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.     

Effect of ephedrine in ketotic hypoglycaemia

The effect of oral ephedrine administration on a child with ketotic hypoglycaemia who had not responded to dietary measures alone was studied. After ephedrine administration, the hypoglycaemia developing after ketogenic stress was less profound and was substantially delayed. The impaired glycaemic response to glucagon during hypoglycaemia, characteristic of ketotic hypoglycaemia, was not altered.These observations are compatible with the proposition that ketotic hypoglycaemia is associated with impaired gluconeogenesis and they suggest that ephedrine may be a useful adjunct to therapy in this condition.     

From hyperinsulinaemic hypoglycaemia to ketotic hypoglycaemia: the range of glucose abnormalities in patients born with intrauterine growth retardation

Introduction Newborns with intrauterine growth retardation (IUGR) have multiple risk factors for developing hypoglycaemia. Hyperinsulinism, both transient and prolonged, is one of the major risk factors responsible for the hypoglycaemia observed in some newborns with IUGR. Once the child has progressed beyond the infancy period, the most common cause of hypoglycaemia is ketotic hypoglycaemia. We report our observations of ketotic hypoglycaemia in six children who were born with IUGR and developed hyperinsulinaemic hypoglycaemia (HH) that required treatment with diazoxide and chlorothiazide. Results In one of these children the ketotic hypoglycaemia was found to be due to growth hormone deficiency; in the remaining five patients, however, no cause for the hypoglycaemia could be found, despite extensive investigations. These observations suggest that ketotic hypoglycaemia may be more common in children with a history of IUGR. Further studies are required to understand why some newborns with IUGR and HH have an increased risk of ketotic hypoglycaemia in childhood. Conclusion Newborns with a history of IUGR and HH have an increased risk of developing ketotic hypoglycaemia in the childhood period.     

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.     

Effect of insulin on leucine kinetics in maple syrup urine disease

Leucine turnover was measured using [1-14C] L-leucine in three patients with classical maple syrup urine disease. There was measurable leucine oxidation although it was lower than in normal adults. Leucine production rate was greater than normal in all three patients with an increased rate of incorporation of leucine into protein and increased protein catabolism. These fluxes were both relatively insensitive to exogenous insulin.     

Glucose kinetics in glucose-infused small for gestational age infants

To evaluate the maturation of glucose homeostasis in the small for gestational age (SGA) neonate, glucose kinetics were measured with 78% enriched D-[U-13C]glucose by the prime plus constant infusion technique in nine SGA infants and compared with the rate obtained in seven term appropriate for gestational age infants and 13 preterm appropriate for gestational age infants. All of the infants had received glucose intravenously from birth and continued to receive the glucose infusion throughout the study. Fasting plasma glucose and plasma insulin concentrations and plasma [13/12C]ratios were measured during the steady state turnover period. From this data, the glucose production rate was derived. During the turnover period, the SGA and both groups of appropriate for gestational age infants had similar average plasma glucose, plasma insulin, plasma glucagon concentrations, and similar persistent rates of glucose production during glucose infusion. We conclude that under stimulation of glucose infusion, the SGA infant and his AGA counterpart have similar hormonal regulatory responses as well as functional integrity in handling glucose during the second day after birth.     

Insulin-like growth factors and leucine kinetics during exercise training in children with cystic fibrosis

BACKGROUND: Little is known about the metabolic effects of exercise training in children with cystic fibrosis. The hypothesis for the current study was that in patients with declining clinical status, exercise increases circulating insulin-like growth factors (IGFs) and improves protein kinetics. METHODS: This was a prospective intervention study in 10 children with cystic fibrosis who participated in a structured isoenergetic exercise (cycling) training program for 3 months. Measurements of IGFs, protein kinetics (using intravenous [13C]-1-leucine tracer infusions) and nutritional balance studies were conducted at baseline and after 3 months. RESULTS: Standard deviation scores of plasma IGF-I, IGF-II, and IGF binding protein (BP)-3 were all decreased at baseline (mean +/- SE: -2.0+/-0.2, -2.0+/-0.2. -0.6+/-0.2, respectively). IGF-I and IGF-II concentrations were significantly higher after exercise training (standard deviation scores -1.4+/-0.3 and -1.3 +/-0. 1, respectively; compared with baseline: one-tailed t-test P = 0.03 and 0.002). The standard deviation score of the IGF-I/IGF BP-3 ratio, an indicator of free IGF-I in the circulation, normalized during exercise training (0.0+/-0.6 vs. -1.3+/-0.2 SD units at baseline, one-tailed t-test P = 0.04). There was no significant difference in protein intake and fasting protein breakdown, oxidation, and protein synthesis or in energy balance and fat absorption. CONCLUSIONS: These results show that isoenergetic exercise training can be safely recommended to patients with cystic fibrosis. It provides a positive anabolic stimulus to IGF status but is not sufficient to adequately augment protein accretion in patients with diminished nutritional status.     

Effects of early amino acid administration on leucine and glucose kinetics in premature infants

We previously showed that, in prematurely born infants, an anabolic state without metabolic acidosis can be achieved upon intravenous amino acid (AA) administration in the immediate postnatal phase, despite a low energy intake. We hypothesized that the anabolic state resulted from an increased protein synthesis and not a decreased proteolysis. Furthermore, we hypothesized that the energy needed for the higher protein synthesis rate would be derived from an increased glucose oxidation. To test our hypotheses, 32 ventilated premature infants (<1500 g) received intravenously either solely glucose or glucose and 2.4 g AA/kg/d immediately postnatally. On postnatal d 2, each group received primed continuous infusions of either [1-13C]leucine or [U-13C6]glucose. 13CO2 enrichments in expiratory air and plasma [1-13C]alpha-KICA (as an intracellular leucine precursor) and [U-13C6]glucose enrichments were measured by mass spectrometry techniques. The AA administration resulted in an increased incorporation of leucine into body protein and a higher leucine oxidation rate, whereas leucine release from proteolysis was not affected. Glucose oxidation rate did not increase upon AA administration. In conclusion, the anabolic state resulting from AA administration in the immediate postnatal period resulted from increased protein synthesis and not decreased proteolysis. The energy needed for the additional protein synthesis was not derived from an increased glucose oxidation.     

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.     

Plasma C peptide in hyperinsulinaemic hypoglycaemia.

We describe two children with hypoglycaemia due to pancreatic beta cell hyperactivity. Both had low serum insulin but raised plasma C peptide concentrations when hypoglycaemic. Measurement of C peptide is valuable in the diagnosis of hyperinsulinaemic hypoglycaemia in children.     

Neural dysfunction during hypoglycaemia.

There is controversy over the definition of hypoglycaemia in neonates and children and over its significance when ''asymptomatic''. We measured sensory evoked potentials in relation to blood glucose concentration in 17 children: 13 were fasted or given insulin to investigate endocrine or metabolic abnormalities and four had spontaneous episodes of hypoglycaemia. Abnormal evoked potentials were recorded in 10 of the 11 children whose blood glucose concentration fell below 2.6 mmol/l; five of these 10 children were ''asymptomatic''. No change in evoked potentials was recorded in the six children whose blood glucose concentration remained above 2.6 mmol/l. Our findings suggest that the blood glucose concentration should be maintained above 2.6 mmol/l to ensure normal neural function in children irrespective of the presence or absence of abnormal clinical signs.