Sports and diabetes in children and adolescents

The triad of insulin, diet and exercise has been the basis for treatment of diabetes for several decades. However, the choice of sporting activities for young diabetics requires an understanding of: a) the energy metabolism and the adaptation to physical activity in the healthy; b) the metabolic adaptation during physical activity in the diabetic child; and c) the practical recommendations concerning diet and insulin that have to be learned by the children themselves. The healthy child utilises immediately available substrates, such as ATP and creatine phosphate in much the same fashion as the adult. However, the capacity for anaerobic degradation of glycogen and glucose seems limited in the muscles of children relative to that of adults. Consequently, the adaptation to resistance exercise should be undertaken with prudence in children and adolescents. The release of insulin tends to decrease during effort. Diverse hypotheses have been proposed to explain this phenomenon. However a low concentration of insulin is required: insulin is said to play a "permissive" role. In diabetic children, an adequate insulin therapy is required to allow the full benefit of muscular activity on glucose assimilation and to reach the same level of physical performance as the non-diabetic. In the case of insufficient metabolic control, exercise can provoke severe hypoglycaemic episodes, even after muscle activity has ceased, or increase glucose levels and lead to ketoacidosis. Regular physical training induces a reduction in postexercise proteinuria measured in diabetic adolescents but its role in metabolic control remains controversial.(ABSTRACT TRUNCATED AT 250 WORDS)     

Normal hepatic glycogen storage after fasting and feeding in children and adolescents with type 1 diabetes

Abstract: Objective: Hypoglycemia is the most important acute complication in patients with type 1 diabetes. Liver glycogen is an important storage form of glucose and thus important for maintaining glucose homeostasis. To test the hypothesis whether abnormal storage of glycogen in the liver is contributing to the risk of hypoglycemia in type 1 diabetic children and adolescents, liver glycogen was measured. Study design: Hepatic glycogen concentrations were measured in 19 type 1 diabetic children and adolescents as well as in 19 age‐matched controls, following overnight fasting and 4 h after two standardized meals. Hepatic glycogen was assessed by natural abundance ¹³C nuclear magnetic resonance spectroscopy (MRS). Results: Mean (± SEM) fasting hepatic glycogen concentrations measured in arbitrary units (au) were similar in type 1 diabetic subjects and controls (4.98 ± 0.36 vs. 4.48 ± 0.33 au; p = 0.31). Both groups presented with an increase in liver glycogen concentrations 4 h after the standardized meals (diabetic subjects 5.70 ± 0.37 au, p = 0.01; controls 5.78 ± 0.47 au, p < 0.01). Hepatic glycogen accumulation after feeding was 19.1% in diabetic children and adolescents compared with 35.8% in controls, but this difference did not reach significance. Conclusion: In children and adolescents with moderately controlled type 1 diabetes, hepatic glycogen stores after fasting and feeding are comparable to those of matched controls.     

Determination of blood level of muscle enzymes in glycogenoses with liver involvement: a diagnostic criterion

Serum muscle enzyme activity assays were routinely performed in 36 patients with glycogen storage diseases (15 types 1a and 1b, 12 type III, and 9 types VI and IX). Creatine phosphokinase serum activity was increased only in type III. Glutamate-pyruvate transaminase, aldolase and lactate dehydrogenase serum activities were increased in all the forms of glycogen storage disease studied. Muscle involvement may at least partly explain the increased serum enzyme activities in type III.     

Amylopectinosis disease isolated to the heart with normal glycogen branching enzyme activity and gene sequence

We report a 17-month-old female patient with a rare cause of cardiomyopathy secondary to accumulation of amylopectin-like material (fibrillar glycogen) isolated to the heart. Evidence of amylopectinosis isolated to cardiac myocytes in this patient was demonstrated by histology and electron microscopy. Glycogen content, glycogen branching enzyme (GBE) activity, as well as phosphofructokinase enzyme activities measured in liver, skeletal muscle, fibroblasts and ex-transplanted heart tissue were all in the normal to lower normal ranges. Normal skeletal muscle and liver tissue histology and GBE activity, normal GBE activity in skin fibroblasts, plus normal GBE gene sequence in this patient exclude the classical branching enzyme deficiency (type IV GSD). We believe that this is an as yet uncharacterized and novel phenotype of GSD associated with cardiomyopathy, in which there is an imbalance in the regulation of glycogen metabolism limited to the heart.     

