Glucose and leucine kinetics in idiopathic ketotic hypoglycaemia

Aims

To investigate glucose and leucine kinetics in association with metabolic and endocrine investigations in children with ketotic hypoglycaemia (KH) in order to elucidate the underlying pathophysiology.

Methods

Prospective interventional study using stable isotope tracer in nine children (mean age 4.23 years, range 0.9–9.8 years; seven males) with KH and 11 controls (mean age 4.57 years, range 0.16–12.3 years; four males).

Results

Plasma insulin levels were significantly lower in KH compared to subjects in the non‐KH group. Plasma ketone body levels were significantly higher in KH than in non‐KH. Basal metabolic rate was significantly higher in subjects with KH (45.48±7.41 v 31.81±6.72 kcal/kg/day) but the respiratory quotients were similar in both groups (KH v non‐KH, 0.84±0.05 v 0.8±0.04. Leucine oxidation rates were significantly lower in children with KH (12.25±6.25 v 31.96±8.59 μmol/kg/h). Hepatic glucose production rates were also significantly lower in KH (3.84±0.46 v 6.6±0.59 mg/kg/min).

Conclusions

KH is caused by a failure to sustain hepatic glucose production rather than by increased glucose oxidation rates. Energy demand is significantly increased, whereas leucine oxidation is reduced.     

Fasting adaptation in idiopathic ketotic hypoglycemia: a mismatch between glucose production and demand

In order to study the pathophysiology of hypoglycemia in idiopathic ketotic hypoglycemia (KH), glucose kinetics during fasting in patients with KH were determined. A fasting test was performed in 12 children with previously documented KH. Besides determination of glucoregulatory hormones, plasma ketones, FFA and alanine, the rates of endogenous glucose production (EGP), glucose uptake, gluconeogenesis (GNG) and glycogenolysis (GGL) were quantified using the [6,6-(2)H(2)] glucose isotope dilution method and the deuterated water method. The five youngest subjects (age 2.5-3.9 years) became hypoglycemic (glucose <3.0 mmol/l) during the test. Mean differences in glucose kinetics between overnight fasting and the end of the test in the hypoglycemic vs. the normoglycemic subjects were: EGP: -31.9% vs. -17.9% (p = 0.007), GGL: -66.2% vs. -50.8% (p = 0.465) and GNG 6.8% vs. 19.5% (p = 0.465). Plasma alanine levels were significantly lower (p = 0.028) at the end of the test in the hypoglycemic subjects. Plasma ketones and FFA levels were in the normal range for fasting duration in all subjects. We conclude that hypoglycemia in KH is caused by the inability to sustain an adequate EGP during fasting in view of the higher glucose requirement in young children. The decrease in GGL is not accompanied by a significant increase in GNG, possibly because of a limitation in the supply of alanine. Our results support the hypothesis that KH represents the lower tail of the Gaussian distribution of fasting tolerance in children.     

Changes in protein turnover after the introduction of parenteral nutrition in premature infants: comparison of breast milk and egg protein-based amino acid solutions.

Rates of protein turnover were measured in 20 infants receiving either Vamin Infant (group A) or Vamin 9 glucose (group B) as the amino acid source in total parenteral nutrition. A constant infusion of L-[1-13C]leucine was used to measure whole body leucine flux, and leucine oxidation rates were derived from measurements of total urinary nitrogen excretion. Infants were first studied when receiving only i.v. glucose and again on each of the next 4 d as total parenteral nutrition was gradually increased to a maximum of 430 mg nitrogen/kg/d and 90 nonprotein kcal/kg/d. Net protein gain and protein synthesis and breakdown rates increased progressively for all infants taken together over the study period as i.v. nutrition was increasing (p less than 0.001). There were no differences between groups in the changes in net protein gain and rates of protein synthesis and breakdown throughout the study period. Nitrogen retention on d 5 for the two groups was similar (60 +/- 16% and 67 +/- 11% in groups A and B, respectively). In a subgroup of infants, measurements were repeated on d 8, when the intake had been constant for 3 d. Protein retention was the same as on d 5, but both synthesis and breakdown were increased. It is concluded that rates of protein turnover increase significantly in response to increasing i.v. nutrition and that this elevation was not influenced by the composition of the amino acid mixture given.     

The dawn phenomenon: comparison between normal and insulin-dependent diabetic adolescents.

