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Original Article |
Department of Pediatrics, Research Institute for Endocrinology, Reproduction and Metabolism, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
Address all correspondence and requests for reprints to: Dr. M. M. van Weissenbruch, Department of Pediatrics, VU University Medical Center, Postbox 7057, 1007 MB Amsterdam, The Netherlands. E-mail: m.vanweissenbruch{at}vumc.nl.
Abstract
Intrauterine growth retardation is associated with an increased risk of developing adult diseases, such as noninsulin-dependent diabetes mellitus (NIDDM). NIDDM could result from a decreased insulin sensitivity or a reduced insulin secretion or a combination of both. Glucose tolerance, insulin sensitivity, and insulin secretion were studied in prepubertal children born small for gestational age (SGA). Twenty-nine SGA children with a mean age of 9.1 ± 1.1 yr and 24 children born appropriate for gestational age (AGA), with a mean age of 9.0 ± 1.1 yr, were studied. All children were born at term and were prepubertal. Children were studied on two separate days after 12 h of overnight fasting. Day 1: Glucose tolerance was studied with an oral glucose tolerance test. AUCins0–120min/AUCgluc0–120min was used to estimate ß-cell function in the two groups. Day 2: A hyperinsulinemic euglycemic clamp study was performed to determine insulin sensitivity (M-value). Glucose tolerance and ß-cell function were not different between the two groups. M-value in SGA children was significantly lower than M-value in AGA children: 12.9 ± 4.0 mg/kg·min vs. 15.6 ± 2.3 mg/kg·min [P = 0.009; after adjustment for appropriate gestational age body mass index (BMI), P = 0.001]. The M-value tended to be higher in SGA children without catch-up growth compared with SGA children with catch-up growth (15.8 ± 4.3 vs. 12.3 ± 3.8 mg/kg·min; P = 0.079) and was comparable to AGA controls (15.6 ± 2.3 mg/kg·min). The M-value in SGA children who had shown catch-up growth was comparable to AGA children (13.4 ± 3.4 vs. 15.6 ± 2.3 mg/kg·min; P = 0.06), provided they had a BMI of 17 kg/m2 or less. However, the SGA children with catch-up growth and a BMI greater than 17 kg/m2 were those having the lowest M-values (9.3 ± 3.4 mg/kg·min). In conclusion, during oral glucose tolerance tests, no differences were found in glucose tolerance and ß-cell function between the SGA and AGA groups. However, the hyperinsulinemic clamp showed a reduced insulin sensitivity in SGA children, which may contribute to the enhanced risk of developing NIDDM in adult life, especially in SGA children with catch-up growth and a high BMI. The implications of our findings in relation to height are unclear, but might be of potential importance when considering GH treatment. In addition, interventions to improve fetal growth and to control obesity in childhood seem to be important factors in the prevention of NIDDM.
INTRAUTERINE GROWTH RETARDATION (IUGR) is associated with an increased risk of developing chronic diseases in adulthood, such as noninsulin-dependent diabetes mellitus (NIDDM). Inverse associations of NIDDM in adult life with size at birth were first identified in two cohorts of adults born in England (1, 2) and have since been confirmed in three other populations (3, 4, 5). Few studies, however, specifically investigated subjects born small for gestational age (SGA) because length of gestation was not precisely known.
NIDDM is often undiagnosed for many years in a lot of patients and is in time attended by cardiovascular, renal, and neurological complications. Most studies concerning NIDDM are done in adults when environmental effects could have been of influence in the development of NIDDM. To avoid these effects, it seems to be important to study young adults and children as well, who are at an increased risk of developing NIDDM in later life. Leger et al. (6) showed that young adults born after IUGR had normal glucose tolerance, but higher plasma insulin and proinsulin levels during an oral glucose tolerance test (OGTT) than controls. This hyperinsulinemia suggests the development of insulin resistance in early adulthood, which was recently confirmed (7). Studies in young prepubertal children have shown that plasma glucose levels after an oral glucose load are inversely related to birth weight (BW; Ref. 8) or to ponderal index (9) and that low BW is associated with increased insulin resistance estimated according to the homeostatic model (homeostasis model assessment–insulin resistance; Refs. 10, 11). Until now, there has been general agreement that the euglycemic insulin clamp technique is the best available standard for the measurement of insulin action. Mechanisms underlying the relation between low BW and NIDDM are still unclear. The relationship could be mediated by alterations in insulin sensitivity (12, 13), insulin secretion (14), or a combination of both. The aim of the present study was to investigate glucose tolerance, ß-cell function during OGTT, and insulin sensitivity using the hyperinsulinemic euglycemic clamp technique in prepubertal Caucasian children born SGA, compared with that in children born appropriate for gestational age (AGA). All children were born at term. The influence of catch-up growth in height and body mass index (BMI) was taken into account.
