PEDIATRICS Vol. 120 No. 5 November 2007, pp. 958-965 (doi:10.1542/peds.2007-0165)
ARTICLE |
Lipolysis and Insulin Sensitivity at Birth in Infants Who Are Large for Gestational Age
Department of Women's and Children's Health, Uppsala University, University Children's Hospital, Uppsala, Sweden
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. In addition to neonatal hypoglycemia, infants who are born large for gestational age are at risk for developing obesity, cardiovascular disease, and diabetes later in life. The aim of this study was to investigate glucose production, lipolysis, and insulin sensitivity in infants who were born large for gestational age to mothers without diabetes. The effect of glucagon administration on production of energy substrates was also investigated.
METHODS. Ten healthy term infants who were born large for gestational age to mothers without diabetes were studied 16 ± 8 hours postnatally after a 3-hour fast. Rates of glucose production and lipolysis were analyzed by gas chromatography–mass spectrometry following constant rate infusion of [6,6-2H2]glucose and [2-13C]glycerol. Insulin sensitivity was assessed by the Homeostasis Assessment Model. In 8 of the infants, the effect of an intravenous injection of 0.2 mg/kg glucagon was also analyzed.
RESULTS. Plasma glucose and glycerol averaged 3.8 ± 0.5 mmol/L and 384 ± 183 µmol/L, respectively. The glycerol production rate, reflecting lipolysis, was 12.7 ± 2.9 µmol/kg per min. Mean rate of glucose production was 30.2 ± 4.6 µmol/kg per min. Homeostasis Assessment Model insulin sensitivity corresponded to 82% ± 19%, β-cell function to 221% ± 73%, and insulin resistance to 1.3 ± 0.3. After glucagon administration, rate of glucose production increased by 13.3 ± 8.3 µmol/kg per min and blood glucose by 1.4 ± 0.5 mmol/L. Glycerol production decreased from 12.8 ± 3.0 to 10.7 ± 2.9 µmol/kg per min. Mean insulin concentration increased from 10.9 ± 3.0 to 30.9 ± 10.3 mU/L. There was a strong inverse correlation between the decrease in lipolysis and increase in insulin after glucagon administration.
CONCLUSIONS. Infants who are born large for gestational age show increased lipolysis and a propensity for decreased insulin sensitivity already at birth. The simultaneous increase in plasma insulin correlated strongly with the noted decrease in lipolysis, indicating an antilipolytic effect of insulin in these infants.
Key Words: LGA • glucose production • lipolysis • newborn infant • insulin sensitivity
Abbreviations: LGA—large for gestational age • AGA—appropriate for gestational age • m/z—mass-to-charge ratio • SGA—small for gestational age • IGF-1—insulin-like growth factor 1 • IGFBP-1—insulin-like growth factor–binding protein 1 • GPR—rate of glucose production • CV—coefficient of variation • HOMA—homeostasis model assessment
Obesity is a major health problem in the Western world. There has been a marked increase in the prevalence of overweight and obesity among children during the past few decades.1,2 Correspondingly, the relative number of infants who are born large for gestational age (LGA) has also increased.3 Data show that infants who are born LGA have a high prevalence of overweight when they reach adolescence and are at increased risk for developing cardiovascular disease and type 1 as well as type 2 diabetes in adult life.4–7 Infants who are born LGA, irrespective of its cause, are also at risk for having neonatal hypoglycemia.8–10
At birth, the continuous placental flow of nutrients, mostly glucose and amino acids, is terminated. Before breastfeeding is established, the newborn infant has to produce glucose, mainly to meet the needs of the central nervous system.11,12 Glucose is the most important energy substrate for the brain, and during rest, the central nervous system consumes the major part of the hepatic glucose production.
Neonatal energy substrate production has been extensively studied in both infants who are appropriate for gestational age (AGA) and infants who belong to risk groups (eg, those born preterm or small for gestational age [SGA], infants of mothers with diabetes).13–15
The immediate postnatal glucose production and lipolysis are under hormonal regulation. Hepatic glucose production is stimulated by a decreased insulin/glucagon ratio, and lipolytic hydrolysis of depot fat is enhanced by the marked increase in thyrotropin that occurs during the first day of life.16 In contrast to the situation later in life, it is not established whether insulin has a role in the regulation of lipolysis in newborn infants.
