Energy substrate metabolism in pyruvate dehydrogenase complex deficiency
-
Maria Halldin Stenlid
,
Anders Forslund
Abstract
Pyruvate dehydrogenase (PDH) deficiency is an inherited disorder of carbohydrate metabolism, resulting in lactic acidosis and neurological dysfunction. In order to provide energy for the brain, a ketogenic diet has been tried. Both the disorder and the ketogenic therapy may influence energy production. The aim of the study was to assess hepatic glucose production, lipolysis and resting energy expenditure (REE) in an infant, given a ketogenic diet due to neonatal onset of the disease. Lipolysis and glucose production were determined for two consecutive time periods by constant-rate infusions of [1,1,2,3,3-2H5]-glycerol and [6,6-2H2]-glucose. The boy had been fasting for 2.5 h at the start of the sampling periods. REE was estimated by indirect calorimetry. Rates of glucose production and lipolysis were increased compared with those of term neonates. REE corresponded to 60% of normal values. Respiratory quotient (RQ) was increased, indicating a predominance of glucose oxidation. Blood lactate was within the normal range. Several mechanisms may underlie the increased rates of glucose production and lipolysis. A ketogenic diet will result in a low insulin secretion and reduced peripheral and hepatic insulin sensitivity, leading to increased production of glucose and decreased peripheral glucose uptake. Surprisingly, RQ was high, indicating active glucose oxidation, which may reflect a residual enzyme activity, sufficient during rest. Considering this, a strict ketogenic diet might not be the optimal choice for patients with PDH deficiency. We propose an individualised diet for this group of patients aiming at the highest glucose intake that each patient will tolerate without elevated lactate levels.
Acknowledgments
We are grateful to many people for their assistance in this work: The nurses at the ward for excellent help in the study; Christina Eklund for skilful dietary instructions; Elisabeth Söderberg for expert assistance with the stable isotope analysis; the staff at CMMS, Karolinska University Hospital, Huddinge, Sweden, for skilful laboratory assistance; and Roger Olsson for assistance in the indirect calorimetry and the REE calculations.
References
1. Pithukpakorn M. Disorders of pyruvate metabolism and the tricarboxylic acid cycle. Mol Genet Metab 2005;85:243–6.10.1016/j.ymgme.2005.06.006Search in Google Scholar
2. McKusick VA. Genetic studies in American inbred populations with particular reference to the Old Order Amish. Isr J Med Sci 1973;9:1276–84.Search in Google Scholar
3. Wikland KA, Luo ZC, Niklasson A, Karlberg J. Swedish population-based longitudinal reference values from birth to 18 years of age for height, weight and head circumference. Acta Paediatr 2002;91:739–54.10.1111/j.1651-2227.2002.tb03322.xSearch in Google Scholar
4. Food and Drug Administration. Guideline on Validation of Limulus Amebocyte Lysate Test as End-Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological Products and Medical Devices. Washington, DC: Food and Drug Administration, 1987.Search in Google Scholar
5. Halldin MU, Brismar K, Tuvemo T, Gustafsson J. Insulin sensitivity and lipolysis in adolescent girls with poorly controlled type 1 diabetes: effect of anticholinergic treatment. Clin Endocrinol (Oxf) 2002;57:735–43.10.1046/j.1365-2265.2002.01656.xSearch in Google Scholar
6. Sunehag A, Gustafsson J, Ewald U. Glycerol carbon contributes to hepatic glucose production during the first eight hours in healthy term infants. Acta Paediatr 1996;85:1339–43.10.1111/j.1651-2227.1996.tb13921.xSearch in Google Scholar
7. Halldin MU, Forslund A, von Dobeln U, Eklund C, Gustafsson J. Increased lipolysis in LCHAD deficiency. J Inherit Metab Dis 2007;30:39–46.10.1007/s10545-006-0296-xSearch in Google Scholar
8. Ahlsson FS, Diderholm B, Ewald U, Gustafsson J. Lipolysis and insulin sensitivity at birth in infants who are large for gestational age. Pediatrics 2007;120:958–65.10.1542/peds.2007-0165Search in Google Scholar
