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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2007-0079
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 10 3836-3843
Copyright © 2007 by The Endocrine Society

Insulin Resistance in Hispanic Large-for-Gestational-Age Neonates at Birth

Jennifer Shine Dyer, Charles R. Rosenfeld, Julie Rice, Mark Rice and Dana S. Hardin

Department of Pediatrics (J.S.D., J.R., M.R., D.S.H.), Division of Endocrinology, The Ohio State University School of Medicine, Columbus, Ohio 43205; and Department of Pediatrics (C.R.R.), Divisions of Neonatal-Perinatal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390

Address all correspondence and requests for reprints to: Jennifer Shine Dyer, M.D., Department of Pediatrics, Division of Endocrinology, The Ohio State University, 700 Children’s Drive, W322, Columbus, Ohio 43205. E-mail: dyerj{at}pediatrics.ohio-state.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Content: Intrauterine exposure to maternal diabetes and large size at birth are known risk factors for the subsequent development of insulin resistance and metabolic syndrome. Although Hispanic youth have been shown to have a high prevalence of metabolic syndrome, it is unknown whether metabolic abnormalities and a predisposition for glucose intolerance are present at birth.

Objective: The objective of the study was to determine whether abnormalities in insulin sensitivity exist at or soon after birth in large-for-gestational-age neonates born to Hispanic women with and without gestational diabetes.

Design/Patients/Setting: Forty-two term Hispanic neonates were enrolled for cross-sectional studies at 24–48 h after birth and included nine large-for-gestational-age neonates delivered of women with gestational diabetes (large-for-gestational-age-IDM), 12 large-for-gestational-age but not IDM neonates, 11 poorly grown (at the fifth to 10th percentile), and 10 appropriate-for-gestational-age neonates. Insulin sensitivity and secretion were measured by shortened fasting iv glucose tolerance test.

Main Outcome Measure: Insulin sensitivity index was measured within 48 h of birth.

Results: Neonates were studied at 36 ± 11 h postnatally, and all groups were euglycemic at the time of study. However, insulin sensitivity was significantly lower (P < 0.05, ANOVA) in large-for-gestational-age-IDM [3.0 ± 0.7 (SEM) mU/liter·min] and large-for-gestational-age-non-IDM (2.2 ± 0.4 mU/liter·min) cohorts in comparison with poorly grown (5.0 ± 0.7 mU/liter·min) and appropriate-for-gestational-age controls (5.4 ± 0.8 mU/liter·min). Insulin secretion did not differ between groups.

Conclusions: Reduced insulin sensitivity is present soon after birth in Hispanic large-for-gestational-age neonates born to mothers with and without gestational diabetes, demonstrating the onset of insulin resistance before birth and evidence of altered fetal programming.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE PREVALENCE OF metabolic syndrome during childhood and adolescence has increased in the past decade, paralleling increases in childhood obesity. The prevalence of metabolic syndrome in the Third National Health and Nutrition Examination Survey was 29% in obese adolescents ages 12–19 yr, with the highest rates among Hispanic youth (1). Ten years later, the prevalence was 50% in markedly obese children and adolescents aged 4–20 yr (2). Insulin resistance, a key component of metabolic syndrome, is an early pathogenic event in the development of type 2 diabetes mellitus (T2DM) (3). Progressive impairment of compensatory insulin secretion reflected by chronic insulin resistance is a predictor of adult-onset T2DM (4). Thus, the progression of chronic insulin resistance and metabolic syndrome toward the development of T2DM may explain the increased prevalence of T2DM in American youth in the past 10 yr (5). However, it is unclear when in infancy or childhood this begins.

Despite improved understanding of the pathophysiology of metabolic syndrome and T2DM, the association of alterations during development and the occurrence of these processes are unclear. Evidence from animal studies suggests that modifications in the fetal environment at a critical time in development may result in a milieu that benefits the developing fetus but is adverse after birth (6). Thus, alterations in normal fetal programing in utero may contribute to development of adult-onset chronic diseases, including metabolic syndrome and T2DM (7).

