight (r = 0.36, P < 0.01), birth length (r = 0.30, P = 0.02), MPH (r = 0.32, P = 0.01), and HOMA-IR (r = 0.29, P = 0.02). Corrected stature correlated with birth weight (r = 0.30, P = 0.02), birth length (r = 0.33, P = 0.02), and MPH (r = -0.36, P < 0.005).
TSH was inversely related to ponderal index (r = -0.34, P = 0.01). LDL-cholesterol levels were significantly inversely related to actual height (r = -0.29, P < 0.05). ALT correlated with fasting insulin (r = 0.28, P = 0.02) and HOMA-IR (r = 0.28, P = 0.02). GGT correlated with fasting insulin (r = 0.40, P = 0.001) and HOMA-IR (r = 0.36, P = 0.004).
Multiple regression and forward stepwise regression analyses revealed that the major predictors of actual stature were birth length, BMI, and MPH (P < 0.001, adjusted R2 = 0.39). The major predictors of corrected stature were birth weight and BMI (P < 0.001, adjusted R2 = 0.28).
Among the anthropometric variables, stepwise regression analysis showed that only BMI was predictive of HOMA-IR (P = 0.002, adjusted R2 = 0.18). However, when we added ALT and GGT into the analysis, these hepatic parameters turned out to be strongly predictive of HOMA-IR (P < 0.0001, adjusted R2 = 0.36).
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Discussion |
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There is general agreement that the euglycemic insulin clamp technique is the best available standard for the measurement of insulin action; however, it is hardly applicable on large scale, especially when children must be evaluated. To overcome these difficulties, we determined the fasting G/I ratio (23, 26) and HOMA (24, 27) that are considered useful screening tests for insulin resistance. Our data suggest that SGA children do not have altered insulin sensitivity when compared with auxologically identical AGA subjects.
The relationship between liver function (ALT and -glutamyltransferase) and insulin sensitivity, independent of BMI, is consistent with recent reports showing that ALT and GGT are closely related to insulin resistance in childhood (28) and to type 2 diabetes and metabolic syndrome in adulthood (29, 30). This finding suggests that liver might be a target organ of the reprogramming process, as previously proposed (3).
The results of this study show, for the first time, that SGA children have a significant reduction of glucose concentrations. This finding is consistent with recent studies in animal models using a low-protein diet during pregnancy to produce growth restriction of the offspring (31). It is noteworthy that in young adult life, low-protein offspring have an improved glucose tolerance, compared with controls (32, 33). This is associated with increased muscle and adipocytes insulin receptors and augmented insulin-stimulated glucose uptake into skeletal muscle (34) and adipocytes (35). Later on, however, offspring undergo an age-dependent loss of glucose tolerance, such that by 15 months of age, low-protein offspring have a significantly worse glucose tolerance, compared with controls (33).
In male rats, the glucose intolerance results from insulin resistance, the low-protein offspring having elevated plasma insulin concentrations during the glucose tolerance test (33). Recently, the impaired phosphatidylinositol 3-kinase function and, consequently, the reduced protein kinase B activation in adipocytes have been suggested to explain, at least in part, this late onset insulin resistance (36).
It is tempting to speculate that, in human, an early phase of increased insulin sensitivity during childhood might precede the onset of insulin resistance in young adult SGA subjects, and a study of the insulin intracellular signaling pathways at different stages of maturation might be worth doing.
In our children, the major predictors of postnatal growth were birth size, nutritional status, and genetic growth potential. This finding implies that the height outcome of SGA children is largely dependent on the intrauterine pattern of growth and genetic predisposition. In addition, postnatal adequate nutrition seems to positively influence CG. However, the inverse relationship between height and insulin sensitivity is in accord with the CG hypothesis (16) and with the previous studies suggesting that CG in height and/or weight increases the risk of developing type 2 diabetes in later life (11, 17, 18, 19).
In the present study, NCG-SGA children showed higher, though normal, TSH concentrations than did CG-SGA subjects. A significant reduction in circulating free T4, free triiodothyronine, and a modest elevation in TSH has been reported in fetuses with intrauterine growth retardation (37). More recently, a significant reduction of the expression of thyroid receptor isoforms in the human fetal nervous system of children with intrauterine growth restriction has been described (38). All subjects of our study had normal TSH levels; however, there is evidence that variation of thyroid function within the normal range might lead to a different outcome (39). Individuals with TSH values greater that 2.0 mU/liter have an increased risk of developing overt hypothyroidism and thyroid autoantibodies (40, 41, 42). In addition, levels between 2.0 and 4.0 mU/liter have been associated with increased risk of heart disease (42). Finally, Michaloupoulou et al. (43) have reported that T4 administration to subjects with TSH values in the range 2.0–4.0 mU/liter lowers cholesterol levels, whereas has no effect with initial TSH in the range 0.4–1.99 mU/liter.
These findings suggest that intrauterine reprogramming might involve thyroid function, which, in turn, might affect postnatal growth and cholesterol metabolism, eventually increasing the risk of cardiovascular disease.
In conclusion, our results show the presence of reduced blood glucose levels in SGA children and higher TSH concentrations in those with blunted CG. Further longitudinal case-control studies are needed to establish whether the lower glucose levels are attributable to an early phase of augmented insulin sensitivity, as previously reported in animal models, and whether the higher levels of TSH in SGA children with blunted CG signifies a higher risk of atherosclerosis and cardiovascular disease in adulthood.
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Footnotes |
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-glutamyltransferase; G/I, glucose/insulin; HDL, high-density-lipoprotein; HOMA, homeostasis assessment model; HOMA-IR, homeostasis assessment model for insulin resistance; IRMA, immunoradiometric assay; LDL, low-density-lipoprotein; MPH, midparental height; NCG, non-catch-up growth; SGA, small for gestational age. Received December 3, 2002.
Accepted February 24, 2003.
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