Effect of maternal fasting on ovine fetal and maternal branched-chain amino acid transaminase activities

Activities of branched-chain amino acid transaminase were assayed in maternal skeletal muscle, liver and fetal skeletal muscle, cardiac muscle, liver, kidney and placenta obtained from fed and 5-day-fasted late gestation ewes. Very high activities were found in placenta; fetal skeletal muscle also had high activity. Fetal brain had intermediate activity, followed by cardiac muscle and kidney. Fetal liver possessed negligible activity. Activities were low in both maternal liver and skeletal muscle. Trends were seen for fasting to increase activities in fetal placenta, skeletal muscle, brain, kidney, heart and maternal liver, but these changes were statistically significant only for fetal brain and placental tissue. Fetal skeletal muscle activity was 100 times that of maternal skeletal muscle. These data imply differences in the metabolism of the branched-chain amino acids by fetal and adult ruminants and expand the thesis that branched-chain amino acids are important to the metabolism of the ovine fetus.     

Diurnal changes in plasma amino acids in maple syrup urine disease

Protein turnover is a cyclic process with a net loss of protein in the (catabolic) fasted state and a net gain in the (anabolic) fed state. In maple syrup urine disease (MSUD) the early block of degradation of the branched-chain amino acids (BCAA) brings about the opportunity for evaluation of the diurnal variation in net protein anabolism and catabolism by studying cyclic changes in the plasma concentrations of BCAA. The alterations in plasma BCAA in a 3-y-old boy with classical MSUD were studied in the fed and fasted state over a period of 19 months. For each amino acid a total of 34 data pairs was calculated. The plasma concentrations of the BCAA leucine, valine and isoleucine were constantly higher in the fasted than in the fed state. Plasma concentrations of alloisoleucine, being a non-protein amino acid, did not participate in cyclic changes. In contrast, the essential amino acid pair tyrosine and phenylalanine increased after meals. The fasting concentration of alanine increased after feeding, while glycine did not change significantly. Healthy subjects show a decrease in all amino acids in the fasted (mild catabolic) state and an increase in the fed state. These findings in MSUD suggest a net decrease in non-BCAA as result of a greater rate of amino acid oxidation rate than of protein breakdown and a net entry of BCAA into plasma in the fasted state due to the specific metabolic block. Such changes in amino acid plasma pools have to be taken into account during monitoring of treatment and especially when in vivo leucine oxidation is assessed.     

Effects of glucose infusion on leucine transamination and oxidation in the ovine fetus.

During fasting of the ewe, the rate of amino acid oxidation by the ovine fetus increases substantially. We hypothesized that the increase in amino acid oxidation derived mainly from reduced protein synthesis. We further hypothesized that fetal glucose supplementation would result in diminished amino acid oxidation. To test these hypotheses, nine ovine fetuses were infused with [15N,1-13C]leucine to determine the rates of leucine appearance and disposal. Simultaneously, the fetal uptake of leucine was determined. Animals were studied in the fed and fasted state. After baseline measurements, glucose was infused into the fetal inferior vena cava at a rate estimated to match the fetal glucose uptake. Results of these studies indicate that leucine nitrogen flux, leucine carbon flux and fetal leucine uptake were constant. Leucine oxidation was increased by 50% in the fasted state (6.3 versus 13.4 mumol/min); glucose infusion resulted in a 25% decline in oxidation (to 10.4 mumol/min) in the fasted state, but had no effect in the fed state. Mean leucine umbilical uptake during fasting was 9.3 mumol/min, 4.1 mumol/min less than leucine oxidation. These data suggest that leucine (and potentially other amino acids) may be in negative balance during maternal fasting, and can be spared by supplementation of the fetus with exogenous glucose.     