Ovine fetal and maternal glycogen during fasting.

The present study was undertaken to assess the role of hepatic glycogen metabolism in fetal and maternal glucose homeostasis during a prolonged fast in the pregnant ewe. A control fed group of 13 ewes and 16 fetuses were compared to a 5-day-fasted group of 13 ewes and 17 fetuses, studied at 125 days gestation (term = 147 days). Tissue samples were obtained during pentobarbital anesthesia and frozen in liquid nitrogen. Protein, glycogen, active phosphorylase and total phosphorylase activity were determined. Fetal weight (3.61 vs. 2.86 kg) was decreased in the fasted group (p less than 0.001) while fetal hepatic glycogen was unchanged (59.8 vs. 52.4 mg/g tissue). Maternal liver glycogen decreased during fasting (38.2 vs. 4.0 mg/g tissue, p less than 0.001). Fetal active phosphorylase and total phosphorylase did not change between fed and fasted states (fed active phosphorylase 398 vs. fasted 441 and fed total phosphorylase 510 vs. fasted 574 mumol/h/g tissue). The maternal active phosphorylase and total phosphorylase decreased between fed and fasted (active phosphorylase 690 vs. 238 and total phosphorylase 981 vs. 599 mumol/h/g tissue, p less than 0.001). During fasting, the pregnant ewe depletes her hepatic glycogen stores, associated with a reduction in glycogen catabolizing enzyme activity. The fetus maintains a relatively large glycogen catabolizing enzyme activity, a relatively large glycogen reserve and substantial phosphorylase activity.     

Effects of maternal protein-calorie malnutrition on the phospholipid composition of surfactant isolated from fetal and neonatal rat lungs. Compensation by inositol and lipid supplementation.

The effects of a maternal protein-calorie malnutrition during gestation and lactation were analyzed on fetal and postnatal lung growth and maturation, including a surfactant fraction isolated from lung tissue. There was a considerable reduction in body weight and in wet and dry lung weights of malnourished pups. Lung protein and DNA concentrations were similar in both groups except in late gestation (lung hyperplasia) and 2 and 15 d after delivery (hypocellularity). Lung glycogen breakdown was slowed down in malnourished newborns. Surfactant material was decreased the most perinatally and the reduction was more marked than for the nonsurfactant fraction of the lung. Disaturated phosphatidylcholine, the major surface active surfactant component, was decreased the most at birth (1.70 +/- 0.31 nmol/mg wet wt versus 3.68 +/- 0.17 nmol/mg in controls, n = 8) and on d 2 (5.04 +/- 0.53 nmol/mg versus 7.67 +/- 0.44 nmol/mg in controls, n = 8). There was an apparent recovery in the composition of surfactant in malnourished rats 5 d after delivery, due in fact to a decrease in controls, and an actual return to normal levels 15 to 20 d after birth. Postnatal lipid supplementation with Intralipid led to partial recovery on d 10. Inositol supplementation totally reverted the effects of malnutrition on surfactant phospholipids (8.36 +/- 0.94 nmol disaturated phosphatidylcholine/mg wet wt on d 2 versus 7.67 +/- 0.44 nmol/mg in controls and 5.55 +/- 0.62 nmol/mg in untreated malnourished rats, n = 10; 2.43 +/- 0.32 nmol disaturated phosphatidylcholine/mg wet wt on d 10 versus 3.26 +/- 0.32 nmol/mg in controls and 1.18 +/- 0.27 nmol/mg in untreated malnourished rats, n = 8).(ABSTRACT TRUNCATED AT 250 WORDS)     