Barker and Osmond (8) hypothesized that birth weight (BW) was a measure of fetal adaptation and programing during pregnancy and a risk factor for adult-onset ischemic heart disease (8). Barker and Hales (9) subsequently reported a relationship between low BW at term gestation and the subsequent diagnosis of metabolic syndrome and T2DM, leading to the thrifty phenotype hypothesis. Similar associations have been observed in other populations and are no longer considered peculiar to the initial population studied. A relationship between large-for-gestational-age BW, in the presence and absence of maternal diabetes and the later onset of metabolic syndrome and T2DM, was observed in Pima Indians, who have a very high prevalence of metabolic syndrome and T2DM (10, 11). This relationship between large-for-gestational-age and development of metabolic syndrome and T2DM also occurs in American children and adolescents (12, 13). Therefore, a collective U-shaped risk curve involving term and near-term infants at the extremes of the BW spectrum has evolved.

There are no longitudinal outcome studies of the evolution of metabolic syndrome and T2DM in children. In a cross-sectional study of small-for-gestational-age (SGA) neonates, Soto et al. (14) observed greater insulin sensitivity at birth in SGA neonates vs. controls. However, at 1 yr of age, insulin sensitivity decreased, compared with controls, at a time when weight gain exceeded linear growth, suggesting a maladaptation of fetal programming to the environment in the first year. In contrast, a cross-sectional study of Asian-Indian SGA, appropriate-for-gestational-age (AGA), and large-for-gestational-age term neonates at 7 d postnatal demonstrated high fasting insulin levels in SGA and large-for-gestational-age groups (15). There are no cross-sectional studies that examine the insulin sensitivity at birth in large-for-gestational-age neonates born to mothers with and without gestational diabetes. Furthermore, studies of Hispanic neonates, who are high risk for development of metabolic syndrome and T2DM in adolescence, are lacking. Given that current temporal trends suggest an increase in large-for-gestational-age births (16), that the incidence of gestational diabetes has increased over the past decade (17), and that current U.S. census projections predict a doubling of the Hispanic population by 2050 (18), understanding the pathogenesis of metabolic syndrome and T2DM in this high-risk population is critical.

The objective of this study was to measure insulin sensitivity soon after birth in large-for-gestational-age neonates born to Hispanic women with and without gestational diabetes to determine whether there are prenatal metabolic changes that might set the stage for the subsequent development of metabolic syndrome or T2DM. We also measured and compared insulin sensitivity in AGA neonates and neonates with BW at the 10%, a group considered to be at risk for development of metabolic syndrome (9).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

We studied Hispanic neonates delivered at Parkland Memorial Hospital, Dallas County Hospital District, between December 1, 2004, and February 28, 2006. Parkland Memorial Hospital has an annual birth rate of approximately 16,000. The delivery population is 79% Hispanic and 15% African-American; maternal age is younger than 20 yr in 20%, and 95% of women receive prenatal care (19). Inclusion criteria included postnatal age of 24–48 h and gestational age 37–40 wk. Exclusion criteria included any acute illness requiring intensive care; maternal HIV; exclusive breast-feeding; hypoglycemia (serum glucose < 40 mg/dl) beyond 6 h of life (20); and evidence of congenital abnormalities, pituitary disorders, cystic fibrosis, neonatal diabetes, or hepatic or renal disease. Informed consent was obtained from the parent(s) at recruitment. Alexander growth curves were used to determine BW distribution for gestational age (21). Neonates of diabetic mothers (IDM) were defined as neonates born to women with any class of diabetes during pregnancy. Once classifications for BW and diabetes were made, neonates were placed into one of four study groups: large-for-gestational-age-IDM, large-for-gestational-age-non-IDM, AGA, or poorly grown. Large-for-gestational-age had a BW greater than the 90th percentile for gestational age and AGA had BW at the 25–75th percentile for age. Poorly grown neonates, who have an increased prevalence of adult-onset metabolic syndrome (9), had a BW at the fifth to 10th percentile for age. They were included to contrast with the large-for-gestational-age cohorts, who also have an increased prevalence of metabolic syndrome later in life. Only Hispanic neonates were enrolled because of their increased prevalence rates of metabolic syndrome per the Third National Health and Nutrition Examination Survey (1) and to eliminate the confounding effects of ethnic variations in insulin sensitivity (22). This study was approved by the Institutional Review Board at the University of Texas Southwestern Medical Center at Dallas.