To determine the role of insulin clearance in the dawn phenomenon, we studied 10 adolescents with IDDM in comparison to 10 healthy, matched control subjects reported previously. In diabetics, metabolic clearance rate of insulin was calculated during i.v. infusion of insulin from 0100 to 0430 h and from 0430 to 0800 h (0.17 and 0.33 mU/kg/min, respectively), with a Harvard pump, while maintaining nocturnal euglycemia. In controls, metabolic clearance rate of insulin was calculated from the prehepatic insulin secretion rate based on C-peptide levels. In diabetic and control subjects, plasma glucose, free insulin, and glucagon concentrations were similar and did not change during the dawn period. However, metabolic clearance rate of insulin increased during the dawn period in diabetic (9.42 +/- 0.91 to 19.89 +/- 1.52 mL/kg/min, p less than 0.0001) and control subjects (4.87 +/- 1.11 to 9.30 +/- 1.50 mL/kg/min, p = 0.008). Plasma cortisol and adrenocorticotropic hormone levels increased and growth hormone (GH) decreased significantly during the dawn period. Diabetic adolescents had significantly higher plasma GH levels than control subjects throughout the night. We conclude the 1) increased insulin clearance is responsible for the dawn phenomenon in healthy and diabetic adolescents and 2) insulin resistance due to GH is an unlikely cause for the dawn phenomenon because diabetic subjects, despite higher GH levels, maintain plasma glucose levels similar to control subjects without requiring higher plasma free insulin concentrations.     

Bone mineral density of the lumbar spine in children and adolescents with celiac disease on a gluten-free diet in São Paulo, Brazil

BACKGROUND: To compare bone mineral density (BMD) in children and adolescents with celiac disease (CD) and control subjects and to evaluate diet adequacy and calcium metabolism in patients with CD. METHODS: Thirty patients with asymptomatic CD (17 children, 13 adolescents), on a gluten-free diet, and 23 healthy subjects were studied. BMD of the lumbar spine (dual energy x-ray absorptiometry) was performed on all patients and control subjects. In patients, food diaries for nine nonconsecutive days were obtained and analyzed. In patients, laboratory tests pertaining to calcium balance were obtained. RESULTS: The mean weight and height of the adolescents with CD were lower than those of control subjects (weight: 45.8 +/- 10.5 kg v 55.3 +/- 10.5 kg, P = 0.037; height: 153.0 +/- 11.0 cm v 167 +/- 12.0 cm, P = 0.007). The mean BMD in adolescents with CD was significantly lower than that of the control subjects (0.917 +/- 0.116 g/cm2 v 1.060 +/- 0.158 g/cm2, P = 0.015), whereas no significant difference was found between children with CD and control subjects (P = 0.595). A multiple-regression model shows that increases in BMD relative to height were lower in adolescents with CD than in control subjects. The proportion of adolescents who had started a gluten-free diet after 2 years of age was higher than that of children with CD (P < 0.001). High percentages of magnesium, calcium, and phosphorous deficiencies were present in CD patients' diets. The serum levels of ionized and total calcium and parathormone were normal. CONCLUSIONS: The BMD of adolescents with CD was lower than that of the control subjects, whereas no difference was found between the BMD of children with CD and that of control subjects.     

Whole-body leucine kinetics and the acute phase response during acute infection in marasmic Malawian children

This study compared leucine kinetics and acute-phase protein and cytokine concentrations in three groups of Malawian children who were fed an isoenergetic, isonitrogenous diet: children with marasmus with (n = 25) and without (n = 17) infection and well-nourished children with infection (n =13). The hypotheses tested were that whole-body leucine kinetics will be less in marasmic acutely infected children than in well-nourished acutely infected children but greater than in marasmic uninfected children. Children were studied after 24 h of therapy using standard (13)C-leucine stable isotope tracer techniques. Well-nourished children with acute infection had greater leucine kinetic rates than did marasmic children with acute infection; nonoxidative leucine disposal was 153 +/- 31 versus 118 +/- 43 micromol leucine. kg(-1). h(-1), leucine derived from whole-body proteolysis was 196 +/- 34 versus 121 +/- 47, and leucine oxidation was 85 +/- 31 versus 45 +/- 13 (p < 0.01 for all comparisons). Leucine kinetic rates were similar in marasmic children with and without acute infection. Well-nourished children with acute infection increased their serum concentration of five of six acute-phase proteins during the first 24 h, whereas marasmic children with infection did not have any increases. The serum concentrations of IL-6 were elevated in well-nourished and marasmic children with infection. These data suggest that the cytokine stimulus for the acute-phase protein kinetic response to acute infection is present in marasmic children but that the acute-phase protein metabolic response is blunted by malnutrition.     