9. Weir JB. New methods for calculating metabolic rate with special reference to protein metabolism. J Physiol 1949;109:1–9.10.1113/jphysiol.1949.sp004363Search in Google Scholar
10. Persson B. Determination of plasma acetoacetate and D-beta-hydroxybutyrate in new-born infants by an enzymatic fluorometric micro-method. Scand J Clin Lab Invest 1970;25:9–18.10.3109/00365517009046184Search in Google Scholar
11. Lundin A, Arner P, Hellmer J. A new linear plot for standard curves in kinetic substrate assays extended above the Michaelis-Menten constant: application to a luminometric assay of glycerol. Anal Biochem 1989;177:125–31.10.1016/0003-2697(89)90026-2Search in Google Scholar
12. Schofield WN. Predicting basal metabolic rate, new standards and review of previous work. Hum Nutr Clin Nutr 1985;39:5–41.Search in Google Scholar
13. Bier DM, Leake RD, Haymond MW, Arnold KJ, Gruenke LD, et al. Measurement of “true” glucose production rates in infancy and childhood with 6,6-dideuteroglucose. Diabetes 1977;26:1016–23.10.2337/diab.26.11.1016Search in Google Scholar PubMed
14. Bougneres PF, Karl IE, Hillman LS, Bier DM. Lipid transport in the human newborn. Palmitate and glycerol turnover and the contribution of glycerol to neonatal hepatic glucose output. J Clin Invest 1982;70:262–70.Search in Google Scholar
15. Patel D, Kalhan S. Glycerol metabolism and triglyceride-fatty acid cycling in the human newborn: effect of maternal diabetes and intrauterine growth retardation. Pediatr Res 1992;31:52–8.10.1203/00006450-199201000-00010Search in Google Scholar PubMed
16. Siesjo BK. Hypoglycemia, brain metabolism, and brain damage. Diabetes Metab Rev 1988;4:113–44.10.1002/dmr.5610040203Search in Google Scholar PubMed
17. Clarke D, Sokoloff L. Circulation and energy metabolism of the brain: substrates of cerebral metabolism. In: Siegel GJ, Agranoff B, Albers RW, Fisher SK, Uhler MD, editors. Basic neurochemistry molecular, cellular and medical aspects, 6th ed. Philadelphia: Lippincott, Williams & Wilkins, 1999:637–70.Search in Google Scholar
18. Kruszynska Y. Normal metabolism: the physiology of fuel homeostasis. In: Pickup J, Williams G, editors. Textbook of diabetes, 2nd ed. London, England: Blackwell Sciences Ltd., 1997:11.1–.37.Search in Google Scholar
19. Boden G. Interaction between free fatty acids and glucose metabolism. Curr Opin Clin Nutr Metab Care 2002;5:545–9.10.1097/00075197-200209000-00014Search in Google Scholar PubMed
20. van Kempen AA, Ackermans MT, Endert E, Kok JH, Sauerwein HP. Glucose production in response to glucagon is comparable in preterm AGA and SGA infants. Clin Nutr 2005;24:727–36.10.1016/j.clnu.2005.02.004Search in Google Scholar PubMed
21. Sunehag AL, Treuth MS, Toffolo G, Butte NF, Cobelli C, et al. Glucose production, gluconeogenesis, and insulin sensitivity in children and adolescents: an evaluation of their reproducibility. Pediatr Res 2001;50:115–23.10.1203/00006450-200107000-00021Search in Google Scholar PubMed
22. Stumvoll M, Jacob S. Multiple sites of insulin resistance: muscle, liver and adipose tissue. Exp Clin Endocrinol Diabetes 1999;107:107–10.10.1055/s-0029-1212083Search in Google Scholar PubMed
23. Carpentier A, Mittelman SD, Lamarche B, Bergman RN, Giacca A, et al. Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation. Am J Physiol 1999;276:E1055–66.10.1152/ajpendo.1999.276.6.E1055Search in Google Scholar PubMed
24. McClave SA, Lowen CC, Kleber MJ, McConnell JW, Jung LY, et al. Clinical use of the respiratory quotient obtained from indirect calorimetry. J Parenter Enteral Nutr 2003;27:21–6.10.1177/014860710302700121Search in Google Scholar PubMed
25. Sharma N, Okere IC, Brunengraber DZ, McElfresh TA, King KL, et al. Regulation of pyruvate dehydrogenase activity and citric acid cycle intermediates during high cardiac power generation. J Physiol 2005;562:593–603.10.1113/jphysiol.2004.075713Search in Google Scholar PubMed PubMed Central
©2014 by De Gruyter