Data collection

Maternal records were reviewed for prepregnancy obesity, weight gain during pregnancy, gestational diabetes screening, diabetes control, and family history of diabetes. Prepregnancy weights within 1 yr of the current pregnancy were reported by the mothers at the time of study. Heights and weights before delivery were measured at each prenatal clinic visit. Maternal weight on the day of delivery was documented in the medical record. We examined results of diabetes screening, conducted according to American Diabetes Association position statement (23), at 24–28 wk gestation in all women who received prenatal care. We also reviewed all available hemoglobin A1C (HbA1C) values to assess glycemic control in the diabetic women. Gestational age was determined by Ballard exam (24). BW to the nearest gram was obtained within the first hour postnatal while naked and before the first feeding using an electronic integrating scale (TLC 120A; Tanita, Tokyo, Japan) as well as crown-heel length to the nearest millimeter using a recumbent infant board and a Harpenden stadiometer (Crymych, Pembs, UK). Head, waist, and arm circumferences were measured with a tape. Body mass index (BMI) and ponderal index (PI) were calculated: PI = [BW(grams)/length(centimeters)3] x 100. Head circumference was measured by placing the tape firmly above the supraorbital ridge and occiput. Waist circumference was measured just above the umbilicus in a fasting state and arm circumference at the midhumerus before iv placement. Body composition was assessed at the conclusion of each feed by bioelectrical impedance analysis (model 310e body composition analyzer machine; Biodynamics, Seattle, WA) while the neonate was on a nonconductive surface and wearing a dry diaper. Bioresistance correlates negatively with lean body mass measurements obtained by dual-energy x-ray absorptiometry and deuterium oxide dilution methodologies in adults, children, and neonates (25, 26, 27). Normal values for bioresistance are available in Italian infants (28), but values for Hispanic neonates have not been reported. All measurements were made by one investigator (J.S.D.).

Measurement of insulin sensitivity and insulin secretion

Studies were performed in the fasting state, defined as 3 h from the most recent feeding. At the time of study, 0.5 g/kg of dextrose (20 g/100 cc) was infused over 3 min. Blood samples for measurements of glucose and insulin were collected at –3, 1, 3, 5, and 10 min (14). Additional blood was collected before infusion for other assays, resulting in a total collection of 2.6 ml. Baseline samples were obtained in all but one AGA neonate in whom iv access was unsuccessful.

Bergman’s minimal model was used to assess glucose-insulin kinetics with shortened frequently sampled iv glucose tolerance test (FSIVGTT). Tolbutamide and insulin infusions were omitted, given that neonates without prenatal growth restriction are presumed to have normal endogenous insulin secretion before and at birth (29, 30). The validity and reproducibility of the shortened FSIVGTT without tolbutamide or insulin infusion has been shown to estimate insulin sensitivity accurately in nondiabetic subjects with normal endogenous insulin levels (31). MinMod Millennium software (32) was used to calculate insulin sensitivity, acute first-phase insulin secretion (AIRg), glucose effectiveness (Sg), and disposition index (DI) from paired glucose and insulin samples obtained from shortened FSIVGTT. The insulin sensitivity quantifies the capacity of insulin to promote glucose disposal; AIRg quantifies the adequacy of insulin secretion; Sg quantifies the capacity of glucose to mediate its own disposal independent of insulin. The DI is the product of AIRg x insulin sensitivity and provides an evaluation of whether insulin secretion is appropriate for the level of insulin sensitivity.

Other laboratory measures

Additional blood was collected to measure leptin, triglycerides, total cholesterol, high-density lipoprotein (HDL)-cholesterol, blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Samples were centrifuged at 16,100 x g, the serum removed, and stored at –20 C until analysis. Insulin (ultrasensitive insulin ELISA, Mercodia, Uppsala, Sweden) and leptin (leptin ELISA, Diagnostic Systems Laboratories, Webster, TX) were measured by enzyme immunoassay. Both had intraassay coefficients of variation less than 5%. The insulin assay had an interassay coefficient of variation of 10%, whereas the leptin assay was close to 70%, reflecting decreased reproducibility most notable at higher values. Plasma glucose was measured by automated random-access analyzer (YSI, Yellow Springs, OH) with intra- and interassay coefficients of variation of 2% and less than 15%, respectively. BUN/creatinine, AST, ALT, triglycerides, total cholesterol, and HDL-cholesterol were measured with a clinical chemistry analyzer (Synchron clinical chemistry analyzer, CX9ALX model; Beckman, Ramsey, MN) in the CLIA-certified General Clinical Research Center laboratory at Parkland Memorial Hospital at which quality assurance procedures were used. Low-density lipoprotein (LDL) was calculated by the Friedwald LDL formula [LDL-cholesterol = total cholesterol [minus] (HDL-cholesterol + triglycerides/5)], given that all triglyceride levels were less than 400 mg/dl. All results are noted to be independent from the time at which the tests were performed because samples were frozen at –70 C just after collection.