The relation between fetal/neonatal nutrition and adult metabolic disease has been discussed extensively in recent years.17 It has been reported, for instance, that infants who are born SGA have increased insulin sensitivity18 at birth, although they may develop insulin resistance already in childhood.19
Besides the risk for neonatal hypoglycemia10 infants who are born LGA are at risk for developing obesity and metabolic disease later in life. No information is available on neonatal insulin sensitivity or formation of energy substrates in infants who are born LGA. The aim of this study was to estimate the rates of glucose production and lipolysis and also to assess the insulin sensitivity in infants who are born LGA to mothers without diabetes. In view of the risk for hypoglycemia, despite large energy depots20 in this particular group of infants, the effect of exogenous glucagon on energy substrate production was also investigated.
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METHODS |
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The Human Ethics Committee of the Medical Faculty, University of Uppsala, approved the study.
Study Infants
Ten healthy newborn term infants who had a mean gestational age of 40 ± 1.6 weeks and a mean birth weight of 4734 ± 487 g and were born LGA (4 girls) to mothers who did not have diabetes (Table 1) were recruited at the maternal ward of Uppsala University Hospital. Oral consent was obtained from both parents after oral and written information. Five of the infants were delivered by cesarean section and 5 vaginally. The pregestational BMI of the mothers averaged 29.5 ± 7 kg/m2. Eight of the mothers were healthy, and 1 was receiving medication for depression (Sertraline 150 mg/day) and 1 had mild asthma treated intermittently with beclomethasone. For screening of the pregnant population, fasting blood glucose levels are measured 4 times during pregnancy (weeks 10–14, 20–24, 28–32, and 32–36). If the blood glucose exceeds 8.0 mmol/L, then an oral glucose tolerance test is performed. This was necessary for 1 woman, and the results of here oral glucose tolerance test were normal.
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LGA was defined as a birth weight >2 SD for gestational age according to the Swedish fetal growth chart.21 Five infants were also tall for gestational age.21 Gestational age was determined by ultrasound examination in weeks 16 to 18 of pregnancy. The infants were studied at a postnatal age of 16 ± 8 hours. Before the study, all infants were breastfed. Two infants also received formula. The interval between the last feed and the study was at least 3 hours. No infant developed hypoglycemia during the investigation.
Isotope Tracers
[6,6-2H2]Glucose (isotopic purity: 98%) and [2-13C] glycerol (isotopic purity: 98%) were purchased from Cambridge Isotope Laboratories (Woburn, MA). The [6,6-2H2]glucose and [2-13C]glycerol were dissolved in 0.9% saline in concentrations of 4.5 and 1.2 mg/mL, respectively. The tracers were tested for sterility and pyrogenicity as described previously.22
Study Design
The study was performed at the neonatal care unit of the University Children's Hospital (Uppsala, Sweden). Two peripheral vein catheters were inserted, 1 for infusion of the tracers and the other for collection of blood samples. The tracers were infused for 140 minutes.15 Blood samples were obtained before the start of the tracer infusion and then every 10 minutes between 60 and 140 minutes (a total of 8–9 samples; 1 mL per sample corresponded to 
2.2% of the estimated blood volume). The effect of an intravenous injection of 0.2 mg/kg glucagon (Glucagon; Novo Nordisk, Bagsvaerd, Denmark; 1.0 mg/mL), given 90 minutes after the start of isotope infusion, was analyzed in 8 of the infants.
Chemical Procedures
Blood glucose was measured directly by the glucose oxidase method (ABL 735; Radiometer, Copenhagen, Denmark). The blood from the EDTA tubes was instantly centrifuged, and the plasma was frozen at –70°C until further analyzed. For measurement of plasma glycerol, an internal standard of [1,1,2,3,3-2H5]glycerol (isotopic purity: 98%), purchased from Cambridge Isotope Laboratories, was added to the plasma samples. The plasma proteins were precipitated with acetone, and after evaporation to dryness, equal amounts of pyridine and acetic anhydride were added for the preparation of the pentaacetate derivative of glucose and triacetate derivative of glycerol. The isotopic enrichments of [6,6-2H2]glucose, [2-13C] glycerol, and [1,1,2,3,3-2H5]glycerol were determined by gas chromatography–mass spectrometry. A Finnigan SSQ 70 mass spectrometer (Finnigan MAT, San Jose, CA) equipped with a an HP 5890 gas chromatograph (Hewlett-Packard, Palo Alto, CA) with a nonpolar (DB1) capillary column (15 m x 0.25 mm) was used. The temperatures in the oven were changed according to a program, from 180 to 250°C and from 100°C to 140°C for glucose and glycerol, respectively. Methane was used for chemical ionization with selective monitoring of ions. The ions monitored had m/z (mass-to-charge ratio) of 331, 332, and 333, corresponding to unlabeled, 13C-labeled (M + 1), and dideuterated glucose (M + 2). For glycerol, the ions m/z 159, 160, and 164 were monitored, reflecting unlabeled glycerol, 13C-labeled glycerol (M + 1), and the 5-deuterated internal standard (M + 5). The contribution of 13C2-glucose to M + 2 was analyzed for 2 of the infants (4 and 5). This was done by gas chromatography–mass spectrometry of the saccharic acid tetraacetate derivative of glucose with monitoring of ions 347 (M) and 349 (M + 2).23 13C2-glucose was shown to contribute <10% to the M + 2 enrichment of plasma glucose in both cases.