Subjects and Methods
Study population
The study was a case-control study in which all subjects were selected according to their birth data. Since 1980, information of all pregnancies, deliveries, and perinatal events of children born in this hospital have been registered. This database was used to trace individuals. The study protocol was approved by the ethics committee of the VU University Medical Center of Amsterdam.
The study was performed in 29 Caucasian prepubertal SGA children with a mean age of 9.1 ± 1.1 yr (range, 7.1–11.0 yr). Twenty-four Caucasian children, born AGA, with a mean age of 9.0 ± 1.1 yr (range, 7.1–11.8) served as controls because there are no standards of insulin sensitivity in literature in children born AGA. AGA controls were selected from the same database according to their birth data. One AGA control was a girl friend of a SGA subject, and two AGA controls were relatives of children who were treated at the outpatient clinic. All parents and children received a letter with information of the study and an invitation for an information meeting at which they were more extensively informed and at which they could ask questions. SGA was defined as a BW less than the 10th percentile corrected for gestational age, gender, and parity; AGA was defined as a BW of the 10th percentile or above, using Dutch references (15). All children were born at term. At the time of the study, all subjects were in good health as assessed by medical history and physical examination. They were at a prepubertal stage according to the criteria of Tanner (16), confirmed by measurements of plasma testosterone in males and estradiol in females. Questionnaires of family history in terms of type 2 diabetes, cardiovascular disease, and hypertension were recorded. None received any medication that could interfere with the tests. After full explanation of the study, all subjects and parents gave written informed consent.
Methods
Children were studied on two separate days after 12 h of overnight fasting.
Day 1. Measurements of the subject’s weight, using an electronic scale (SECA, Hanover, MD), and height, with a stadiometer (Holtain Ltd., Crymych, Dyfed, UK), were used to calculate the BMI, defined as weight divided by the height squared. A tape measure was used to measure waist and hip circumferences, and skin-fold thickness were measured by a single observer with Harpenden skin-fold calipers at the biceps, triceps, subscapular, and suprailiacal sites. Total body fat mass was calculated by the sum of the four sites in millimeters.
After physical examination, an OGTT (1.75 g/kg glucose, with a maximum of 75 g) was performed. Blood samples were taken every 15 min during 2 h for the measurement of glucose and insulin concentrations. To assess ß-cell capacity, AUCins0–120min/AUCgluc0–120min was determined (17). Bone age was determined in all subjects by making an x-ray of the left hand.
Day 2. A 2-h hyperinsulinemic euglycemic clamp was performed to determine insulin sensitivity by peripheral glucose uptake as described by De Fronzo et al. (18). Two children of the AGA group dropped out and decided not to participate in the clamp study because of the invasive character of the study. Insulin (Velosulin, Novo Nordisk A/S, Bagsvaerd, Denmark) was infused at a rate of 60 mU/kg·h after a priming dose of 6 mU/kg. Hepatic glucose production is known to be suppressed in nondiabetic subjects by this insulin infusion rate (19). The blood glucose level was measured every 5 min. Every 15 min, blood was drawn to determine plasma insulin concentrations. Euglycemia (5 mmol/liter) was maintained with 20% D-glucose infusion. Under steady state conditions of euglycemia, the rate of exogenous glucose infusion is equal to the rate of insulin-stimulated glucose disposal. Insulin sensitivity was calculated from the glucose infusion rate (milligrams per minute) between 60 and 120 min of the euglycemic clamp, divided by body weight (kilograms; M-value).