Placental growth and glycogen metabolism in streptozotocin diabetic rats

Placental glycogen metabolism was investigated in rat pregnancies complicated by streptozotocin-induced diabetes mellitus. Both diabetic and control placentas had increasing glycogen concentration from day 14 to day 16, after which glycogen concentration declined rapidly. The diabetic placentas had significantly elevated glycogen concentration when compared to controls from day 16 through term (day 22). Near term, when control glycogen content fell close to zero, the diabetic placentas still had appreciable glycogen levels. Total phosphorylase activity in the diabetic placentas was significantly higher than control values from day 16-22. Phosphorylase A activity, however, was lower in the diabetic placentas late in gestation, corresponding to the increased glycogen concentration seen at that time. Diabetic placentas had increased total synthase activity on the final 3 days of gestation, although synthase A activity was lower than corresponding control values. The placentas in this model are markedly increased in size late in gestation. No difference in protein concentration or protein/DNA ratio was noted. Total DNA content per placenta was significantly increased in the diabetic placentas after day 16 when compared to controls. Placental DNA in the diabetics continued to increase until day 18-19 of gestation, whereas DNA content in control placentas remained constant after day 16. Thus, the diabetic placentas apparently continue the process of DNA replication after DNA synthesis is complete in the controls.     

Hepatocyte glycogen accumulation in patients undergoing dietary management of urea cycle defects mimics storage disease

OBJECTIVES: Anecdotal reports have described excess hepatocyte glycogen in patients with urea cycle enzyme defects. Retrospectively, the authors evaluated the prevalence and possible cause of liver glycogen accumulation in such patients. METHODS: The authors searched the files of the Division of Pathology at Cincinnati Children's Hospital from 1975 and 2004 for cases of urea cycle enzyme defects and identified 11 patients who had had liver biopsy performed and/or liver transplantation. All patients were on diets containing essential amino acids as the protein source before liver biopsy and/or transplantation. RESULTS: All but one patient had focal or diffuse glycogen accumulation in hepatocytes in at least one specimen by light microscopic examination. Two young infants also had cholestasis. Electron microscopy performed on six patients showed diffuse or focal glycogen excess in the cytoplasm of individual hepatocytes. Biochemical studies of three patients revealed two with hepatic glycogen content in the upper normal range and one that was abnormally high. Glycolytic enzyme activities were normal in two patients, and one patient had low phosphorylase activity. CONCLUSIONS: Hepatocyte glycogen accumulation in urea cycle enzyme defects resembles that seen in glycogen storage disease but can be distinguished in most cases by non-uniformity of distribution and/or the absence of sinusoidal compression by expanded hepatocytes. We speculate that therapeutic modification of dietary protein content by restriction to essential amino acids, including leucine, may promote glycogen accumulation by increasing insulin secretion.     

Recent data on Lafora disease. Apropos of 17 cases]

This study reviews 99 anatomically verified case of Lafora body disease (82 from the literature and 17 personal cases). The clinical symptoms of the disease are characterised by the triad; epilepsy, myoclonus and dementia. An anatomical and histochemical study has been undertaken and as a result emphasis is given to recent hypotheses that suggest there are similarities with Type IV glycogen storage disease (Andersen's disease) which, although clinically distinct, has the same enzyme defect.     

Phospholipase A2 is present in meconium and inhibits the activity of pulmonary surfactant: an in vitro study

Atelectasis, a major contributor to pulmonary dysfunction in meconium aspiration syndrome (MAS), is produced by bronchiolar obstruction and surfactant inactivation. It has been shown that substances in meconium, e.g. fatty acids, inhibit surfactant activity. However, the role of the enzyme phospholipase A2 (PLA2), which hydrolyses surfactant in adult respiratory distress syndrome (ARDS), has not yet been studied. Our objective was to investigate whether PLA2 is present in meconium and inhibits pulmonary surfactant activity in vitro. Therefore, the presence of PLA2 activity in meconium, collected from 10 newborns, was measured by the formation of lysophosphatidylcholine after incubation of meconium with radioactively labelled dipalmitoylphosphatidylcholine. Meconium was fractionated by Sephadex G-100 column chromatography and the fractions were assayed for PLA2 activity. Also, their effect on the surface tension of surfactant (Curosurf) was measured using a pulsating bubble surfactometer (PBS). PLA2 activity was present in all meconium samples. Addition of meconium to surfactant significantly increased surface tension (mean +/- SD: 1.7 +/- 1.6 mN/m to 24.3 +/- 6.7 mN/m, p = 0.0001) and only the addition of the PLA2 containing fraction from meconium to surfactant also significantly increased surface tension (mean 1.7 +/- 1.6 mN/m to 19.0 +/- 3.58 mN/m, p < 0.0001). Conclusion: PLA2 is present in meconium and inhibits the activity of pulmonary surfactant in vitro. Therefore, PLA2 in meconium may contribute to surfactant inactivation and alveolar atelectasis in MAS.     