Amino acids in amniotic fluid in the second trimester of gestation

The concentrations of amino acids in amniotic fluid have been used in the prenatal diagnosis of several inherited metabolic disorders. However, previous studies have usually examined only a small number of control amniotic fluid samples. We have, therefore, measured the amino acids in amniotic fluid samples from 183 normal pregnancies between the 13th and the 23rd wk gestation of women ranging in age from 17 to 43 yr. The concentrations of Ala, Lys, Val, Glu, Pro, Thr, and Gly, in descending order, accounted for about 70% of the amino acids in amniotic fluids. A negative correlation with gestational age (-0.34 to -0.24) was found for Leu, Val, Ile, Phe, Lys, Ala, Asp, Tyr, Glu, and Pro, with Leu showing the greatest rate of change. The concentration of Gln increased slightly (r = 0.18), whereas the other amino acids did not change significantly during this period. Statistically significant positive correlations, at all gestational ages, were observed among Val, Leu, and Ile. These branched-chain amino acids also correlated positively with Phe, Lys, Asp, Thr, Ser, Glu, Pro, Gly, Ala, and Tyr, and the amino acids within this group correlated with each other. Additionally, strong positive correlations were observed between Phe and Tyr and between Gly and Ser. No significant correlations were found between any of the amino acids and maternal age or fetal sex. Significant positive correlations between amino acids may be indicative of common transport or degradative pathways and suggest that maintenance of specific relative concentrations in amniotic fluid may be essential for normal fetal development.(ABSTRACT TRUNCATED AT 250 WORDS)     

Uteroplacental insufficiency alters liver and skeletal muscle branched-chain amino acid metabolism in intrauterine growth-restricted fetal rats

Uteroplacental insufficiency causes intrauterine growth restriction (IUGR) and decreases plasma levels of the branched-chain amino acids in both humans and rats. Increased fetal oxidation of these amino acids may contribute to their decline in the IUGR fetus. The rate-limiting step of branched-chain amino acid oxidation is performed by the mitochondrial enzyme branched-chain alpha-keto acid dehydrogenase (BCKAD), which is regulated by a deactivating kinase. We therefore hypothesized that uteroplacental insufficiency increases BCKAD activity through altered mRNA and protein levels of BCKAD and/or the BCKAD kinase. In IUGR fetal liver, BCKAD activity was increased 3-fold, though no difference in hepatic BCKAD protein or mRNA levels were noted. Hepatic BCKAD kinase mRNA and protein levels were significantly decreased in association with the increase in BCKAD activity. In IUGR fetal skeletal muscle, BCKAD mRNA levels were significantly increased. IUGR skeletal muscle BCKAD protein levels as well as BCKAD kinase mRNA and protein levels were unchanged. We also quantified mRNA levels of two amino acid transporters: LAT1 (system L) and rBAT (cysteine and dibasic amino acids). Both hepatic and muscle LAT1 mRNA levels were significantly increased in the IUGR fetus. We conclude that uteroplacental insufficiency significantly increases hepatic BCKAD activity in association with significantly decreased mRNA and protein levels of the deactivating kinase. We speculate that these changes contribute to the decreased serum levels of branched-chain amino acids seen in the IUGR fetus and may be an adaptation to the deprived milieu associated with uteroplacental insufficiency.     

Exchange transfusion in acute episodes of maple syrup urine disease

Two neonates with maple syrup urine disease were treated by exchange transfusion. Within 15 h blood leucine and KICA concentrations were lowered from 2.6 mM to 1.1 mM using 570 to 620 ml blood per kg body weight. The other branched-chain amino acid/keto acid pairs fell to normal. During exchange transfusion the patient's nitrogen balance seems to be negative. Further exchange transfusion was useless. More importantly the patient should be forced into an anabolic state by high caloric supply or insulin plus glucose treatment. More KICA than leucine was eliminated, however, KICA blood levels remained slightly higher than that of leucine indicating different leucine/KICA equilibria in extravascular compartments than in blood. In a given time interval exchange transfusion was more effective than peritoneal dialysis, probably due to a lack of an additional (peritoneal) membrane. Renal excretion of branched-chain amino and keto acids was very inefficient. The allegedly most toxic metabolite, KICA, had the lowest renal clearance of the branched-chain keto acids.Abbreviations BCAA's branched-chain alpha-amino acids - BCKA's branched-chain alpha-keto acids - KICA alpha-keto-isocaproic acid - KIVA alpha-keto-isovaleric acid - MEVA alpha-keto--methyl-n-valeric acid - MSUD maple syrup urine disease - HICA alpha-hydroxy-isocaproic acid - HIVA alpha-hydroxy-isovaleric acid - HMVA alpha-hydroxy--methyl-n-valeric acid With support of the Landesamt für Forschung des Ministeriums für Wissenschaft und Forschung des Landes Nordrhein-Westfalen. U.L. was supported by Deutsche Forschungsgemeinschaft, Bad Godesberg, G.F.R. (La 201 and SFB 33).     