Analytical methods
Blood glucose was measured immediately by the glucose oxidase method using a Yellow Springs Instrument Co. glucose analyzer (YSI, Inc., Yellow Springs, OH). Plasma insulin concentrations were measured by RIA techniques (Immunoradiometric Assay, Medgenics Diagnostics, Fleurus, Belgium).
Statistical analysis
Statistical analysis was performed using the Statistical Package for Social Sciences 9.0 software (SPSS, Inc., Chicago, IL). Results are expressed as means ± SD. Differences between the SGA and AGA group were tested by 
2 test for qualitative variables and t test for quantitative variables. Glucose concentrations were normally distributed. Insulin concentrations were normalized by log transformation. The effect of group (SGA vs. AGA) on peripheral glucose uptake, adjusting for BMI, total of skin-fold thickness, or waist circumference was studied using regression models (general linear models procedure). The independent effect of SGA on insulin secretion relative to insulin sensitivity was tested using the log-transformed variables in a general linear models procedure. A P value of 0.05 or less was considered to be significant.
Results
Clinical characteristics
Family history in terms of type 2 diabetes, cardiovascular disease, and hypertension was not statistically different in the two groups (Table 1
).
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shows the clinical characteristics of the two groups at birth and at the time of the study. As defined, BW was significantly lower in SGA children (P < 0.001). Length at birth as well as ponderal index were significantly lower in SGA children. Gestational age and gender distributions were similar in both groups. At the time of the study, mean age, actual length, and BMI did not significantly differ between the two groups (Table 2). When an arbitrarily chosen cut-off of BMI greater than 17 kg/m2 was used, 7 children in the SGA group were considered having a high BMI, whereas in the AGA group 11 children had a BMI greater than 17 kg/m2 (data not shown). In the SGA group, five children did not show catch-up growth, defined as an actual height 1.3 SD or more below the target height SD score (height SD score - target height SD score). Characteristics are shown in Table 2. All AGA children did grow within their target height SD score. Bone ages, expressed as bone age minus chronological age, were not different in SGA and AGA children (-0.1 ± 14.1 months vs. -1.6 ± 11.1 months respectively; P = 0.7; Table 2). Bone ages of the five SGA children with attenuated linear growth were not different from those of the SGA children with normal growth (-10.0 ± 19.1 months vs. 0.2 ± 9.1 months; P = 0.09).
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Blood glucose levels in the IUGR group were slightly higher at all time points studied, but not statistically significant. Table 3 shows the results of oral glucose tolerance testing at 0, 30, and 120 min in the two groups. Plasma insulin levels were not different between SGA children and AGA children during the first and second hours of the test.
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The ratio of areas under the curves (AUCins0–120min/AUCgluc0–120min) was not significantly different between AGA children (n = 22) and SGA children (n = 28) (151.3 ± 78.1 vs. 140.6 ± 82.7 pmol/mmol; P = 0.44); means adjusted for M-value for the two groups were 154.9 ± 18.9 vs. 129.9 ± 16.2 pmol/mmol (P = 0.34).
Hyperinsulinemic euglycemic clamp
Plasma insulin and blood glucose measured at steady state (60–120 min) did not differ significantly between SGA subjects and AGA children (plasma insulin, 383 ± 89 vs. 407 ± 85 pmol/liter; plasma glucose, 5.0 ± 0.2 vs. 5.0 ± 0.2 mmol/liter). In the 51 children studied, BW correlated significantly to insulin sensitivity (r = 0.30; P = 0.032). In the SGA and AGA groups separately, a positive correlation was also found but was not statistically significant (both r = 0.20; not significant). The M-value was significantly lower in the SGA group than in the AGA group (12.9 ± 4.0 vs. 15.6 ± 2.3 mg/kg·min; P = 0.009) after adjustment for BMI (P = 0.001; Table 2
). BMI had a strong independent effect (P < 0.001) on the insulin-stimulated glucose uptake. A similar result was shown after adjustment for the percentage of body fat (expressed as the total of the skin-fold thickness, P = 0.005; or for the waist circumference, P = 0.001). The M-value tended to be higher in SGA children without catch-up growth compared with SGA children with catch-up growth (15.8 ± 4.3 vs. 12.3 ± 3.8 mg/kg·min; P = 0.079) and was comparable to AGA controls (15.6 ± 2.3 mg/kg·min; Table 2). The M-value in SGA children who had shown catch-up growth was comparable to AGA children (13.4 ± 3.4 vs. 15.6 ± 2.3 mg/kg·min; P = 0.06), provided they had a BMI of 17 kg/m2 or less. SGA children with catch-up growth and a BMI greater than 17 kg/m2 were those having the lowest M-values (9.3 ± 3.4 mg/kg·min; Table 2). This was significantly lower than the M-value in AGA children (15.6 ± 2.3; P < 0.001) and significantly lower than the M-value in SGA children with catch-up growth and a BMI of 17 kg/m2 or less (13.4 ± 3.4; P = 0.02).
