Changes in attention with hypo- and hyperglycaemia in children with insulin dependent diabetes mellitus

We compared the results of a computerized attention test (TOVA) in 38 children with insulin dependent diabetes mellitus in relation to various spontaneously occurring blood glucose levels. Testing was performed at the following blood glucose levels: <3.3 mmol/l (hypoglycaemia), 3.3–8.3 mmol/l (normoglycaemia) and >8.3 mmol/l (hyperglycaemia) . The attention (sum of errors and response time) varied significantly with the blood glucose level (P=0.002). The highest number of errors of omission and the longest response time was observed during the test run with hypoglycaemia. Age, sex, age at manifestation of the disease, metabolic control and the results of the intelligence test had no significant influence on these results. We found that attention in children with diabetes was significantly reduced compared to TOVA norms especially during mild hypoglycaemia (P<0.001). Irrespective of the blood glucose levels, reaction time and the variability of the reaction time differed significantly between TOVA norms and diabetic children (P<0.01). Conclusion In children with diabetes mellitus a significant reduction in attention was found at mild hypoglycaemia but as well at low normal blood glucose levels. Attention deficits due to transient lowering of blood glucose may therefore occur in diabetic children even before they are aware of hypoglycaemic symptoms. Received: 24 November 1997 / Accepted: 2 March 1998     

Neurodevelopmental outcome of hypoglycaemia in healthy, large for gestational age, term newborns

AIMS: To evaluate the effects of transient hypoglycaemia on the first day of life in 75 healthy term large for gestational age (LGA) infants, born to non-diabetic mothers, on their neurodevelopmental outcome at the age of 4 years. METHODS: Screening for hypoglycaemia was performed 1, 3, and 5 hours after birth, and continued if blood glucose levels were low. Treatment with intravenous glucose for hypoglycaemia was started if hypoglycaemia was severe or symptomatic. Patients' development and behaviour was examined at the age of 4 years by the Denver Developmental Scale, a non-verbal intelligence test, and the Child Behaviour Check List. RESULTS: There were no significant differences between children with neonatal normoglycaemia (n = 15) and hypoglycaemia (plasma glucose <2.2 mmol/l 1 hour after birth, or <2.5 mmol/l subsequently; n = 60) in Denver developmental scale scores and child behaviour checklist scores. Although total IQ did not differ between hypoglycaemic and normoglycaemic children, one subscale (reasoning) did (mean difference 9.3, 95% CI 1.3 to 17.2). The correlation between reasoning IQ and neonatal blood glucose levels was weak and not statistically significant. When other definitions for hypoglycaemia were applied, the difference in reasoning IQ was not found. There were no differences in any of the test scores between hypoglycaemic children who had and who had not been treated with intravenous glucose. CONCLUSION: Transient mild hypoglycaemia in healthy, term LGA newborns does not appear to be harmful to psychomotor development at the age of 4 years.     

Hypoglycaemia in Childhood Diabetes I.

ABSTRACT. Hypoglycaemia (blood glucose 1.3–2.5 mmol/l) was induced in twenty-eight diabetic children by reduction of their morning meal. Fatigue and pallor were the most common signs of hypoglycaemia. Compared to findings during normoglycaemia, plasma concentrations of adrenalin, noradrenalin and Cortisol were significantly higher at glucose nadir. Plasma glucagon concentration at glucose nadir was correlated to the fasting C-peptide concentration and inversely to the duration of diabetes. Children who lacked C-peptide also lacked glucagon response to hypoglycaemia. The parents' opinion of the need to give carbohydrates corresponded to the blood glucose level. The presence of adrenergic signs correlated to the plasma adrenalin and the neuroglucopenic signs to blood glucose. The lowest glucose level correlated inversely to the concentration of free insulin. When facilities for glucose infusion are lacking, a rational step in treating the unconscious hypoglycaemic child seems to be the injection of glucagon, considering the blunted or absent glucagon secretion.     

Hypoglycaemia in childhood diabetes. I. Clinical signs and hormonal counterregulation

Hypoglycaemia (blood glucose 1.3-2.5 mmol/l) was induced in twenty-eight diabetic children by reduction of their morning meal. Fatigue and pallor were the most common signs of hypoglycaemia. Compared to findings during normoglycaemia, plasma concentrations of adrenalin, noradrenalin and cortisol were significantly higher at glucose nadir. Plasma glucagon concentration at glucose nadir was correlated to the fasting C-peptide concentration and inversely to the duration of diabetes. Children who lacked C-peptide also lacked glucagon response to hypoglycaemia. The parents' opinion of the need to give carbohydrates corresponded to the blood glucose level. The presence of adrenergic signs correlated to the plasma adrenalin and the neuroglucopenic signs to blood glucose. The lowest glucose level correlated inversely to the concentration of free insulin. When facilities for glucose infusion are lacking, a rational step in treating the unconscious hypoglycaemic child seems to be the injection of glucagon, considering the blunted or absent glucagon secretion.     