Statistical analyses

Two-way ANOVA for multiple groups was used to analyze variance in the comparison of independent means among four groups. Kruskal-Wallis was used when unequal variances were noted. Fasting insulin and leptin values were log transformed before analysis to obtain normal distributions. When differences by ANOVA had P < 0.05, pair-wise comparisons were undertaken using least-squared means of ANOVA. When pair-wise comparisons were analyzed, statistical significance was defined as P < 0.01 and determined by Bonferroni correction for multiple comparisons. SPSS software (SPSS Inc., Chicago, IL) was used. The primary outcome variable was specified as the insulin sensitivity. A fixed sample size of 48 neonates was specified for recruitment based on a priori analysis, which defined {alpha} as 0.05 and ß as 0.2, giving a power of 0.8 to determine an effect of size difference of 2 mU/liter·min. Data are reported as means ± SD for subject characterizations, indicators of glucose metabolism, and fasting lipid levels unless otherwise specified; insulin sensitivity and fasting leptin values are reported as means ± SEM. Prepregnancy weight, weight at delivery, and weight at 24- to 28-wk clinic visits were compared with assessment of differences in pregnancy weight gain, given that animal studies show similarities between the influence on metabolic fetal outcomes when dietary restrictions/excesses are made within the third trimester as when made throughout the entire pregnancy (33).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Maternal characteristics

All but one woman received prenatal care for a minimum of 3 months, and she was the mother of an AGA neonate who presented at the time of delivery. All but four women receiving prenatal care underwent a 1-h glucose challenge test (GCT) at 24–28 wk gestation; two had AGA neonates and two large-for-gestational-age-non-IDM neonates. Maternal factors that might affect BW, including age, gravida, and height, were comparable for all mothers of study neonates (Table 1Go). Minimal ethnic variation was noted, given that both parents had identical countries of origin. Three women were born in El Salvador, one in Colombia, and one was a first-generation descendant of Mexican parents; all other women were born in Mexico. Each set of parents was born in the same country or were first-generation descendants of parents from the same countries of origin. Large-for-gestational-age-IDM mothers were more likely to have BMI greater than 30 kg/m2 and higher 1-h GCT glucose values at 24–28 wk than all other groups; but there were no group differences in weight gain during pregnancy. Large-for-gestational-age-IDM mothers showed moderate metabolic control of their diabetes, as evidenced by a mean HbA1C of 6.8 ± 0.9%. Mothers of large-for-gestational-age-non-IDM, poorly grown, and AGA neonates had comparable 1-h GCT glucose values at 24–28 wk, ruling out any confounding effects of undiagnosed congenital or gestational diabetes. No differences were noted between groups for family history of T2DM.


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  		TABLE 1. Maternal demographics, anthropometrics, and indicators of glucose metabolism during pregnancy

 
Neonatal characteristics

Neonates were studied at 36 ± 11 h postnatal and included nine large-for-gestational-age-IDM, 12 large-for-gestational-age-non-IDM, 11 poorly grown, and 10 AGA neonates. Seven of the large-for-gestational-age-IDM neonates were born to women with class A1 gestational diabetes diagnosed at 24–28 wk gestation and treated with a 2000-calorie American Diabetes Association diet per standard of care. One large-for-gestational-age-IDM neonate was born to a woman with class A2 gestational diabetes diagnosed at 24–28 wk gestation and treated with NPH and regular insulin. One large-for-gestational-age-IDM neonate was born to a woman with insulin-dependent T2DM diagnosed 5 yr earlier during a prior pregnancy and required treatment with NPH and regular insulin. Apgar scores did not differ between groups, 8.1 ± 1.2 (SD) and 8.9 ± 0.5 at 1 and 5 min, respectively. There were no differences in the distribution of gender or gestational age between groups (Table 2Go). Large-for-gestational-age-IDM and large-for-gestational-age-non-IDM neonates had similar anthropometric and demographic features as well as greater BW, head circumference, and BMI than poorly grown and AGA controls. The PI for poorly grown and AGA controls were in the 75–90th percentile range of Lubchenco’s norms for gestational age (34). Both large-for-gestational-age groups had had greater waist and arm circumference measurements and abnormally high mean PIs (3.2–3.3 g/cm3); thus, the larger head circumferences for both large-for-gestational-age groups was proportionate to their heights and BW. There were no differences between groups in body composition determined by estimates of bioresistance.