Discussion
There is no general agreement on whether the association between IUGR with type 2 diabetes in adult life is mediated through insulin resistance or through impairment of ß-cell function as originally suggested by Hales and Barker (14). In the thrifty phenotype hypothesis, it is suggested not only that during intrauterine malnutrition the fetus makes metabolic adaptations that benefit in the short time by increasing fuel availability, but also that these changes become permanent, lasting through life, and are responsible for the development of insulin resistance.
On the other hand, malnutrition may also affect structure and function of the ß-cells causing restricted insulin secretory capacity in further life (20). In rats, a reduced ß-cell mass in the offspring at birth is seen after maternal food restriction during late pregnancy. Subsequent renutrition is followed by increased ß-cell proliferation but insufficiently to fully restore ß-cell mass (21).
In the present study, insulin sensitivity was measured using the hyperinsulinemic-euglycemic clamp technique in young prepubertal children born SGA. Insulin sensitivity, expressed as the M-value, was significantly lower in children who were born SGA, compared with controls. This difference between the two groups became even more significant after adjustment for BMI, which is known to have a strong independent effect on insulin resistance. Some studies have suggested that low BW is a risk factor for the later development of abdominal or truncal obesity, which enhances insulin resistance (22, 23). In our study population, however, BMI and abdominal circumference were higher in AGA than in SGA children, which explains that the reached significance became higher after adjustment for BMI. Consistent with findings of others, we found that SGA children with the highest current BMI are the most insulin resistant (10, 12, 24).
Hofman et al. (25) showed that short prepubertal IUGR children have an impaired insulin sensitivity compared with their normal BW peers. However, they did not include IUGR children who had shown catch-up growth. Interestingly, in the present study, the M-value tended to be higher in SGA children without catch-up growth compared with SGA children with catch-up growth and was comparable to AGA controls. However, in our study, these children without catch-up growth in height in our study group had lower BMI values than the children who did catch-up. Here arises, however, the question whether children who do show catch-up growth in height become fatter as well and so more insulin resistant. This was also recently observed by Forsén et al. (26), who concluded that the increased risk for NIDDM associated with small size at birth is further increased by high growth rates after 7 yr of age. They demonstrated that men and women who developed type 2 diabetes caught up in both height and weight, possibly resulting from high energy intake in childhood and development of above-average BMI values in the women.
Cianfarani et al. (27) did not find a relation between insulin sensitivity and postnatal growth. In the present study, however, the M-value in SGA children who had shown catch-up growth was comparable to AGA children, provided they had a BMI of 17 kg/m2 or less. However, the SGA children with catch-up growth and a BMI greater than 17 kg/m2 were those having the lowest M-values, thus at high risk of developing diabetes type 2 in later life. The implications of our findings in relation to height are unclear, but might be of potential importance when considering GH treatment. In addition, interventions to improve fetal growth and control obesity in childhood seem to be important factors in the prevention of NIDDM.
To ensure normal glucose tolerance in persons with a reduced insulin sensitivity, a higher insulin secretion is needed to compensate for the insulin resistance.
In our study of young prepubertal children, SGA children appeared to be more insulin resistant compared with AGA children. Although not statistically different, during the OGTT, blood glucose levels were higher at all time points in the IUGR group compared with controls. The AUCins0–120/AUCgluc0–120 during the OGTT, which correlates well with ß-cell function, were not different between SGA children and AGA children showing no decreased ß-cell capacity in SGA children.