Effect of fasting on uteroplacental amino acid metabolism in the pregnant sheep.

In the fed state, the net utilization of most amino acids by the ovine uteroplacental unit (defined as uterine uptake minus umbilical uptake) is zero. This study was to determine if this is true for the fasted pregnant ewe also, when uteroplacental glucose uptake is diminished. Glucose and amino acid concentrations were determined in 9 pregnant ewes across the uterine and umbilical circulations. Uterine and umbilical blood flows were determined by the steady state antipyrine diffusion method, and net uptakes across each circulation calculated by application of the Fick principle. Five amino acids were found to have a consistently greater uterine uptake than umbilical uptake. In addition, glutamate had a negative net umbilical uptake coupled with no net uterine uptake. Fasting resulted in an increase in the differences between the respective uptakes for all five amino acids. No additional amino acids were found to have disparate uptakes than were seen in the fed state. Umbilical glutamate uptake became less negative during fasting, but the difference between the uterine and umbilical circulations remained unchanged, as the uterine circulation took up glutamate during fasting. The umbilical circulation took up alpha-ketoisocaproate 0.626 +/- 0.18, fed), and the uptake was increased during fasting (1.8 +/- 0.6). These findings suggest that the branched chain amino acids and glutamine are utilized by the ovine uteroplacenta to a greater degree than are most other amino acids, and at increased rates during fasting of the ewe. These amino acids, through deamination, may be the source of uteroplacental ammonia production, as well as serving as an energy substrate when glucose supply is limited.     

Effect of orthotopic liver transplantation (OLT) on branched-chain amino acid requirement

Little is known regarding the impact of liver transplantation on amino acid requirements in children. Since plasma levels of the branched-chain amino acids (BCAA) are decreased in the presence of normal levels of the aromatic amino acids after liver transplantation, normalization of hepatic function may not fully correct changes in BCAA metabolism that occur in the pretransplant period. The goal of the present study was to determine total BCAA requirements of children following liver transplantation. The requirement of total BCAA was determined using indicator amino acid oxidation (IAAO) in five clinically stable children (5.7 +/- 3.5 y, mean +/- SD) 1-8 y post liver transplantation. Children received in random order 6 graded intakes of total BCAA. Individual BCAA in the test diet were provided in the same proportions as present in egg protein to minimize the potential interactive effects of individual BCAA on assessment of requirement. Total BCAA requirement was determined by measuring the oxidation of L-[1-13C] phenylalanine to 13CO2 [F13CO2 in micromol/kg/h], after a primed, continuous infusion of the tracer and using a two-phase linear regression crossover regression analysis. The estimated average requirement and the upper limit of the 95% CI for total BCAA in children who have undergone liver transplantation were 172 and 206 mg/kg/d), respectively. Total BCAA requirement in children who have undergone orthotopic liver transplantation (OLT) remain increased in the post-liver transplant period when compared with healthy school aged children, but is decreased when compared with children with mild-moderate chronic cholestatic (MCC) liver disease.     

Effect of a maternal fast on the urea cycle enzymes of the ovine fetus

Activities of five urea cycle enzymes were measured in maternal and fetal sheep liver during the normal fed state and following 5 days of fasting. Six ewes and 10 fetuses were studied in both the fed and fasted periods at 132 days gestation (term: 147 days) for liver protein and enzyme levels. Results indicated that protein content increased during fasting in both the maternal and fetal liver. Fetal liver weight was decreased during fasting from 108 +/- 8.5 to 71 +/- 8.2 g (mean +/- SD) (p less than 0.001). Fed state fetal enzyme activities per gram liver were 50-125% of maternal values. After fasting, four of the five fetal enzymes increased approximately twofold to fivefold (per gram tissue) (ornithine transcarbamylase did not change). Only one enzyme (argininosuccinase) increased significantly in maternal liver. Total liver activities gave similar results. These data indicate that the in vivo studies that demonstrate a doubling in fetal urea production in the fasted sheep in later gestation are associated with parallel increases in the fetal hepatic activities of several enzymes that are responsible for urea synthesis.     