Long-term neurological dysfunction and neonatal hypoglycaemia after diabetic pregnancy

AIM: To determine if children born to mothers with diabetes mellitus during pregnancy, who subsequently developed neonatal hypoglycaemia, experienced long-term neurological dysfunction. METHODS: Thirteen children with, and 15 without, neonatal hypoglycaemia (blood glucose < 1.5 mmol/l) were randomly selected from a larger cohort and investigated at the age of 8 years. They were also compared with 28 age matched healthy controls. RESULTS: Children with neonatal hypoglycaemia had significantly more difficulties in a validated screening test for minimal brain dysfunction than controls and were also more often reported to be hyperactive, impulsive, and easily distracted. On psychological assessment, they had a lower total development score than normoglycaemic children born to diabetic mothers, and control children. CONCLUSIONS: Neonatal hypoglycaemia in diabetic pregnancy was associated with long-term neurological dysfunction related to minimal brain dysfunction/deficits in attention, motor control, and perception.     

Abnormal blood glucose concentrations on admission to a rural Kenyan district hospital: prevalence and outcome.

AIMS: To determine the prevalence, clinical characteristics, and outcome of hypoglycaemia on admission in children at a rural Kenyan district hospital. METHODS: Observational study of 3742 children (including 280 neonates) in Kilifi District Hospital, Kenya. Main outcome measures: hypoglycaemia (blood glucose <2.2 mmol/l) and hyperglycaemia (blood glucose >10.0 mmol/l). RESULTS: Non-neonates: the prevalence of hypoglycaemia on admission was 7.3%. Severe illness, malnutrition, last meal >12 hours ago, and a positive malaria slide were independently associated with hypoglycaemia. Overall, mortality in hypoglycaemic children was 20.2% compared to 3.8% in normoglycaemic children (p < 0.001). The brunt of mortality in hypoglycaemic children was borne by those who were severely ill or malnourished (31.8%) as opposed to those who were neither severely ill nor malnourished (9.0%). Neonates: 23.0% of neonates were hypoglycaemic on admission. Inability to breast feed and weight <2500 g were independently associated with hypoglycaemia. Mortality was 45.2% compared to 19.6% in normoglycaemic neonates (p < 0.001). Hyperglycaemia was present in 2.7% of children and was associated with a higher mortality than normoglycaemia, 14.0% versus 3.8% respectively (p < 0.001). CONCLUSIONS: Hypoglycaemia is common in children admitted to a rural Kenyan district hospital and is associated with an increased mortality. Apart from features of severe illness and poor feeding, clinical signs have a low sensitivity and specificity for hypoglycaemia. Where diagnostic facilities are lacking, presumptive treatment of severely ill children is recommended. For other children, the continuation of feeding (by nasogastric tube if necessary) should be part of standard management.     

Cognitive function and mood after profound nocturnal hypoglycaemia in prepubertal children with conventional insulin treatment for diabetes.

OBJECTIVES: To examine the frequency of nocturnal hypoglycaemia, and the effects on cognitive function and mood, in children with insulin dependent diabetes mellitus (IDDM). DESIGN: Two overnight glucose profiles, in the home environment, and assessments of cognitive function and mood the following day. Twenty nine prepubertal patients with IDDM (median age, 9.4 years; range, 5.3-12.9) and 15 healthy controls (single overnight profile), median age 9.5 (range, 5.6-12.1) years were studied. RESULTS: Asymptomatic hypoglycaemia (glucose < 3.5 mmol/l) was observed in 13 of 29 patients studied on night 1: four of these and seven others were hypoglycaemic on night 2. The median glucose nadir was 1.9 (range, 1.1-3.3) mmol/l and the median duration of hypoglycaemia was 270 (range, 30-630) minutes. Hypoglycaemia was related to insulin dose, but not glycosylated haemoglobin (HbA1c) values, and was partially predicted by a midnight glucose of < 7.2 mmol/l. Cognitive performance was not altered after hypoglycaemia but a lowering of mood was observed. CONCLUSIONS: Young children on conventional insulin regimens are at high risk for profound, asymptomatic nocturnal hypoglycaemia, which is difficult to predict. There was no short term effect on cognitive function but mood change was detected.     