Lack of sex differences in antioxidant enzyme development in the fetal rabbit lung

A sex difference characterized by a female advantage in the maturation of the fetal pulmonary surfactant system is well documented. Because the surfactant system and the antioxidant enzyme system of the fetal lung have chronologically similar developmental patterns and share some of the same hormonal regulators, such as glucocorticoids, we questioned whether a sex difference would be present in antioxidant enzyme maturation as it is in surfactant system maturation. We studied fetal rabbits at days 26 and 28 of a 31-day gestational period. Fetal sex was identified histologically. Fetal lung lavage was performed and lavage fluid assayed for phosphatidylcholine, disaturated phosphatidylcholine, and sphingomyelin. Lung tissue from separate fetuses was assayed for disaturated phosphatidylcholine content and total phospholipid content and for the activities of three antioxidant enzymes--superoxide dismutase, catalase, and glutathione peroxidase. No differences were present in antioxidant enzyme maturation between male and female fetal rabbits at the gestational days studied. A female advantage was observed in the lung lavage disaturated phosphatidylcholine/sphingomyelin ratio (at 26 days: female 1.38 +/- 0.42, male 0.99 +/- 0.26; and at 28 days: female 3.29 +/- 0.53; male 2.26 +/- 0.35, p less than 0.05). A female advantage in surfactant development was not reflected in lung tissue disaturated phosphatidylcholine or total phospholipid. We conclude that, unlike the development of the surfactant system, the development of the antioxidant enzyme system in the fetal rabbit lung does not demonstrate a sex difference.     

Development of gluconeogenic enzymes in the newborn guinea pig.

The activities of key gluconeogenic enzymes in the liver of newborn guinea pigs delivered vaginally at term were monitored as a function of time following birth. The activities of glucose-6-phosphatase and fructose-1,6-diphosphatase did not show a significant increase over the first 72 h of life, neither did the activity of mitochondrial phosphoenolpyruvate carboxykinase. The mitochondrial enzyme pyruvate carboxylase and the cytosolic phosphoenolpyruvate carboxykinase (PEPCK) both increased significantly in the first 24 h postpartum. Mitochondrial protein and succinate dehydrogenase activities showed only slight increases in the 72-hour period. Rapid depletion of liver glycogen was evident in these animals following birth, but severe hypoglycaemia was not evident. Mitochondrial and cytosolic PEPCK showed similar kinetic behaviour with respect to their affinities for oxalacetate and divalent metal cation Mn++, though the mitochondrial enzyme would accept Mg++ as the divalent metal in place of Mn++. The role of the compartmented PEPCK activities is discussed.     

Sex differences in newborn myocardial metabolism and response to ischemia

In children with congenital heart disease, female sex has been linked to greater in-hospital mortality associated with low cardiac output, yet the reasons for this are unclear. Therefore, we examined whether newborn sex differences in the heart's metabolic response to ischemia exist. Left ventricular (LV) in vivo and ischemic biopsies of newborn male and female piglets were compared. Tissue ATP, creatine phosphate (CP), glycogen, anaerobic end-products lactate and hydrogen ion (H), and key regulatory enzymes were measured. Compared with males, newborn females displayed 14% lower ATP, 22% lower CP, and 32% lower glycogen reserves (p < 0.05) at baseline. During ischemia, newborn females accumulated 17% greater lactate and 40% greater H accumulation (p < 0.02), which was associated with earlier cessation of glycolysis and lower ischemic ATP levels (p < 0.02) compared with males. Newborn females demonstrated a greater ability to use their glycogen reserves, resulting in significantly lower (p < 0.003) glycogen levels throughout the ischemic period. Thus, newborn females are at a metabolic disadvantage because they exhibited lower energy levels and greater tissue lactic acidosis, both linked to an increase susceptibility to ischemic injury and impair myocardial function on reperfusion.     

Corticosteroids, thyrotropin-releasing hormone, and antioxidant enzymes in preterm lamb lungs.