Insulin, glucagon, insulin-like growth factor 1 (IGF-1), and insulin-like growth factor–binding protein 1 (IGFBP-1) were measured in pooled samples, obtained during periods of approximate steady state. The radioimmunoassay technique was used to measure insulin,24 IGF-1,25 IGFBP-1,26 and glucagon (kit RB 310; Euro-Diagnostica AB, Medeon, Malmö, Sweden).
Calculations
The concentrations of plasma glycerol were calculated during periods of approximate steady state before and after injection of glucagon (mean coefficients of variation [CVs]: 8% and 10%, respectively) from the ion current ratio 159:164 by the use of a standard curve. For preparation of a standard solution, an amount of the internal standard equal to that added to the plasma samples was added to increasing amounts of unlabeled glycerol. The mean CVs for plasma glucose concentration during approximate steady state before and after administration of glucagon were 7% and 5%, respectively. Isotopic enrichments of [6,6-2H2]glucose and [2-13C]glycerol were used to calculate appearance rates of glucose and glycerol during periods of approximate steady state before and after injection of glucagon. The CVs were 4% and 2%, respectively, for glucose (m/z: 333:331) and 6% and 4%, respectively, for glycerol (m/z: 160:159). The standard curves used were prepared by gradually increasing the amounts of labeled glucose and glycerol in relation to the corresponding unlabeled compounds.15 The glucose production rate (GPR) and the rate of glycerol production were calculated as follows: Production rate = (i x 100/IE), where i is the infusion rate of the tracer and IE is the isotopic enrichment of the tracer in plasma (given as molar ratio [ie, labeled (tracer)/unlabeled substrate in %]). The fraction of glycerol converted to glucose and the fraction of glucose derived from glycerol were calculated from 13C enrichment of glucose reflected by an m/z of 332:331 before and after glucagon injection (mean CVs were 2% and 1.5%, respectively, during approximate steady state) as described by Patel and Kalhan.13 As stated already, the contribution of 13C2-glucose to M + 2 of plasma glucose was calculated in 2 of the infants as described by Hellerstein et al.23 Insulin sensitivity was assessed by using homeostasis model assessment (HOMA). The HOMA Calculator 2.2 program (Diabetes Research Laboratory, Oxford, United Kingdom) was used. The HOMA index correlates well with more complex measures of insulin resistance in adults.27
Insulin sensitivity was also assessed by calculating the plasma glucose (mg/dL)/insulin (mU/L) ratio. This ratio and the HOMA index were used by Bazaes et al18 for calculating insulin sensitivity in infants who were born AGA and SGA. Enteral contributions to the rates of appearance of glucose and glycerol could not be calculated, but because the mean duration of fasting was at least 3 hours, these contributions should have been minimal.
Statistical Analysis
The results are presented as mean ± SD or median and range when not normally distributed. Correlation analyses were performed with Pearson's correlation 2-tailed test. Comparisons between measurements before and after glucagon injection were made with the paired Student's t test. Differences and correlations were considered significant at P < .05.
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RESULTS |
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Glucose
The mean plasma glucose concentration in the infants who were born LGA was 3.8 ± 0.5 mmol/L, and the mean GPR was 30.2 ± 4.6 µmol/kg per min.
Lipolysis
The mean plasma concentration of glycerol was 384 ± 183 µmol/L, and the mean rate of glycerol production was 12.7 ± 2.9 µmol/kg per min. The fraction of glycerol converted to glucose averaged 59% ± 20%,which corresponded to 13% ± 5% of the total glucose production (Table 2).
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Hormones
Serum concentrations of insulin, glucagon, IGF-1, and IGFBP-1 were 10.8 ± 2.8 mU/L, 52 pmol/L (range: 34–107 pmol/L), 38 ± 17 µg/L, and 231 ± 79 µg/L, respectively.
Insulin Sensitivity
The glucose/insulin ratio was 6.6 ± 1.6. As calculated according to the HOMA, insulin sensitivity was 82% ± 19%, β-cell function was 221% ± 73%, and insulin resistance was 1.3 ± 0.3.