Effect of birth-related events on metabolism in fetal sheep

At birth, changes in utilization of metabolic substrates occur as the fetus, dependent upon carbohydrates and amino acids available continuously from the placenta, becomes a neonate, dependent primarily upon fat obtained intermittently by suckling. In addition to changes in substrates, at birth, metabolic rate increases dramatically as the activity of several organs and thermoregulatory mechanisms increase. To determine whether metabolic changes are related to certain events that occur at birth, we studied 15 fetal sheep instrumented chronically with vascular catheters and an endotracheal tube at 133 to 137 d gestational age. We measured blood flow with radionuclide-labeled microspheres and arteriovenous concentration differences for oxygen content, blood glucose, and lactate across the placental, cerebral, myocardial, and hindlimb circulations at rest, during in utero ventilation of the fetal lungs with 3% O2, during in utero ventilation with 100% O2, and during ventilation with 100% O2 and umbilical cord occlusion. Ventilation with 3% O2 decreased oxygen uptake by the fetus and by the cerebral circulation but produced no other significant changes. Ventilation with the low and high oxygen gas mixture reduced glucose uptake by the fetus from the placental circulation dramatically to zero. In contrast, blood glucose concentrations increased and glucose uptake by the fetal brain, heart, and hindlimb were not altered significantly. These data indicate that, for a short time at least, complete cessation of glucose supply to the fetus from the placenta is not associated with decreases in blood glucose concentrations or utilization of glucose by a major portion of the fetal body.     

Developmental changes of glutamate dehydrogenase activity in rat liver mitochondria and its enhancement by branched-chain amino acids.

The developmental changes of glutamate dehydrogenase activity in the fetal and neonatal rat liver were investigated, as well as the effects of branched-chain amino acids on this enzyme. Hepatic glutamate dehydrogenase activity showed a marked increase at the end of the fetal period and peaked on the 5th day of neonate at approximately 3 times higher than the adult level. Glutamate dehydrogenase was activated by leucine, isoleucine, and valine in this order when they were added to isolated intact liver mitochondria in vitro. The enhancement of enzyme activity was more marked in fetal rats than in adults. In contrast, when branched-chain amino acids were added after disrupting the mitochondrial membrane by sonication, only leucine slightly activated glutamate dehydrogenase, while isoleucine and valine slightly inhibited its activity. Our findings suggest that glutamate may be actively synthesized in the developing rat liver mitochondria and then transaminated to other nonessential amino acids for protein synthesis, and that increased intramitochondrial branched-chain amino acid concentrations may enhance glutamate dehydrogenase activity. This anabolic metabolism will contribute to the fetal growth and development.     

Nitrogen and mineral balance in preterm infants fed human milks or formula

Growth as well as nitrogen, calcium, sodium, and potassium balances were evaluated in 16 preterm infants weighing less than 1,600 g at birth, who were fed either their mother's milk, donated mature human milk, or standard commercial formula. Birthweight, gestational age, age of balance, and energy and fluid intakes were similar between groups. There were no differences between groups in the rate of growth. The infants fed their mother's milk (obtained 11-30 days into lactation) demonstrated nutrient balance similar to infants fed mature human milk. Infants fed standard commercial formula demonstrated significantly greater intake and retention of calcium compared to either human milk group. Infants fed either their mother's milk or mature human milk demonstrated net nitrogen and calcium retention below estimates of fetal nitrogen and calcium accretion. Infants fed standard formula demonstrated retentions that more closely approach the fetal estimates. This study did not demonstrate an advantage to feeding premature infants their mother's milk when compared to the feeding of mature donor milk.     

Effects of fasting on glucose turnover rate and metabolite levels in conscious pregnant guinea pigs

The effect of fasting during pregnancy is of particular interest in the guinea pig because of the large fetal mass carried to term. The present studies examined the effect of acute and chronic starvation on maternal glucose turnover in the guinea pig. In the first experiment, 7 near-term pregnant guinea pigs were fasted for 6 h. The maternal glucose concentration and glucose production decreased rapidly, falling to about 65-70% of fed levels at 4 h of starvation. Mothers demonstrated a 2.6-fold elevation in ketoacids after 2, 4 and 6 h starvation. In a second experiment, 5 non-pregnant and 11 near-term pregnant animals were studied in the control period and after 24 h of fasting. The maternal glucose concentration in the control state was independent of fetal mass. The maternal glucose turnover rate in the fed state correlated linearly with fetal mass. After 24 h of fasting, the glucose concentration and glucose turnover rate both decreased, with the magnitude of each decrease proportional to fetal mass. We conclude that, in the pregnant guinea pig, the fetal mass impacts significantly on maternal glucose metabolism in the fed and fasting states.     