Forty-three twin lamb fetuses of 121 +/- 1 d gestation were catheterized and received i.v. saline (n = 8), 0.75 mg/kg/h cortisol for 60 h (n = 15), 5 micrograms/kg thyrotropin-releasing hormone (TRH) every 12 h for five doses (n = 9), or cortisol and TRH (n = 11) before delivery at 128 +/- 1 d. After delivery, the lambs were randomized for natural sheep surfactant treatment or sham treatment, ventilated for 75 min, and killed. Superoxide dismutase, catalase, and glutathione peroxidase activities were measured in fetal lung tissue. Superoxide dismutase and catalase activities were increased in both the corticosteroid (p less than 0.001) and the corticosteroid with TRH (p less than 0.01) groups. Glutathione peroxidase activity was higher after prenatal corticosteroid treatment, but statistical significance was not reached (p = 0.06). Although prenatal exposure to corticosteroids increased superoxide dismutase, catalase, and glutathione peroxidase activities, TRH alone or TRH added to corticosteroids provided no additional benefit. Lambs treated with surfactant had higher lung catalase activities than lambs that did not receive surfactant, probably secondary to the presence of catalase activity in the surfactant preparation. Increased pulmonary antioxidant enzyme activity may be an additional feature of the overall beneficial effect of corticosteroids on fetal lung development.     

Sports doping in the adolescent athlete the hope,hype, and hyperbole

A well-balanced diet with appropriate training is the key to maximizing athletic performance. Nutritional counseling should be an essential part of anticipatory guidance, especially for certain teens, such as those who are vegetarians or those with low-calorie intakes. Other considerations for anticipatory guidance are listed in Box 8. Adequate hydration before, during, and after practice or a game is important to maintain hemodynamic balance, prevent heat disorders, and optimize performance. Cool water is adequate for short-duration activities, while carbohydrate-electrolyte fluids are more desirable for long-term activities, especially those lasting more than an hour. Such drinks are also more palatable and the athlete is more likely to consume them. Carbohydrates (meaning hydrates of carbon) are an important part of the athlete's diet; carbohydrates are rapidly broken down and their energy is quickly supplied to the body. The body stores only a small amount of carbohydrates in the form of glycogen in the liver, while muscle glycogen is an immediate source of energy. Thus, carbohydrate loading has been used to increase glycogen stores and aid the athlete involved in endurance events.     

Prenatal hormone treatment with thyrotropin releasing hormone and with thyrotropin releasing hormone plus dexamethasone delays antioxidant enzyme maturation but does not inhibit a protective antioxidant enzyme response to hyperoxia in newborn rat lung.

Whereas glucocorticoid administration to pregnant rats produces parallel acceleration of lung surfactant and antioxidant enzyme system maturation in late gestation, prenatal thyroid hormone treatment results in acceleration of surfactant maturation, with a paradoxical decrease in antioxidant enzyme (AOE) development. In these studies, we tested whether prenatal thyroid releasing hormone (TRH) treatment would act like prenatal thyroid hormone on pulmonary surfactant and AOE system maturation and whether combined prenatal treatment with TRH plus dexamethasone (DEX) would alter these effects. Secondly, we tested whether prenatal TRH and prenatal TRH plus DEX would inhibit the ability of newborn rats to respond to hyperoxia with protective increases in AOE activities. Results of the developmental studies revealed significantly increased fetal lung disaturated phosphatidylcholine content with significantly decreased pulmonary AOE activities as a result of prenatal TRH treatment that was not reversed with the addition of DEX. Combined TRH plus DEX treatment resulted in statistically significant decreases in body weight, lung weight, and lung weight to body weight ratios at both 21 and 22 d of gestation; growth effects were not seen with TRH alone. In terms of hyperoxic AOE response, despite being born with lower baseline AOE levels, the newborn animals prenatally treated with TRH or TRH plus DEX were able to induce a normal pulmonary AOE response to high O2 exposure. Although requiring further investigation, this reassuring finding suggests that clinical prenatal therapy with TRH or the combination of TRH plus DEX is not contraindicated for those infants delivered prematurely who go on to require intensive hyperoxic therapy.     

Glycogen storage disease type IV: inherited deficiency of branching enzyme activity in cats.