Abnormal blood glucose concentrations on admission to a rural Kenyan district hospital: prevalence and outcome

Aims: To determine the prevalence, clinical characteristics, and outcome of hypoglycaemia on admission in children at a rural Kenyan district hospital. Methods: Observational study of 3742 children (including 280 neonates) in Kilifi District Hospital, Kenya. Main outcome measures: hypoglycaemia (blood glucose <2.2 mmol/l) and hyperglycaemia (blood glucose >10.0 mmol/l). Results: Non-neonates: the prevalence of hypoglycaemia on admission was 7.3%. Severe illness, malnutrition, last meal >12 hours ago, and a positive malaria slide were independently associated with hypoglycaemia. Overall, mortality in hypoglycaemic children was 20.2% compared to 3.8% in normoglycaemic children (p < 0.001). The brunt of mortality in hypoglycaemic children was borne by those who were severely ill or malnourished (31.8%) as opposed to those who were neither severely ill nor malnourished (9.0%). Neonates: 23.0% of neonates were hypoglycaemic on admission. Inability to breast feed and weight <2500 g were independently associated with hypoglycaemia. Mortality was 45.2% compared to 19.6% in normoglycaemic neonates (p < 0.001). Hyperglycaemia was present in 2.7% of children and was associated with a higher mortality than normoglycaemia, 14.0% versus 3.8% respectively (p < 0.001). Conclusions: Hypoglycaemia is common in children admitted to a rural Kenyan district hospital and is associated with an increased mortality. Apart from features of severe illness and poor feeding, clinical signs have a low sensitivity and specificity for hypoglycaemia. Where diagnostic facilities are lacking, presumptive treatment of severely ill children is recommended. For other children, the continuation of feeding (by nasogastric tube if necessary) should be part of standard management.     

Impact of home blood glucose monitoring on childhood diabetes.

Ninety diabetic children each provided at least one 24-hour blood glucose profile at home using an impregnated filter paper strip. The mean 24-hour blood glucose level correlated significantly with urine control, height velocity, and Hb A1. The correlation coefficient for individual blood glucose values (r = 0.61) and for mean 24-hour blood glucose values (r = 0.73) repeated within 14 days showed an acceptable degree of reproducibility for the blood glucose profiles. Mean 24-hour blood glucose values fell significantly overall (11.4 to 9.8 mmol/l; 205 to 176 mg/100 ml) in 47 children who had repeated profiles more than 2 weeks apart. Unrecognised nocturnal hypoglycaemia (less than 3.0 mmol/l; 54 mg/100 ml) was found in 19% of children on twice-daily Semitard insulin. The study shows that children over age 7 years manage home blood glucose monitoring without difficulty. It shows that the results are reproducible and correlate with other indices of control, and that it provides a practical basis for the improvement of diabetic control.     

Cognitive function and mood after profound nocturnal hypoglycaemia in prepubertal children with conventional insulin treatment for diabetes

OBJECTIVES—To examine the frequency of nocturnal hypoglycaemia, and the effects on cognitive function and mood, in children with insulin dependent diabetes mellitus (IDDM).DESIGN—Two overnight glucose profiles, in the home environment, and assessments of cognitive function and mood the following day. Twenty nine prepubertal patients with IDDM (median age, 9.4 years; range, 5.3-12.9) and 15 healthy controls (single overnight profile), median age 9.5 (range, 5.6-12.1) years were studied.RESULTS—Asymptomatic hypoglycaemia (glucose < 3.5 mmol/l) was observed in 13 of 29 patients studied on night 1: four of these and seven others were hypoglycaemic on night 2. The median glucose nadir was 1.9 (range, 1.1-3.3) mmol/l and the median duration of hypoglycaemia was 270 (range, 30-630) minutes. Hypoglycaemia was related to insulin dose, but not glycosylated haemoglobin (HbA1c) values, and was partially predicted by a midnight glucose of < 7.2 mmol/l. Cognitive performance was not altered after hypoglycaemia but a lowering of mood was observed.CONCLUSIONS—Young children on conventional insulin regimens are at high risk for profound, asymptomatic nocturnal hypoglycaemia, which is difficult to predict. There was no short term effect on cognitive function but mood change was detected.     