Leucine kinetics during simultaneously administered insulin and dexamethasone in preterm infants with severe lung disease

The objective of this study was to determine whether insulin administration would prevent the well-documented catabolic effect of dexamethasone given to preterm infants with chronic lung disease. We studied leucine metabolism in 11 very-low-birth-weight infants before dexamethasone treatment and on d 2, 4, and 7 thereafter. During the first 4 d of dexamethasone, insulin was administered i.v. at a dose of 0.5 (n = 7) or 1.0 (n = 5) IU/kg/d. Leucine turnover was not significantly different between d 0 (337 +/- 41.3 micromol leucine/kg/h), d 2 (288 +/- 27.2 micromol leucine/kg/h), d 4 (302 +/- 22.1 micromol leucine/kg/h), and d 7 (321 +/- 21.2 micromol leucine/kg/h), and neither was leucine breakdown (272 +/- 21.9 micromol leucine/kg/h on d 0, 225 +/- 21.5 micromol leucine/kg/h on d 2, 231 +/- 21 micromol leucine/kg/h on d 4, and 242 +/- 17.6 micromol leucine/kg/h on d 7). Weight gain rates were significantly lower during the first week of dexamethasone treatment compared with the week before treatment or the second and third week. We conclude that during insulin and corticosteroid administration in very-low-birth-weight infants, no changes were observed in leucine kinetics in contrast to previous studies. The decrease in weight gain was not reversed.     

Insulin resistance of puberty in African-American children: lack of a compensatory increase in insulin secretion

Type 2 diabetes has been increasing in children, mostly affecting minority populations at around the age of puberty. Despite a multitude of studies demonstrating pubertal insulin resistance/hyperinsulinemia in white children, data are almost non-existent in African-American children. The aim of the present study was to investigate the impact of puberty on glucose metabolism, insulin sensitivity and secretion in African-American children. Twenty prepubertal and 16 pubertal African-American subjects participated. All underwent a 3-h hyperinsulinemic (40 mU/m(2)/min) euglycemic clamp to determine insulin-stimulated glucose disposal, and a 2-h hyperglycemic (12.5 mmol/L) clamp to assess first- and second-phase insulin secretion. Body composition was assessed by dual energy X-ray absorptiometry (DEXA) and visceral and subcutaneous abdominal adiposity with computed tomography (CT) scan at L4-L5. Total glucose disposal, glucose oxidation and non-oxidative glucose disposal were significantly lower in the pubertal group compared with the prepubertal one (53.8 +/- 3.9 vs. 72.2 +/- 5.0 micromol/kg/min, p = 0.009; 23.3 +/- 1.1 vs. 31.6 +/- 1.7 micromol/kg/min, p = 0.001; and 30.0 +/- 3.3 vs. 40.5 +/- 3.9 micromol/kg/min, p = 0.049, respectively). Insulin sensitivity was approximately 30% lower in the adolescents compared with the prepubertal children. However, first- and second-phase insulin secretions were not different between the two groups (971.4 +/- 180.6 vs. 1044.0 +/- 191.4 pmol/L and 999.6 +/- 159.6 vs. 955.8 +/- 142.2 pmol/L, respectively). In conclusion, despite approximately 30% lower insulin sensitivity in African-American adolescents compared with prepubertal children, insulin secretion is not higher. This is in contrast to published findings in white children in whom insulin secretion is higher during puberty. These racial differences in physiologic adaptation to puberty could play a role in the higher prevalence of type 2 diabetes in African-American children at the time of puberty.     

Acute effects of intravenous glutamine supplementation on protein metabolism in very low birth weight infants: a stable isotope study.