Glycogen storage disease type IV due to branching enzyme deficiency was found in an inbred family of Norwegian forest cats, an uncommon breed of domestic cats. Skeletal muscle, heart, and CNS degeneration were clinically apparent and histologically evident in affected cats older than 5 mo of age, but cirrhosis and hepatic failure, hallmarks of the human disorder, were absent. Beginning at or before birth, affected cats accumulated an abnormal glycogen in many tissues that was determined by histochemical, enzymatic, and spectral analysis to be a poorly branched alpha-1,4-D-glucan. Branching enzyme activity was less than 0.1 of normal in liver and muscle of affected cats and partially deficient (0.17-0.75 of normal) in muscle and leukocytes of the parents of affected cats. These data and pedigree analysis indicate that branching enzyme deficiency is a simple autosomal recessive trait in this family. This is the first reported animal model of human glycogen storage disease type IV. A breeding colony derived from a relative of the affected cats has been established.     

Immunoblot analyses of glycogen debranching enzyme in different subtypes of glycogen storage disease type III

To determine the tissue distribution of glycogen debranching enzyme, we used immunoblot analysis with a polyclonal antibody prepared against purified porcine muscle debranching enzyme. Debranching enzyme was identified in porcine brain, kidney, cardiac muscle, skeletal muscle, liver, and spleen; and in human liver, skeletal muscle, lymphocytes, lymphoblastoid cells, skin fibroblasts, cultured chorionic villi, and amniocytes. In each of these tissues the debranching enzyme band was 160 kd. To determine the molecular basis for glycogen storage disease type III at the protein level, tissues from 41 patients with glycogen storage disease type III were also subjected to immunoblot analysis. Three patients having isolated transferase deficiency with retention of glucosidase activity (type IIID disease) had nearly normal amounts of cross-reactive material. In the remaining patients (both transferase and glucosidase deficiency), debranching enzyme was either absent or greatly reduced. These latter patients included 31 with disease that appeared to involve both liver and muscle (type IIIA), four with disease that was present only in the liver (type IIIB), and three with unknown muscle status. In patients with both type IIIA and type IIIB disease, debranching enzyme protein was absent in skin fibroblasts, lymphoblastoid cells, and lymphocytes. The parents of two patients with type IIIA disease had an intermediate level of debranching enzyme protein, consistent with their presumed heterozygote state. An immunoblot analysis of cultured amniotic fluid cells from a woman whose fetus was at risk for type IIIA disease predicted an unaffected fetus; the prediction was confirmed postnatally. Thus Western blot analysis offers an alternate method of prenatal diagnosis for the most common form of glycogen storage disease type III.     

Studies on a patient with in vivo evidence of type I glycogenosis and normal enzyme activities in vitro.

Biochemical and clinical studies on a patient with hepatic glycogen storage disease are reported. The patient showed many of the clinical and biochemical features of type I glycogenosis (glucose-6-phosphatase deficiency), but had normal activities of the following enzymes in liver tissue: glucose-6-phosphatase (EC3.1.3.9); amylo-1,6-glucosidase (EC3.2.1.33); glycogen phosphorylase (EC2.4.1.1); fructose-1,6-diphosphatase (EC3.1.3.11). The urinary excretion of 2-oxoglutaric acid was greatly increased in this patient and in a case of enzymologically proven type I glycogenosis. Abnormal 2-oxoglutaric aciduria has not been previously reported in the glycogen storage diseases. The results are discussed in relation to the possible nature of the underlying biochemical defect in patients of this type.     

Insulin antagonism of dexamethasone-induced increase or argininosuccinate synthetase and argininosuccinate lyase activities in cultured fetal rat liver

In fetal rat liver explants maintained in organ culture, the addition of dexamethasone (4.6 X 10(-6)M) produced a 2- to 3-fold increase in the activity of argininosuccinate synthetase and in argininosuccinate lyase after 24 and 48 h of incubation. Insulin (1.8 X 10(-6)M) alone had no effect on the enzyme activities, but when incubated together with dexamethasone, it abolished the dexamethasone-induced increase of argininosuccinate synthetase and inhibited the argininosuccinate lyase activity by 80%, at 24 h. At 48 h, the inhibition of both enzyme activities was 68%. The antagonistic effect of insulin on the dexamethasone action is discussed in relation to the mechanism of perinatal enzyme induction. Hyperinsulinemia may interfere with the development of enzyme systems during the perinatal period. This could have relevance in the care of infants of diabetic mothers.