Impact of home blood glucose monitoring on childhood diabetes

Ninety diabetic children each provided at least one 24-hour blood glucose profile at home using an impregnated filter paper strip. The mean 24-hour blood glucose level correlated significantly with urine control, height velocity, and Hb A1. The correlation coefficient for individual blood glucose values (r = 0.61) and for mean 24-hour blood glucose values (r = 0.73) repeated within 14 days showed an acceptable degree of reproducibility for the blood glucose profiles. Mean 24-hour blood glucose values fell significantly overall (11.4 to 9.8 mmol/l; 205 to 176 mg/100 ml) in 47 children who had repeated profiles more than 2 weeks apart. Unrecognised nocturnal hypoglycaemia (less than 3.0 mmol/l; 54 mg/100 ml) was found in 19% of children on twice-daily Semitard insulin. The study shows that children over age 7 years manage home blood glucose monitoring without difficulty. It shows that the results are reproducible and correlate with other indices of control, and that it provides a practical basis for the improvement of diabetic control.     

Hypoglycaemia in Childhood Diabetes II.

ABSTRACT. Hypoglycaemia (blood glucose 1.3–2.5 mmol/1) was induced in thirty diabetic children by reduction of their morning meal. Glucagon, 10 or 20 μg/kg was then given by intramuscular or subcutaneous injection. Ten min later, all signs of hypoglycaemia had disappeared and blood glucose concentrations increased by 0.7–3.3 mmol/1. Glucagon plasma concentrations at glucose nadir were low, 23±8 pmol/l, rose to 300±42 ten min after the injection and reached peak values after another ten min. Later, a slow decrease was noted. No significant difference of blood glucose or plasma glucagon concentrations were found after subcutaneous or intramuscular injections of 20 μg/kg. After 10 μg/kg, slightly lower increase of blood glucose was seen, but the clinical effect was equally good. Nausea occurred in four children given 20 μg/kg. The rise of blood glucose did not correlate to the peak glucagon concentration obtained after the injection but showed significant correlations to the lowest glucose concentration and, inversely, to the concentration of free insulin in blood at glucose nadir. It is concluded that glucagon injections are effective in hypoglycaemia in insulin-treated diabetic children and that the injection of 10–20 μg/kg gives long-standing supraphysiological concentrations which make repeated injections unnecessary.     

Pubertal stage and hypoglycaemia counterregulation in type 1 diabetes.

AIMS: To compare physiological and autonomic responses to acute hypoglycaemia in diabetic children in pre-, mid-, and post-pubertal stages of development. METHODS: Twenty seven children (8 pre-pubertal, 7 mid-pubertal, 12 post-pubertal) with type 1 diabetes were studied. Hypoglycaemia was induced by insulin infusion until an autonomic reaction (R) was identified. Counterregulatory hormone levels were measured at baseline, R, R+15, and R+30 minutes. Haemodynamic changes and sweat production were measured. RESULTS: The mean blood glucose level at R was lower in pre-pubertal than mid-pubertal children (2.0 v 2.5 mmol/l), and was positively correlated with HbA1c. Glucagon and noradrenaline responses to hypoglycaemia were minimal in all children. A brisk increase in pancreatic polypeptide (PP) concentration only occurred in post-pubertal children. Only two children showed a sweating response to hypoglycaemia. CONCLUSIONS: The blood glucose level at which sympatho-adrenal responses to hypoglycaemia were activated was associated with glycaemic control, and varied with pubertal stage. As in adults, the glucagon response to hypoglycaemia was deficient within a few years of developing diabetes. However, sweating and secretion of PP in response to hypoglycaemia did not occur until after puberty, indicating some qualitative differences from adults.     

Pubertal stage and hypoglycaemia counterregulation in type 1 diabetes

Aims: To compare physiological and autonomic responses to acute hypoglycaemia in diabetic children in pre-, mid-, and post-pubertal stages of development. Methods: Twenty seven children (8 pre-pubertal, 7 mid-pubertal, 12 post-pubertal) with type 1 diabetes were studied. Hypoglycaemia was induced by insulin infusion until an autonomic reaction (R) was identified. Counterregulatory hormone levels were measured at baseline, R, R+15, and R+30 minutes. Haemodynamic changes and sweat production were measured. Results: The mean blood glucose level at R was lower in pre-pubertal than mid-pubertal children (2.0 v 2.5 mmol/l), and was positively correlated with HbA_1c. Glucagon and noradrenaline responses to hypoglycaemia were minimal in all children. A brisk increase in pancreatic polypeptide (PP) concentration only occurred in post-pubertal children. Only two children showed a sweating response to hypoglycaemia. Conclusions: The blood glucose level at which sympatho-adrenal responses to hypoglycaemia were activated was associated with glycaemic control, and varied with pubertal stage. As in adults, the glucagon response to hypoglycaemia was deficient within a few years of developing diabetes. However, sweating and secretion of PP in response to hypoglycaemia did not occur until after puberty, indicating some qualitative differences from adults.     