Although very low birth weight infants are subjected to severe stress and glutamine is now considered a conditionally essential amino acid that may attenuate stress-induced protein wasting in adults, current amino acid solutions designed for neonatal parenteral nutrition do not contain glutamine. To determine whether a short-term supplementation with i.v. glutamine would affect protein metabolism in very low birth weight infants, 13 preterm neonates (gestational age, 28-30 wk; birth weight, 820-1610 g) receiving parenteral nutrition supplying 1.5 g x kg(-1) x d(-1) amino acids and approximately 60 nonprotein kcal x kg(-1) x d(-1) were randomized to receive an i.v. supplement made of either 1) natural L-glutamine (0.5 g x kg(-1) x d(-1); glutamine group), or 2) an isonitrogenous glutamine-free amino acid mixture (control group), for 24 h starting on the third day of life. On the fourth day of life, they received a 2-h infusion of NaH(13)CO(3) to assess the recovery of (13)C in breath, immediately followed by a 3-h L-[1-(13)C]leucine infusion. Plasma ammonia did not differ between the groups. Glutamine supplementation was associated with 1) higher plasma glutamine (629 +/- 94 versus 503 +/- 83 microM, mean +/- SD; p < 0.05, one-tailed unpaired t test), 2) lower rates of leucine release from protein breakdown (-16%, p < 0.05) and leucine oxidation (-35%, p < 0.05), 3) a lower rate of nonoxidative leucine disposal, an index of protein synthesis (-20%, p < 0.05), and 4) no change in protein balance (nonoxidative leucine disposal - leucine release from protein breakdown, NS). We conclude that although parenteral glutamine failed to enhance rates of protein synthesis, glutamine may have an acute protein-sparing effect, as it suppressed leucine oxidation and protein breakdown, in parenterally fed very low birth weight infants.     

Effect of continuous glucose therapy begun in infancy on the long-term clinical course of patients with type I glycogen storage disease.

BACKGROUND: To evaluate the effects of continuous glucose therapy on metabolic control, occurrence of severe hypoglycemia, physical growth and development, and complications of glycogen storage disease type I (GSD-I). METHODS: Seventeen patients (11 males) with GSD-I were studied, mean age 14.6+/-5.0 (SD) years, in whom continuous glucose therapy was begun at 0.8+/-0.4 years. At the time of this study, subjects had received continuous glucose therapy for a total duration of 13.9+/-5.0 years. Uncooked cornstarch was used as the method of providing glucose continuously for 10.2+/-3.2 years. Subjects were admitted to the Clinical Research Center and followed their usual home dietary regimens, which included cornstarch supplements at 2- to 4-hour intervals during the day and at 4- to 8-hour intervals during the night. Plasma glucose, blood lactate, and glucoregulatory hormones were measured hourly for 24 hours. RESULTS: During a 24-hour period of biochemical monitoring, mean hourly plasma glucose concentrations for the group of 17 subjects ranged from 76+/-17 (SD) mg/dl (4.2+/-0.9 mmol/l) to 108+/-16 mg/dl (6.0+/-0.9 mmol/l), and blood lactate concentrations ranged from 2.1+/-1.2 mmol/l to 3.8+/-2.8 mmol/l. Four subjects had transient plasma glucose levels of 50 mg/dl (2.8 mmol/l) or less in the interval between midnight and 8:00 AM. Mean blood lactate levels were highest (> or =3 mmol/l) between 2:00 and 09:00 AM. Mean height standard deviation score for chronological age (SDS(CA)) was -0.8+/-1.1, significantly (p < 0.01) less than the mean target height SDS of -0.1+/-1.1; mean weight SDS was 0.3+/-1.3. Six (35%) subjects (12.2-21.4 years of age) had anemia with hemoglobin concentrations of 10.6 to 11.6 g/dl. Ultrasound examination showed one or more focal hepatic lesions, consistent with an adenoma in 5 (29%) subjects (10.4 to 21.4 y); 16 subjects had glomerular hyperfiltration; and urinary albumin excretion was increased in 2 subjects, ages 15.9 and 21.1 years. CONCLUSIONS: Long-term continuous glucose therapy with cornstarch, begun in infancy, resulted in mean height 0.7 SDS less than target height. Optimal biochemical control of GSD-I requires meticulous adherence to an individualized dietary regimen that is based on the results of periodic metabolic evaluation and home blood glucose monitoring. Renal glomerular dysfunction and formation of hepatic adenomata remain serious long-term complications.     