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  		TABLE 2. Demographics and anthropometrics of neonate study population

 
Neonatal insulin sensitivity

Minimal model calculations could not be determined for one large-for-gestational-age-IDM, three large-for-gestational-age-non-IDM, and one poorly grown and one AGA neonate due to inability to sustain iv access and collect time points beyond the initial fasting samples. The insulin sensitivity for large-for-gestational-age-IDM and large-for-gestational-age-non-IDM neonates was similar, 3.0 ± 0.7 (SEM) vs. 2.2 ± 0.4 mU/liter·min, respectively (Fig. 1Go; P = 0.4, ANOVA). Although poorly grown and AGA neonates had a similar insulin sensitivity, 5.0 ± 0.7 vs. 5.4 ± 0.8 mU/liter·min, respectively (P = 0.7, ANOVA), their insulin sensitivity exceeded the large-for-gestational-age-non-IDM neonates at 24–48 h of age (Fig. 1Go; P < 0.01, ANOVA for all pair-wise comparisons). Large-for-gestational-age-IDM neonates had low but intermediate insulin sensitivity values, compared with poorly grown and AGA neonates (P < 0.05, ANOVA). Fasting insulin levels in large-for-gestational-age-IDM neonates were greater than poorly grown and AGA neonates (Table 3Go, P < 0.01) but similar to large-for-gestational-age-non-IDM. The correlation between fasting insulin levels and insulin sensitivity was poor (r = –0.04, P = 0.005), as was the correlation between insulin sensitivity and BW (r = –0.4, P < 0.0001). There was no correlation between mean maternal 1-h GCT glucose values and insulin sensitivity (r = –0.1, P = 0.6). There was no relationship between insulin sensitivity and mode of delivery (P = 0.59, Wilcoxon rank sum test) despite the fact that large-for-gestational-age neonates were more likely to be delivered by cesarean section (odds ratio 4.02, 95% confidence interval 0.09, 2.71).


Figure 1
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  		FIG. 1. Comparison of insulin sensitivity indexes (milliunits per liter per minute) in the first 24–48 h after birth in large-for-gestational-age neonates born to mothers with and without diabetes, neonates with birth weights at the fifth to 10th percentile for age (poorly grown), and neonates with birth weights AGA.

 

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  		TABLE 3. Indicators of glucose regulation of neonate study population in first 48 h after birth

 
Neonatal insulin secretion and indicators of glucose regulation

Normal serum glucose levels were observed in all neonates (Table 3Go), and first-phase insulin secretion, assessed by AIRg in the first-phase pancreatic response to an iv glucose load, was comparable between groups. The DI, an assessment of ß-cell compensation for insulin resistance, also was comparable between groups, suggesting good compensation by both large-for-gestational-age groups for insulin resistance (P = 0.06, ANOVA) with a notable large variation between members within each of the groups. Although the Sg was similar in the large-for-gestational-age group and AGA controls (Table 3Go; P > 0.1, ANOVA), poorly grown neonates had elevated values (P < 0.001 for each pair-wise comparison, ANOVA).

Neonatal leptin levels

Fasting serum leptin was 10-fold greater in both large-for-gestational-age groups vs. poorly grown and AGA neonates (P < 0.001, ANOVA) but did not differ from each other (Fig. 2AGo; P = 0.2, ANOVA). Levels in poorly grown and AGA neonates also were similar (Fig. 2AGo; P = 0.06, ANOVA). Leptin levels correlated positively with higher BW (r = 0.86, P < 0.0001), length (r = 0.69, P < 0.0001), BMI (r = 0.84, P < 0.0001), PI (r = 0.75, P < 0.0001), waist circumference (r = 0.80, P < 0.0001), arm circumference (r = 0.80, P < 0.0001), and fasting insulin (r = 0.57, P < 0.0001). There also was a negative correlation between insulin sensitivity and fasting leptin levels (Fig. 2BGo; r = –0.45, P = 0.005).