Fetal and maternal amino acid concentrations during fasting in the ewe

The present investigation was undertaken to quantitate the whole-blood amino acid concentrations of the mother and fetus over an extended period of fasting using a chronic sheep preparation. Fetal amino acid levels generally increased or remained relatively high during the fast (e.g., alanine, glycine, valine, leucine). In contrast to the situation in the fetus, most amino acids (alanine, glycine, glutamine, serine, and threonine) decreased in concentration in the ewe with fasting. Alanine levels changed most dramatically in the ewe, decreasing to less than 50% of the fed state values within 72 h of fasting. Therefore, while the supply of gluconeogenic amino acids becomes limited within the maternal circulation during fasting, levels of these amino acids remain high or increase in the fetal arterial blood.     

Leptin receptor gene Gln223Arg polymorphism is not associated with obesity and metabolic syndrome in Turkish children

The aim of the study was to investigate the relationship between leptin receptor gene (LEPR) Gln223Arg polymorphism and obesity in Turkish children. Ninety-two obese and 99 lean children (between 5-15 years) were included in the study. Twenty-three of the obese children were diagnosed with metabolic syndrome. Blood samples were collected for morning fasting blood glucose, insulin, leptin, and lipid level measurements. LEPR Gln223Arg polymorphism was analyzed by restriction fragment length polymorphism. Significant differences were observed in anthropometric measurements, fasting blood glucose, insulin, leptin, and lipid levels between obese and lean children. Serum leptin levels were markedly higher in obese children. No significant association was noted between Gln223Arg polymorphism and serum leptin, insulin and lipid levels. There were no differences in the genotype frequencies or allele distribution for Gln223Arg polymorphism among obese, obese with metabolic syndrome and lean children. Our findings suggest that there is no association between Gln223Arg polymorphism and obesity in Turkish children.     

Effect of insulin on glucose/oxygen and lactate/oxygen quotients across the hindlimb of fetal lambs

In order to determine whether insulin stimulates glucose uptake by the hindlimb tissue of the fetal lamb, we performed 7 paired, euglycemic glucose 'clamp' experiments in 7 chronically prepared fetal sheep. Four sample sets for oxygen content, glucose and lactate concentration were drawn from the external iliac artery and vein during a control period and repeated during a euglycemic, hyperinsulinemic 'clamp' period. Insulin was infused at constant rate (4 mU/min/kg) and the fetal arterial glucose concentration was maintained by variable glucose infusion. The glucose/oxygen quotient increased significantly: 1.05 +/- 0.07 (control) versus 2.02 +/- 0.16 (hyperinsulinemia). There was no change in lactate/oxygen quotient. The data demonstrate that with maximal insulin stimulation, fetal hindlimb tissues increase glucose uptake by 92% with no large change in lactate production, indicating a net accumulation of glucose carbon under these experimental conditions.     

Plasma amino acids in small preterm infants fed on human milk or formula.

Plasma amino acids were measured in 35 preterm infants, of whom 11 weighed less than 1000 g and 24 weighed between 1000 g and 1500 g at the time of sampling. Repeat samples were obtained in 18 at least seven days later. Seventeen infants were fed with preterm formula milk and 18 with expressed maternal breast milk at one to two hourly intervals during the study period. Formula fed infants gained weight faster than those fed on breast milk but there was little difference in amino acid patterns. Infants fed on breast milk were more likely to have concentrations of essential amino acids below the mid trimester fetal range than formula fed infants, but few infants in either feeding group had values above the fetal range. Those that did were equally distributed between both groups. Only two samples approached toxic concentrations, both in the group fed breast milk. The ratio of branched chain to aromatic amino acids was higher in the group fed on formula after correction for post conceptional age, implying that liver maturation may be accelerated by formula feeding. No correlations were found between plasma amino acid concentrations and nitrogen retention or metabolisable energy intake.     

Mild variant of maple syrup urine disease

Amino acids analysis were made on serum and cerebrospinal fluid samples of a Japanese 5-month-old infant suffering from irritability and mental retardation noticed at 2 months of age. Excessive amounts of branched-chain amino acids and of keto acids were detected in those samples and the large quantity of keto acids was found in urine with a qualitative 2,4-dinitro-phenylhydrazin test and with quantitative estimation. When thiamine hydrochloride (100 mg/day) was administered orally for 7 days to the patient fed with the cow's milk formula containing 2.1 gm/dl milk protein, there was no improvement of the branched-chain amino acidemia. Urinary keto acids, however, showed a marked decrease 7 days after the administration of thiamine hydrochloride. An overnight fast for 13 h resulted in normoglycemia. There was found no difference of blood L-lencine level between both parents and normal infants to whom L-lencine was loaded. The relation between decarboxylase activity for keto acids of branched-chain amino acids and thiamine hydrochloride was studied clinically, in the present communication.     