Protein metabolism in phenylketonuria and Lesch-Nyhan syndrome

Animal and in vitro studies have implicated decreased protein synthesis in the pathogenesis of tissue damage in phenylketonuria (PKU) and of growth failure in Lesch-Nyhan syndrome. Protein turnover was measured in vivo in ten young adult subjects with classical PKU, two subjects with hyperphenylalaninemia, and three children with Lesch-Nyhan syndrome using techniques based on continuous infusions of [13C]leucine and, in Lesch-Nyhan subjects, [2H5]phenylalanine. The PKU subjects had various degrees of dietary phenylalanine restriction and plasma phenylalanine levels at the time of study ranged from 450-1540 mumol/L (mean 1106). Plasma phenylalanine in the two hyperphenylalaninemic subjects was 533 and 402 mumol/L. Rates of protein synthesis in all PKU subjects (mean 3.71 g/kg/24 h, range 2.68-5.10, [13C]leucine as tracer) were in a range similar to or above control values (mean 2.97, range 2.78-3.22, n = 6), as were rates of protein catabolism (PKU mean 4.23 g/kg/24 h, range 3.15-5.45; controls 3.64, 3.50-3.91). Protein turnover values in hyperphenylalaninemia were also similar to those in controls. With [13C]leucine as tracer, both mean protein synthesis and catabolism values in Lesch-Nyhan subjects (mean 4.80 and 5.64 g/kg/24 h, respectively) were higher than values in control children matched for protein intake (synthesis 4.32 +/- 0.74 (SD) and catabolism 4.85 +/- 0.57 (g/kg/24 h, n = 5). Similar results were obtained in Lesch-Nyhan subjects using [2H5]phenylalanine as tracer. These results suggest that protein turnover is not decreased in either PKU or Lesch-Nyhan syndrome. This conclusion is inconsistent with the hypothesis that tissue damage in PKU results from impaired protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucose production and oxidation in preterm infants during total parenteral nutrition

During total parenteral nutrition in preterm infants, glucose may be infused at high rates, but it is not known if the endogenous glucose production is fully suppressed under these circumstances. Eight preterm appropriate for gestational age (AGA) (birth wt: 1613 +/- 151 g, gestational age: 31.1 +/- 1.5 wk) and eight preterm small for gestational age (SGA) newborn infants (1185 +/- 241 g, 32.9 +/- 2.6 wk) receiving a glucose infusion rate of 7.55 +/- 0.56 and 8.16 +/- 0.65 mg/kg.min, respectively, were studied during continuous total parenteral nutrition at postnatal d 8. Glucose oxidation rate was determined with a primed constant infusion of [U-13C] glucose, measuring the 13CO2 production in breath gas by isotope ratio mass spectrometry and the glucose production rate in plasma by gas chromatography mass spectrometry. In breath gas of AGA and SGA infants, 60 and 65%, respectively, of the infused tracer appeared as 13CO2. The glucose production rates were 7.97 +/- 1.61 and 8.12 +/- 1.84 mg/kg.min in AGA and SGA infants, respectively, indicating that no significant endogenous glucose production occurred. The glucose oxidation calculated from the glucose production and 13CO2 production was 4.74 +/- 0.99 mg/kg.min in AGA infants and was significantly different from the carbohydrate oxidation rate of 6.62 +/- 1.23 mg/kg.min measured by simultaneous indirect calorimetry. In SGA infants, however, the glucose and carbohydrate oxidation rates were not significantly different at 5.33 +/- 1.56 and 6.16 +/- 2.45 mg/kg.min. It is concluded that 1-wk-old AGA or SGA preterm infants receiving total parenteral nutrition of 80 kcal/kg.d produce no endogenous glucose and their glucose oxidation rates are similar at 63-65% of the glucose infused. It is suggested that the significant difference between glucose and carbohydrate oxidation rates observed in AGA but not in SGA infants is due either to a higher rate of lipogenesis from carbohydrates, or, less likely, to a higher rate of glycogen oxidation.     

Energy substrate utilization in infants receiving total parenteral nutrition with different glucose to fat ratios