Effects of Glucagon
After injection of glucagon, the mean GPR increased by 13.3 ± 8.3 µmol/kg per min (P < .05; Fig 1), and the mean blood glucose level increased by 1.4 ± 0.5 mmol/L (P < .05; ie, by 44% and 37%, respectively). Simultaneously, the mean rate of glycerol production decreased by 16% from 12.8 ± 3.2 to 10.7 ± 2.9 µmol/min per kg (P < .05; Fig 2). There was also a decrease in the proportion of glucose generated from glycerol (P < .05). The mean insulin concentration increased from 10.9 ± 3.0 to 30.9 ± 10.3 mU/L.
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Correlations
Both the rate of lipolysis (r = 0.680; P < .05) and GPR (r = 0.680; P < .05) correlated with birth weight. In addition, GPR correlated with the blood glucose level (r = 0.716; P < .05). There was a strong inverse correlation between the decrease in lipolysis and the increase in insulin found after administration of glucagon (r = –0.808; P = .015; Fig 3). Furthermore, the level of IGF-1 correlated inversely with postnatal age (r = –0.749; P < .05). No correlations were found between markers for insulin resistance (HOMA index or glucose/insulin ratio) and auxologic parameters (birth weight, BMI, or ponderal index).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Much interest is being focused today on the developmental origin of adult disease, particularly on the long-term metabolic consequences of being born SGA.17 Data have also shown that being born LGA may predispose to overweight, diabetes, and cardiovascular disease in adult life.4–7 The relative number of infants who are born LGA is increasing,3 and one of the underlying reasons for this increase is overweight and obesity among pregnant women.3 The mothers in this study had a mean prepregnancy BMI close to that associated with obesity. Only limited information is available on neonatal metabolism in infants who are born LGA. In this study, energy substrate production and insulin sensitivity were investigated during the first day of life in a group of healthy term infants who were born LGA. In addition, the effect of glucagon administration on energy substrate production was studied. It would have been desirable to compare the data with those of a matched control group of term infants who were AGA, but owing to the problem of recruiting healthy newborn infants for metabolic studies, this was not possible. The results are therefore compared with literature data and also with previous data from our own laboratory on infants who were AGA.
Lipolysis
Lipolysis is an important source of energy in the newborn infant. One principal finding in this study was that infants who were born LGA had an efficient lipolysis. As compared with infants who were born AGA, studied previously in our laboratory at a postnatal age of 4 hours,28 the infants who were born LGA had an almost 50% higher rate of lipolysis, as reflected by the glycerol production. The same was found when the data were compared with those of Patel and Kalhan,13 who studied at a postnatal age of 21 hours (close to that of the infants in this study) term infants who were born AGA. The infants studied by Patel and Kalhan had fasted longer than our infants who were born LGA, which further strengthens that there is a difference in rate of lipolysis between infants who are born LGA and AGA. The difference becomes even more pronounced when our data are compared with those of Bougnères et al,29 who studied infants at a postnatal age of 22 hours who were born AGA. Data on the body composition of infants who were born LGA show that their proportion of body fat is increased compared with infants who were born AGA and SGA.20,30 In this study, there was a strong correlation between the rate of lipolysis and birth weight. This is in agreement both with the finding in adults, showing an association between lipolysis and body weight,31 and with recent results from our laboratory on infants who were born SGA, indicating that lipolysis depends on the amount of stored fat. Reduced adipose tissue insulin sensitivity could be another mechanism contributing to the increase in lipolysis. Insulin is a widely known inhibitor of lipolysis in adults, but this role has been questioned in the newborn. Previous data showed unimpaired lipolysis despite increased insulin concentrations in infants of mothers with diabetes,13,15 findings that contrast to the antilipolytic effects exerted by corresponding levels of insulin in adults.32 The lack of an antilipolytic effect of insulin in newborns has been interpreted as a protective mechanism for securing their supply of energy substrates during hyperinsulinemia; however, in contrast to earlier reports, these data indicate that insulin does in fact have some regulatory role with regard to lipolysis in newborns, at least at higher levels, because a fairly strong correlation was noted between the increase in insulin and the decrease in lipolysis after glucagon administration.