Figure 2
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  		FIG. 2. A, Comparison of fasting leptin levels in first 24–48 h after birth in large-for-gestational-age neonates born to mothers with and without diabetes, neonates with birth weights at the fifth to 10th percentile for age (poorly grown), and neonates with birth weights AGA. B, Linear regression correlation of insulin sensitivity with log-transformed fasting leptin levels in all groups of neonates in first 48 h after birth (r = –0.46, P = 0.005).

 
Neonatal lipid levels and other laboratory measures

There were no differences between groups for fasting lipid levels (Table 4Go), BUN, creatinine, AST, or ALT.


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  		TABLE 4. Fasting lipid levels of neonate study population in first 48 h after birth

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Studies in Pima Indians (10, 11) and recent analyses of American youth (12, 13) have linked large-for-gestational-age-non-IDM, and large-for-gestational-age-IDM neonates with later development of metabolic syndrome and T2DM. One explanation is that the intrauterine exposure to maternal diabetes and alterations in fetal glucose, insulin, or other factors results in altered fetal adaptation and changes in normal fetal programming (35). However, no one to date has examined these neonates for metabolic changes soon after birth, e.g. within 24–48 h, nor has anyone studied the Hispanic population, who have a high risk for childhood development of metabolic syndrome, and T2DM (36). In the present study, we identified abnormalities in insulin sensitivity in large-for-gestational-age-non-IDM and large-for-gestational-age-IDM Hispanic neonates within 48 h of birth, suggesting alterations in fetal programming and onset of insulin resistance, which may be associated with the juvenile or adult-onset of metabolic syndrome or T2DM.

Investigators have consistently demonstrated a relationship between large-for-gestational-age neonates born to women with and without diabetes and the later onset of metabolic syndrome or T2DM. Although our study cannot directly link the decreased insulin sensitivity in large-for-gestational-age-non-IDM and large-for-gestational-age-IDM neonates at birth to the occurrence of metabolic syndrome or T2DM, the possibility is now apparent. Support for this is obtained from studies of Pima Indians, who have been studied longitudinally since 1965 and have one of the highest risks for development of T2DM in the world (37, 38), e.g. 50% of adults older than 35 yr of age have diabetes (10). In these studies, Pima Indians had an increased risk for developing T2DM at earlier ages when they were large-for-gestational-age at birth (11) and delivered of women with diabetic pregnancies (45 vs. 1.4%) (35).

The presence of insulin resistance at birth in Hispanic large-for-gestational-age-non-IDM and large-for-gestational-age-IDM neonates combined with later environmental challenges, including overnutrition and inactivity, may explain the relationship between large-for-gestational-age at birth and later development of metabolic syndrome and T2DM. The presence of chronic insulin resistance and the additional challenges of excessive growth and/or obesity may result in an attenuated capacity to increase insulin secretion, thereby contributing to the natural history of metabolic syndrome and development of T2DM. Although we demonstrated appropriate insulin secretion and compensation at birth for deficiencies in insulin sensitivity in both large-for-gestational-age cohorts as evidenced by appropriate DI values, longitudinal studies in Finnish adults point to baseline insulin resistance and compensatory abnormalities in ß-cell function as evidenced by decreasing DI indexes over time as predictors for later development of T2DM (4). Therefore, longitudinal studies of DI are needed in this population to assess changes in insulin secretion and DI and determine whether DI predicts the later development of T2DM in childhood. Given that there was significant variation in DI within and between groups in our study, a larger sample size would be required to assess for true differences between groups among such large variance.

There were no differences in metabolic measures between large-for-gestational-age-non-IDM and large-for-gestational-age-IDM neonates, which could reflect small sample sizes in the large-for-gestational-age groups. However, if the lack of differences is true, the additive effect of maternal diabetes during pregnancy plus large-for-gestational-age BW on the prevalence of metabolic syndrome in children noted by Boney et al. (13) cannot be explained by our results. It is possible that longitudinal changes over time between the large-for-gestational-age-non-IDM and large-for-gestational-age-IDM cohorts, which are not addressed in our study, account for these discrepancies. However, similarities between the effect of undetected hyperglycemia in nondiabetic mothers and continuous hyperglycemia with gestational diabetes on fetal programming could contribute to the similarities in the large-for-gestational-age cohorts. Although the large-for-gestational-age nondiabetic mothers in our study did not have gestational diabetes by current guidelines, the 1-h GCT test is unreliable at detecting episodic or mild hyperglycemia (39). Furthermore, Franks et al. (40) noted an association with higher 2-h GCT glucose values during pregnancy and diabetes in the offspring of Pima Indians when the women were glucose tolerant. Thus, the occurrence of subclinical maternal hyperglycemia in the presence of a normal 1-h GCT test could modify fetal homeostasis, resulting in the similarities in large-for-gestational-age neonates of diabetic and nondiabetic mothers. Furthermore, the presence of maternal metabolic syndrome in midpregnancy is an independent predictor of fetal macrosomia in women with any degree of hyperglycemia (41). Although we did not assess the mothers in our study for metabolic syndrome, the presence of maternal metabolic syndrome in either large-for-gestational-age cohorts could account for the similarities noted. However, it is unclear in Pima Indians whether the occurrence of fetal macrosomia independent of exposure to maternal diabetes is more influential on the prevalence of diabetes in the offspring than the presence of gestational diabetes alone (42). Further study is necessary to address this possibility.