As the fate of glucose and lipids infused during total parenteral nutrition is not well known in infants, we assessed energy substrate oxidation in 36 patients (mean age: 5.8 +/- 3.6 mo) on continuous total parenteral nutrition. The infants received isocaloric feeding regimens with nonprotein energy intakes either based on glucose alone (group 1) or on glucose-lipid mixtures providing 15% (group 2), 35% (group 3), 50% (group 4), or 70% (group 5) energy as fat for at least 6 d before glucose and fat oxidation rates were measured by open-circuit indirect calorimetry. Oxidative glucose disposal reached a maximal rate of 12.6 +/- 1.2 mg/kg.min (17.9 +/- 1.7 g/kg.d) in patients with the higher glucose infusion rates. Glucose infused in excess of maximal oxidative disposal was stored, mainly as fat. The increase in glucose infusion rate was paralleled by an increase in energy expenditure amounting to 16% of the energy value of infused glucose. Net fat oxidation was only observed in group 3 (1.6 +/- 0.7 g/kg.d), 4 (3.4 +/- 0.6 g/kg.d), and 5 (3.9 +/- 0.4 g/kg.d) patients, with glucose infusion rates lower than 18.3 g/kg.d. However, there was no further increase in fat oxidation in group 5 as compared to group 4 patients, despite a further increase in fat intake, which only resulted in increasing fat deposition. Thus, fat infusion aiming at a significant contribution to coverage of energy expenditure requires that glucose oxidation be equal to or lower than maximal oxidative glucose disposal, hence that glucose infusion rates be lower than 18 g/kg.d.(ABSTRACT TRUNCATED AT 250 WORDS)     

Leucine kinetics during feeding in normal newborns

To examine how leucine and protein metabolism is affected by feeding, leucine kinetics were determined in 11 normal term newborns during feeding using a prime constant tracer infusion of 1-13C leucine combined with respiratory calorimetry. Fed newborns were compared with previously studied fasting newborns. Feeding and fasting newborns had similar rates of leucine oxidation (34 +/- 3 mumol/kg/h versus 31 +/- 4 mumol/kg/h) and leucine release from existing protein (156 +/- 16 mumol/kg/h versus 164 +/- 8 mumol/kg/h). In contrast, nonoxidative disposal rates of leucine (a reflection of protein synthesis) were significantly greater in feeding newborns (170 +/- 13 mumol/kg/h versus 129 +/- 9 mumol/kg/h). A significant positive correlation between birth weight and leucine flux was demonstrated in both feeding and fasting newborns. These results suggest that 1) newborns may accomplish protein accretion primarily by increases in protein synthesis rather than suppression of protein breakdown; 2) an estimate can be made of the minimal leucine intake required to replace irreversible leucine oxidative losses (816 mumol/kg/d, 107 mg/kg/d); and 3) the positive correlation between birth weight and leucine flux in both feeding and fasting newborns may be a result of differences in previous protein and energy supplies.     

Continuous subcutaneous insulin infusion in children and adolescents with diabetes mellitus: decreased HbA1c with low risk of hypoglycemia

AIM: To evaluate blood glucose and HbA1c levels, insulin dosage, hypoglycemia rate and body mass index (BMI) at baseline, and at 3 and 6 months after initiation of continuous subcutaneous insulin infusion (CSII) in children and youth with type 1 diabetes mellitus (DM). METHODS: A 6-month trial of pump therapy was carried out in 40 patients with type 1 DM and one with cystic fibrosis (CF) induced DM (25 males), aged 4-25 years (mean 13.5 +/- 4.2 [SD]; 4-8 years, n = 6; 8-10 years, n = 8; 10-12 years, n = 4; 12-15 years, n = 11; >15 years, n = 12). RESULTS: HbA1c was significantly reduced from 9.5 +/- 1.7% to 8.6 +/- 1.2% at 3 months (p < 0.03), and at 6 months 8.8 +/- 1.5% (p < 0.05). The mean daily values of blood glucose, as well as individual mean values of blood glucose at fasting and before lunch, also exhibited a significant reduction (p < 0.05) at 3 and 6 months. There was a significant reduction in the number of hypoglycemic events (level of plasma glucose <3.3 mmol/l, calculated as number of events per patient/30 days) at 3 months (6.5 +/- 5.5 vs 2.8 +/- 3.3; p = 0.02) and at 6 months (6.5 +/- 5.5 vs 3.5 +/- 3.0; p = 0.04). The insulin requirement dropped by 27.2% (1.03 +/- 0.30 U/kg/day before starting CSII; 0.75 +/- 020 U/kg/day on insulin pump therapy onset; 0.76 +/- 0.18 U/kg/day at 3 months; 0.75 +/- 0.21 U/kg/day at 6 months). During the follow-up 0.10 events of diabetic ketoacidosis/patient/year were recorded. The patients exhibited no increase in BMI during the 6 months of follow-up. CONCLUSION: CSII was safe and effective in improving short- and medium-term metabolic control in young adults, adolescents and younger children with DM.     