Indices of protein metabolism in term infants fed human milk, whey-predominant formula, or cow's milk formula

Relationships between intakes of amino acids and total nitrogen, and blood indices of protein utilization were studied in 37 term infants fed either human milk, whey-predominant formula, or cow's milk formula as the sole nutritional source for 8 weeks. Biochemical analyses of two-hour fasting blood samples, and intakes calculated using three-day dietary records and direct analyses of milk samples were used to evaluate these relationships. Intakes of total nitrogen were positively correlated with plasma valine, leucine, isoleucine, phenylalanine, and serum urea nitrogen concentrations (r = .46 to .62, P less than .01 to .001). Intakes of the four amino acids whose plasma concentrations were positively correlated with total nitrogen intakes plus four additional amino acids (threonine, tyrosine, histidine, and methionine) were correlated with their respective plasma concentrations (r = .41 to .74, P less than .01 to .001). These relationships have not been previously described in term infants. Compared with values in infants fed human milk, plasma concentrations of valine, phenylalanine, methionine, and serum urea nitrogen were elevated with whey-predominant formula and cow's milk formula feeding. Values for four additional amino acids (threonine, lysine, leucine, and isoleucine) were elevated with whey-predominant formula feeding. Data indicate that altering the whey-to-casein ratio and, thus, the amino acid pattern of formulas will not achieve the desired blood indices characteristic of human milk feeding without a reduction in the total nitrogen content of formulas.     

Ala54Thr polymorphism of the fatty acid-binding protein 2 gene (intestinal-type FABP) is associated with changes in insulin sensitivity in SGA pubertal girls

INTRODUCTION: Associations between FABP2 Ala54Thr polymorphism and increased fasting insulin concentration, fasting fatty acid oxidation and reduced glucose uptake have been identified in several populations. The aim of this study was to evaluate the association of Ala54 Thr polymorphism of the FABP2 gene with insulin sensitivity in pubertal girls born small for gestational age (SGA). RESULTS: The frequency of the Thr54 allele did not differ between AGA and SGA girls (0.52 vs 0.43). Girls born SGA positive for the Ala/Thr polymorphism were older at the beginning of puberty compared to girls born AGA with the Thr54 allele (p < 0.01). These girls had lower whole body insulin sensitivity index (WBISI) (4.1 +/- 1.7 vs 9.2+/-7.4, p < 0.05), higher leptin (17.3 +/- 5.9 vs 12.1 +/- 13.7, p < 0.02), insulin area under the curve (AUC) (64,272 +/- 9,209 vs 27,981 +/- 15,637, p < 0.001), proinsulin (17.3 +/- 5.4 vs 10.9 +/- 3.6, p < 0.01) and insulinogenic index (4.6 +/- 3.0 vs 2.9 +/- 5.9, p < 0.01). Conversely, girls born SGA positive for the Ala/Thr polymorphism were older at the beginning of puberty (ns) compared to girls born SGA positive for the Ala/Ala polymorphism. These girls had higher insulin AUC (64,272 +/- 9,209 vs 33,322 +/-7,533, p < 0.01), insulinogenic index (4.6 +/- 3.0 vs 2.5 +/- 3.6, p < 0.01) and lower WBISI (4.1 +/- 1.7 vs 6.3 +/- 1.8, p < 0.05). DISCUSSION: Our results suggest that the Thr54 variant of the FABP2 gene could be associated with a synergic effect in the SGA group regarding higher leptin levels (p < 0.05), lower insulin sensitivity by WBISI (p < 0.05) and higher insulin secretion determined by higher insulinogenic index (p < 0.01), insulin AUC (p < 0.01) and beta-cell stress measured by higher proinsulin (p < 0.05). Our data suggest an involvement of genetic factors in the insulin resistance associated with reduced fetal growth and strengthen the hypothesis that this association could be the consequence of interactions between detrimental factors during fetal life and genetic susceptibility.