Hypoglycaemia in childhood diabetes. II. Effect of subcutaneous or intramuscular injection of different doses of glucagon

Hypoglycaemia (blood glucose 1.3-2.5 mmol/l) was induced in thirty diabetic children by reduction of their morning meal. Glucagon, 10 or 20 micrograms/kg was then given by intramuscular or subcutaneous injection. Ten min later, all signs of hypoglycaemia had disappeared and blood glucose concentrations increased by 0.7-3.3 mmol/l. Glucagon plasma concentrations at glucose nadir were low, 23 +/- 8 pmol/l, rose to 300 +/- 42 ten min after the injection and reached peak values after another ten min. Later, a slow decrease was noted. No significant difference of blood glucose or plasma glucagon concentrations were found after subcutaneous or intramuscular injections of 20 micrograms/kg. After 10 micrograms/kg, slightly lower increase of blood glucose was seen, but the clinical effect was equally good. Nausea occurred in four children given 20 micrograms/kg. The rise of blood glucose did not correlate to the peak glucagon concentration obtained after the injection but showed significant correlations to the lowest glucose concentration and, inversely, to the concentration of free insulin in blood at glucose nadir. It is concluded that glucagon injections are effective in hypoglycaemia in insulin-treated diabetic children and that the injection of 10-20 micrograms/kg gives long-standing supraphysiological concentrations which make repeated injections unnecessary.     

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.     

Unrecognised hypoglycaemia in children and adolescents with type 1 diabetes using the continuous glucose monitoring system: prevalence and contributors

AIM: To determine prevalence of hypoglycaemia, and contributing factors, in children with type 1 diabetes, using the Medtronic MiniMed continuous glucose monitoring system (CGMS). METHODS: Fifty-one children and adolescents with diabetes were studied with the CGMS. The studies were analysed for frequency and duration of hypoglycaemia (below 3.5 and 2.5 mmol/L). Contributing clinical factors were determined. Occurrence of nocturnal hypoglycaemia was related to bedtime and fasting home glucose recording. RESULTS: Hypoglycaemia was common, with 1 (0-4.2) (median (range)) episode per patient per 24 hours, and 0.33 (0-2) episodes per patient per night. Nocturnal episodes were longer than daytime episodes [97.5 (5-720) versus 35 (5-295) minutes for episodes below 3.5 mmol/L, P < 0.001; and 75 (10-640) versus 25 (5-200) minutes for episodes below 2.5 mmol/L, P < 0.001], and less likely to be recognised by the subject (P < 0.001 for episodes below both 3.5 and 2.5 mmol/L). Nocturnal hypoglycaemia was more common with a bedtime glucose recording <6 mmol/L, but also occurred frequently in subjects with glucose recordings >10 mmol/L. No bedtime glucose value reduced the risk of nocturnal hypoglycaemia to <10%. CONCLUSION: Hypoglycaemia, assessed using the CGMS, is common in children with type 1 diabetes and can be prolonged (although is predominantly mild). Bedtime home glucose recordings are poorly predictive of hypoglycaemia during the following night. Continuous glucose monitoring has proven very useful in management of individual patients, particularly adolescents experiencing difficulties with adherence to diabetes management.     

Continuous subcutaneous insulin infusion in diabetes mellitus. A year's prospective trial.