Serum leptin levels in obese Indian children relation to clinical and biochemical parameters

OBJECTIVE: To evaluate serum leptin levels in obese Indian children and its correlation to anthropometric and biochemical parameters. DESIGN: Cohort study. SETTING: Referral tertiary hospital. METHODOLOGY: Leptin levels were measured in 36 children (26 boys, age 1.5 to 15 years) and 37 adults (21 men, age 25 to 69 years) with obesity and 29 normal weight controls (15 children and 14 adults). RESULTS: Leptin levels were higher than controls in obese children (19.4 +/- 6.4 ng/mL against 5.4 +/- 1.7 ng/mL, p = 0.0001) and obese adults (18.9 +/- 6.4 ng/mL against 7.8 +/- 5.6 ng/mL, p = 0.0001). Leptin levels were higher than males in obese girls (23.5 +/- 1.7 ng/mL against 18.0 +/-7.6 ng/mL, p = 0.040) and women (21.3 +/- 4.4 ng/mL against 15.8 +/- 7.4 ng/mL). Leptin levels correlated with body mass index, waist circumference and waist to-hip ratio. A positive correlation was observed between serum leptin and cholesterol, triglycerides and LDL-cholesterol. No correlation was seen with fasting blood glucose and HDL-cholesterol. CONCLUSIONS: Leptin levels correlate significantly with anthropometric and laboratory parameters in obese children. There is a need for further studies on the role of leptin in childhood obesity and metabolic syndrome.     

Body composition and components of energy expenditure in children with end-stage liver disease

BACKGROUND: Better understanding of body composition and energy metabolism in pediatric liver disease may provide a scientific basis for improved medical therapy aimed at achieving optimal nutrition, slowing progression to end-stage liver disease (ESLD), and improving the outcome of liver transplantation. METHODS: Twenty-one children less than 2 years of age with ESLD awaiting liver transplantation and 15 healthy, aged-matched controls had body compartment analysis using a four compartment model (body cell mass, fat mass, extracellular water, and extracellular solids). Subjects also had measurements of resting energy expenditure (REE) and respiratory quotient (RQ) by indirect calorimetry. Nine patients and 15 control subjects also had measurements of total energy expenditure (TEE) using doubly labelled water. RESULTS: Mean weights and heights were similar in the two groups. Compared with control subjects, children with ESLD had higher relative mean body cell mass (33 +/- 2% vs 29 +/- 1% of body weight, P < 0.05), but had similar fat mass, extracellular water, and extracellular solid compartments (18% vs 20%, 41% vs 38%, and 7% vs 13% of body weight respectively). Compared with control subjects, children with ESLD had 27% higher mean REE/body weight (0.285 +/- 0.013 vs 0.218. +/- 0.013 mJ/kg/24h, P < 0.001), 16% higher REE/unit cell mass (P < 0.05); and lower mean RQ (P < 0.05). Mean TEE of patients was 4.70 +/- 0.49 mJ/24h vs 3.19 +/- 0.76 in controls, (P < 0.01). CONCLUSIONS: In children, ESLD is a hypermetabolic state adversely affecting the relationship between metabolic and nonmetabolic body compartments. There is increased metabolic activity within the body cell mass with excess lipid oxidation during fasting and at rest. These findings have implications for the design of appropriate nutritional therapy.     

Metabolic syndrome in childhood obesity

OBJECTIVES: We determined the frequency of metabolic risk factors and the prevalence of Metabolic Syndrome in childhood obesity. SUBJECTS: 186 obese children (97 females and 89 males), aged 11.2 +/- 2.8 (6-16) years and 98 healthy children (46 females and 52 males), aged 10.9 +/- 3.2 (6-16) years were recruited for the study, as study and control groups, respectively. METHODS: Subjects were evaluated for anthropometry, blood pressure (BP) and biochemical cardiovascular risk factors. Metabolic syndrome was defined in presence of > 3 of the following: (i) fasting triglyceride > 100 mg/dL; (ii) high density lipoprotein cholesterol < 50 mg/dL, except in boys aged 15 to 19 years, in whom the cutoff point was 45 mg/dL; (iii) fasting glucose >110 mg/dL; (iv) waist circumference > 75th percentile for age and gender and (v) systolic BP > 90th percentile. RESULTS: We found that 144 (77.4%) children in the obese group had one, two or more cardiovascular risk factors. Using a pediatric definition, the prevalence of metabolic syndrome was 2.1%. In the control group, the clustering of one, two and three risk factors was very rare. CONCLUSION: Childhood obesity is associated with increased frequency of cardiovascular risk factors and metabolic syndrome.     