Glucose
The mean GPR in our study cohort was at the high end of the range reported for infants who are born AGA.28,33,34 The correlation between birth weight and length shows that the infants were symmetrically large. Consequently, the high GPR should reflect brain size. This is supported by the finding of a mean head circumference corresponding to +1.5 SD. Glycogenolysis is probably still an important source of glucose 16 hours post partum in infants who are born LGA, because the proportion of glycerol converted to glucose accounted for only 10% of the total GPR. The contribution made by glycerol to glucose production was smaller than that reported by Patel and Kalhan13 for infants who were born AGA and were of the same postnatal age but close to that found by our group in infants who were born AGA and had a postnatal age of 4 hours.28
Insulin Sensitivity
Previous studies indicated that infants who are born LGA are at higher risk for developing both type 1 and type 2 diabetes5,7,35 than are infants who were born AGA. In our infants, the mean level of insulin was higher than that reported previously for term infants who were born AGA13,18,28,36,37 This and the fact that β-cell function according to HOMA was increased compared with that reported by Bazaes et al18 for infants who were born AGA indicate a decreased insulin sensitivity at birth in infants who are born LGA, analogous to that in older children with overweight or obesity.
The risk for type 1 diabetes in infants who are born LGA has been suggested to be attributable to a high β-cell activity, in turn leading to increased expression of antigens that are associated with diabetes.35 This study demonstrates that infants who are born LGA in fact have a high β-cell activity. A decreased insulin sensitivity already at birth in combination with a propensity for obesity later in life may predispose for type 2 diabetes in this particular group of infants.
That GPR showed no correlation to the insulin level or the insulin/glucagon ratio is in agreement with data reported by Hawdon et al38 indicating that the neonatal hepatocyte may be insensitive to insulin. The strong increase in insulin after glucagon administration indicates a good pancreatic secretory response, a finding that contrasts to the report in the literature39 that only a weak insulin response to the increase in glucose was obtained after glucagon treatment of hypoglycemia in infants who were born AGA.
IGF-1
It is widely known that IGF-1 is important for fetal growth. Numerous studies have shown that the IGF-1 level in cord blood40–42 correlates with birth weight, but data on IGF-1 levels during the first 24 to 48 hours of life are limited; however, some data on IGF-1 levels during the first day of life are available. For example, our infants who were born LGA had markedly higher IGF-1 levels than those found in infants who were born AGA at a postnatal age of 24 hours by de Zegher et al43 and Giudice et al.44 Furthermore, the inverse correlation between IGF-1 level and postnatal age observed in our study is in agreement with the reported decline in IGF-1 during the first days of life.43,44
It has been reported that the IGFBP-1 concentration is decreased in infants who are born LGA.44 The infants who were born LGA in this investigation had lower IGFBP-1 levels than newborn infants who were born SGA and recently studied in our laboratory, probably reflecting the effect of a higher insulin tone on the liver in the infants who were born LGA.
Effect of Glucagon
Infants who are born LGA both to mothers with and without diabetes are prone to develop neonatal hypoglycemia10,45 This occurs despite increased stores of fat20 and liver glycogen46; therefore, administration of glucagon should be a suitable treatment for hypoglycemia in these infants. After intravenous injection of glucagon, the blood glucose level and endogenous glucose production increased in all infants studied. Data on the conversion of glycerol to glucose indicate that under these conditions, glycogenolysis is stimulated more than gluconeogenesis. This is in agreement with recent findings by van Kempen et al,47 who studied the effect of glucagon in moderately preterm (30 weeks) infants who were born AGA and SGA; however, if glucagon is used for treatment of neonatal hypoglycemia, then the risk for nausea in the treated infants has to be considered.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Infants who were born LGA had an increased lipolysis and a propensity for decreased insulin sensitivity already at birth as compared with infants who were born AGA. Administration of glucagon markedly increased the blood glucose levels and glucose production. The simultaneous increase in insulin correlated strongly with the decrease in lipolysis after glucagon injection, indicating an antilipolytic effect of insulin in newborn infants who were born LGA.
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ACKNOWLEDGMENTS |
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This study was supported by grants from the Medical Research Council, the Gillberg's Foundation and, Wera Ekström Foundation.
We are grateful to Elisabeth Söderberg for excellent technical assistance. We also thank Cecilia Ewald and the staff of the NICU, Uppsala University Children's Hospital, for skillful assistance and Yvonne Strömberg, Elvi Sandberg, Kerstin Brismar, and Claes-Göran Östensson (Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden) for insulin, glucagon, IGF-1, and IGFBP-1 analyses.
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FOOTNOTES |
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Accepted May 21, 2007.
Address correspondence to Fredrik S.E. Ahlsson, MD, Department of Women's and Children's Health, Uppsala University, University Children's Hospital, SE-751 85 Uppsala, Sweden. E-mail: fredrik.ahlsson{at}kbh.uu.se
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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