Thirteen children aged between 8 and 16 years were entered into a 12 month prospective trial comparing continuous subcutaneous insulin infusion with intensified conventional treatment. Two of seven children on insulin infusion withdrew after eight and nine weeks, and three of six children on conventional treatment withdrew after four to eight weeks. Withdrawals in both groups were related to dissatisfaction with the techniques. The group on insulin infusion treatment achieved a mean plasma glucose of 9.8 mmol/l (176.4 mg/100 ml), a median M value of 50 mmol/l (900 mg/100 ml) and a mean glycosylated haemoglobin of 9.1% during the year. This represents a significant improvement compared with the previous values, and also when compared with the conventional treatment group whose trial values of a mean plasma glucose of 15.5 mmol/l (279 mg/100 ml), median M value of 167 mmol/l (3006 mg/100 ml), and glycosylated haemoglobin of 10.4% were not significantly different from those before the trial. Two children on insulin infusion developed subcutaneous abscesses in the early months. There was an increased incidence of diabetic ketoacidosis in this group, but no difference in the incidence of serious hypoglycaemia between the two groups. The children reported improved well-being when using insulin infusion and continued with the technique after the trial finished. Insulin infusion offers an acceptable means of improving glycaemic control for some diabetic children.     

Neonatal hypoglycaemia in infants of diabetic mothers

OBJECTIVE: To determine whether umbilical cord blood glucose correlates with subsequent hypoglycaemia after birth in infants of well-controlled diabetic mothers. METHODOLOGY: Thirty-eight term infants of well-controlled diabetic mothers were enrolled. Five mothers had pre-existing diabetes. Of the 33 gestational diabetic mothers, 16 were managed on insulin and 17 on diet. Maternal blood glucose was maintained between 4 and 8 mmol/L during labour and delivery. Infants' plasma glucose levels were measured from venous cord blood and serially, at less than 30 min, 1 h and 2 h of life by glucose hexokinase method. Blood glucose levels were further monitored by bedside Dextrostix for 24 h. RESULTS: Eighteen (47%) infants developed hypoglycaemia (blood glucose level less than 2 mmol/L) during the first 2 h of life. There was no difference in the cord blood glucose levels between infants with or without hypoglycaemia (3.7 +/- 1.1 vs 4.5 +/- 1.1 mmol/L, respectively). Infants of mothers with diabetes diagnosed prior to 28 weeks gestation were at a higher risk of developing hypoglycaemia (8 of 10 vs 10 of 28, OR 7.2, 95%CI 1.3-40.7). Hypoglycaemic infants were of significantly higher birthweight, and were more likely to be born to Caucasian mothers and by Caesarean section. Raised maternal fructosamine blood level, the need for insulin treatment or the infant's haematocrit were not different between infants with or without hypoglycaemia. CONCLUSIONS: In well-controlled diabetic mothers, the incidence of early hypoglycaemia in infants is still high, particularly in those mothers who had a longer duration of diabetes. Cord blood glucose level did not identify the infants with hypoglycaemia.     

Investigation of the mechanisms of therapy-related hypoglycaemia in children with acute lymphoblastic leukaemia

Aim: To determine the mechanisms of fasting hypoglycaemia occurring during maintenance therapy (MT) for childhood acute lymphoblastic leukaemia (ALL). Methods: Thirty-five children and adolescents with ALL, aged 2.4-17.4 y, were fasted for up to 16 h during MT. Nineteen of the children developed hypoglycaemia after 11 to 16 h of fasting. Blood samples for determination of metabolic changes were taken on completion of fasting. Nineteen patients underwent a glucagon stimulation test after 4 to 16 h of fasting during MT. Erythrocyte concentrations of the metabolites of methotrexate (E-MTX) and 6-mercaptopurine (E-TGN) were measured at the time of fasting. Fifteen out of 19 patients who became hypoglycaemic were re-studied 3 to 4 mo after cessation of therapy. Results: In the hypoglycaemia group, plasma levels of gluconeogenic amino acids alanine and glutamine were lower (medians 117 vs 190 3mol L 31 , p = 0.009, and medians 396 vs 448 3mol L 31 , p = 0.031, respectively) than in the normoglycaemia group. Serum levels of free carnitine were lower (medians 20.3 vs 29.8 3mol L 31 , p = 0.027), free fatty acids higher (medians 3.09 vs 1.23 mmol L 31 , p 3 0.001) and marked dicarboxylic aciduria was more common in the patients with hypoglycaemia (in 14/16 vs in 2/14, p 3 0.001). Impaired responses to glucagon stimulation occurred in 36% (4/11) in the hypoglycaemia group and in 12.5% (1/8) in the normoglycaemia group ( p = 0.243). No significant differences were detected in E-MTX and E-TGN between the groups. Most of the metabolic abnormalities returned to normal after cessation of chemotherapy. Conclusions: Low levels of gluconeogenic amino acids, especially of alanine, are associated with hypoglycaemia. Reduced hepatic glycogen stores may also be involved in the aetiology.