Effect of minimal enteral feeding on splanchnic uptake of leucine in the postabsorptive state in preterm infants

We conducted a controlled, randomized trial to study the effect of minimal enteral feeding on leucine uptake by splanchnic tissues, as an indicator of maturation of these tissues, in preterm infants in the first week of life. Within a few hours after birth, while receiving only glucose, a primed constant infusion of [1-(13)C]-leucine was started and continued for 5 h via the nasogastric tube, whereas 5,5,5 D3-leucine was infused intravenously (for both tracers, priming dose 2 mg/kg, continuous infusion 2 mg/kg/h). Patients were thereafter randomized to receive solely parenteral nutrition (C), parenteral nutrition and 20 mL breast milk/kg/d (BM), or parenteral nutrition and 20 mL formula/kg/d (F). On d 7, the measurements were repeated, after discontinuing the oral intake for 5 h. Fourteen infants were included in group C, 12 in group BM, and 12 in group F. There was no difference in energy intake or nitrogen balance at any time. On d 1, plasma enrichment for the nasogastric tracer was lower than for the intravenous tracer for all three groups, both for leucine and for alpha-keto-isocaproic acid. On d 7, the enrichment for leucine and alpha-keto-isocaproic acid for the nasogastric tracer was lower than for the intravenous tracer for the groups BM and F (BM: 3.65 +/- 1.20 nasogastric versus 4.64 +/- 0.64 i.v.; F: 4.37 +/- 1.14 nasogastric versus 5.21 +/- 0.9 i.v.). In the control group, there was no difference between tracers. The lower plasma enrichment for the nasogastric tracer compared with the intravenous tracer suggests uptake of leucine by the splanchnic tissues. We conclude that minimal enteral feeding--even in low volumes of 20 mL/kg/d--increases the leucine uptake by the splanchnic tissue. We speculate that this reflects a higher protein synthesis of splanchnic tissues in the groups receiving enteral nutrition.     

Pharmacokinetics of terbinafine in young children treated for tinea capitis

BACKGROUND: Dermatophytes are the most common cause of human fungal infections. Response rates to existing therapy are lower than optimal, but newer agents like terbinafine hold promise for improved management of such infections. This investigation was designed to evaluate the single dose and steady state pharmacokinetics of terbinafine in young children with tinea capitis. METHODS: Twenty-two otherwise healthy children (4-8 years) with tinea capitis were eligible for enrollment. Children were treated with terbinafine once daily according to body weight (<25 kg, 125 mg; 25-35 kg, 187.5 mg), and pharmacokinetic sampling was conducted after the first dose, at the midpoint of treatment and at steady state. Plasma terbinafine concentrations were quantitated, and the pharmacokinetic indices compared with adult data. RESULTS: Absolute estimates of Cmax and area under the concentration curve (AUC)0-24 were comparable between children and adults for the administered dose; however, children demonstrated significantly lower estimates of exposure when dose was corrected for weight (Cmax SS 200 +/- 104 versus 454 +/- 185 ng/mL per mg/kg dose, P < 0.01; AUCSS: 1110 +/- 640 versus 2756 +/- 1775 ng*h/mL per mg/kg dose, P < 0.01). When examined along a continuum, age accounted for approximately 50% of the variability observed in dose-normalized Cmax and AUC (P < 0.01). A slight but significant reduction in apparent oral clearance was observed with increasing age (0.02 L/h/kg per yr) that likely accounts for the lesser degree of accumulation observed in children at steady state (accumulation ratio, 1.5 +/- 0.8 versus 2.3 +/- 0.6, P < 0.01). Adverse events consisted principally of headache (n = 3) and gastrointestinal complaints (altered eating habits n = 3, loss of appetite n = 3, stomachache n = 4, diarrhea n = 2). A reduction in neutrophil count was observed in 5 children and thought to be related to study drug in 2. CONCLUSIONS: Children require significantly larger weight-normalized doses to approximate the exposure estimates observed in adults. The dosing scheme used in this investigation results in absolute exposure estimates at steady state and a safety profile that are not appreciably different from adults.