Although a strong association with low BW and later development of metabolic syndrome and T2DM has been shown (9, 43), the insulin sensitivity was normal in the cohort of poorly grown neonates. Glucose/insulin kinetics have been examined in SGA neonates at 48 h postnatal and 1 yr (14). These infants had a high insulin sensitivity, compared with AGA controls at 1 month of age, but low insulin sensitivity at 1 yr. This, however, was seen in SGA infants with increased weight catch-up growth. Our results in the poorly grown cohort at less than 48 h are consistent with these observations, i.e. a lack of insulin resistance at birth. However, we did not detect differences between AGA controls and poorly grown neonates. These discrepancies may reflect differences in BW inclusion criteria [SGA (< the third percentile) vs. Barker’s poorly grown (fifth to 10th percentile)]. Noncomparable methodologies for assessment of insulin sensitivity at birth (glucose to insulin ratio vs. FSIVGTT) may also account for the differences between studies. Further studies are needed to assess changes in insulin sensitivity in this high-risk group.

Our study is the first to correlate leptin levels with decreased insulin sensitivity in neonates. Given that exogenous, high-dose leptin improves insulin sensitivity in patients with Rabson-Mendenhall syndrome and severe insulin resistance due to an insulin receptor mutation (43), the elevated leptin levels in the presence of insulin resistance in our study have been termed leptin resistance. Whether leptin resistance causes insulin resistance or insulin resistance causes leptin resistance is unclear.

The lack of intergroup differences in lipids is consistent with studies in Asian-Indian neonates at 7 d postnatal (15), suggesting that abnormalities of insulin sensitivity at birth do not apply to lipolysis. However, our sample size was not designed to detect differences between groups. In light of the large SD values observed, it is possible that differences in lipolysis would be identified in a larger study population.

We have demonstrated that large-for-gestational-age neonates born to mothers with and without diabetes have defects in insulin sensitivity at birth, reflecting prenatal alterations in metabolic programming that could contribute to the later development of metabolic syndrome or T2DM in childhood or adulthood. The permanence of these changes and plasticity of these fetal metabolic adaptations, both perinatally and postnatally, are important areas for further research.


   Footnotes
 
This work was supported by a grant from the Children’s Medical Center at Dallas Clinical Research Advisory Committee’s and a grant from the Genentech Center for Clinical Research in Endocrinology Fellowship.

First Published Online July 17, 2007

Abbreviations: AGA, Appropriate for gestational age; AIRg, acute first-phase insulin secretion; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BUN, blood urea nitrogen; BW, birth weight; DI, disposition index; FSIVGTT, frequently sampled iv glucose tolerance test; GCT, glucose challenge test; HbA1C, hemoglobin A1C; HDL, high-density lipoprotein; IDM, women with gestational diabetes; LDL, low-density lipoprotein; PI, ponderal index; Sg, glucose effectiveness; SGA, small for gestational age; T2DM, type 2 diabetes mellitus.

Received January 12, 2007.

Accepted July 9, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH 2003 Prevalence of a metabolic phenotype in adolescents: findings from the Third National Health and Nutrition Examination Survey, 1988–1994. Arch Pediatr Adolesc Med 157:821–827[Abstract/Free Full Text]
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J. Beltrand, R. Verkauskiene, R. Nicolescu, O. Sibony, P. Gaucherand, D. Chevenne, O. Claris, and C. Levy-Marchal
Adaptive Changes in Neonatal Hormonal and Metabolic Profiles Induced by Fetal Growth Restriction
J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 4027 - 4032.
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