For now, we can only ascertain insulin resistance as a fixed condition in SGA newborns. Close follow-up of these patients is needed to allow early intervention to prevent or postpone long-term complications of NIDDM. Special attention should be paid to additional factors such as obesity and physical inactivity that further increase insulin resistance, and it may even be questioned whether high energy intake should be encouraged in infancy and early childhood in children who were born SGA.
Acknowledgments
We thank R. J. Heine, M.D., Ph.D., for his help as advisor of the study protocol. We thank the staff of the endocrine laboratory of the VU University Medical Center (head, Dr. C. Popp-Snijders) for performing the hormone determinations. We also thank Novo Nordisk A/S and the Netherlands Organization for Scientific Research for financial support of the project.
Footnotes
Abbreviations: AGA, Appropriate for gestational age; AUC, area under the curve; BW, birth weight; IUGR, intrauterine growth retardation; NIDDM, noninsulin-dependent diabetes mellitus; OGTT, oral glucose tolerance test; SGA, small for gestational age.
Received December 6, 2001.
Accepted June 10, 2002.
References
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P. Cettour-Rose, S. Samec, A. P. Russell, S. Summermatter, D. Mainieri, C. Carrillo-Theander, J.-P. Montani, J. Seydoux, F. Rohner-Jeanrenaud, and A. G. Dulloo Redistribution of Glucose From Skeletal Muscle to Adipose Tissue During Catch-Up Fat: A Link Between Catch-Up Growth and Later Metabolic Syndrome Diabetes, March 1, 2005; 54(3): 751 - 756. [Abstract] [Full Text] [PDF]
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G. Radetti, L. Renzullo, E. Gottardi, G. D'Addato, and H. Messner Altered Thyroid and Adrenal Function in Children Born at Term and Preterm, Small for Gestational Age J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6320 - 6324. [Abstract] [Full Text] [PDF]
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A. Fjellestad-Paulsen, D. Simon, and P. Czernichow Short Children Born Small for Gestational Age and Treated with Growth Hormone for Three Years Have an Important Catch-Down Five Years after Discontinuation of Treatment J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1234 - 1239. [Abstract] [Full Text] [PDF]
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R. A. Bazaes, A. Alegria, E. Pittaluga, A. Avila, G. Iniguez, and V. Mericq Determinants of Insulin Sensitivity and Secretion in Very-Low-Birth-Weight Children J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1267 - 1272. [Abstract] [Full Text] [PDF]
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S. Cianfarani, C. Martinez, A. Maiorana, G. Scire, G. L. Spadoni, and S. Boemi Adiponectin Levels Are Reduced in Children Born Small for Gestational Age and Are Inversely Related to Postnatal Catch-Up Growth J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1346 - 1351. [Abstract] [Full Text] [PDF]
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N. Soto, R. A. Bazaes, V. Pena, T. Salazar, A. Avila, G. Iniguez, K. K. Ong, D. B. Dunger, and M. V. Mericq Insulin Sensitivity and Secretion Are Related to Catch-Up Growth in Small-for-Gestational-Age Infants at Age 1 Year: Results from a Prospective Cohort J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3645 - 3650. [Abstract] [Full Text] [PDF]
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M. A. Veening, M. M. van Weissenbruch, R. J. Heine, and H. A. Delemarre-van de Waal {beta}-Cell Capacity and Insulin Sensitivity in Prepubertal Children Born Small for Gestational Age: Influence of Body Size During Childhood Diabetes, July 1, 2003; 52(7): 1756 - 1760. [Abstract] [Full Text] [PDF]
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S. Cianfarani, A. Maiorana, C. Geremia, G. Scire, G. L. Spadoni, and D. Germani Blood Glucose Concentrations are Reduced in Children Born Small for Gestational Age (SGA), and Thyroid-Stimulating Hormone Levels are Increased in SGA with Blunted Postnatal Catch-up Growth J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2699 - 2705. [Abstract] [Full Text] [PDF]
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