Articles in the same Issue
- Frontmatter
- Highlight: Cushing syndrome
- Fundamental principles of clinical and biochemical evaluation underlie the diagnosis and therapy of Cushing’s syndrome
- Cushing syndrome secondary to CRH-producing Wilms tumor in a 6 year old
- Cushing’s disease presenting as cholestatic hepatitis
- How early can one diagnose Cushing’s disease? An early diagnosis in a case of prepubertal Cushing’s disease
- Review article
- Subclinical hypothyroidism in childhood and adolescense
- Original articles
- Energy substrate metabolism in pyruvate dehydrogenase complex deficiency
- Chromosome 6q24 transient neonatal diabetes mellitus and protein sensitive hyperinsulinaemic hypoglycaemia
- Measures of pituitary gland and stalk: from neonate to adolescence
- Are preterm newborns who have relative hyperthyrotropinemia at increased risk of brain damage?
- Pseudohypoparathyroidism vs. tricho-rhino-phalangeal syndrome: patient reclassification
- Association of serum 25-hydroxyvitamin D with race/ethnicity and constitutive skin color in urban schoolchildren
- A nonsense thyrotropin receptor gene mutation (R609X) is associated with congenital hypothyroidism and heart defects
- Acanthosis nigricans, vitamin D, and insulin resistance in obese children and adolescents
- Clinical characteristics and chromosome 11p15 imprinting analysis of Silver-Russell syndrome – a Chinese experience
- Change in reference body mass index percentiles and deviation in overweight and obesity over 3 years in Turkish children and adolescents
- Long-term outcomes of pediatric Graves’ disease
- Accessibility of the reference center as a protective factor against ketoacidosis at the onset of diabetes in children
- Vitamin D, parathormone, and insulin resistance in children born large for gestational age
- Prevalence of vitamin D deficiency in apparently healthy children in north India
- Prevalence of autoantibodies in type 1 diabetes patients and its association with the clinical presentation – UAE Eastern Region experience
- Clinical and molecular studies related to bone metabolism in patients with congenital adrenal hyperplasia
- Islet neogenesis-associated protein-related pentadecapeptide improves the function of allograft after islets transplantation
- Anti-Mullerian hormone may be a useful adjunct in the diagnosis of polycystic ovary syndrome in nonobese adolescents
- Early infant feeding practice and childhood obesity: the relation of breast-feeding and timing of solid food introduction with childhood obesity
- Late onset X-linked adrenal hypoplasia congenita with hypogonadotropic hypgonadism due to a novel 4-bp deletion in exon 2 of NR0B1
- The correlation between GnRH stimulation testing and obstetric ultrasonographic parameters in precocious puberty
- The DATAC study: a new growth database. Description of the epidemiology, diagnosis and therapeutic attitude in a group of Spanish children with short stature
- Concentrations of tumour necrosis factor-α and its soluble receptors in the serum of teenagers with atherosclerosis risk factors: obesity or obesity combined with hypertension
- Are HDL levels lower in children with type 1 diabetes and concurrent celiac disease compared with children with type 1 diabetes only?
- Patient reports
- Hereditary vitamin D rickets: a case series in a family
- Two heterozygous mutations of the AMH gene in a Japanese patient with persistent Müllerian duct syndrome
- Two case reports of severe pediatric hyperosmolar hyperglycemia and diabetic ketoacidosis accompanied with rhabdomyolysis and acute renal failure
- Acquired hypothyroidism due to iodine deficiency in an American child
- Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome
- Amylase/creatinine clearance ratio in diabetic ketoacidosis: a case report
- Worsening hypertriglyceridemia with oral contraceptive pills in an adolescent with HIV-associated lipodystrophy: a case report and review of the literature
- Congenital hyperinsulinism in a newborn with a novel homozygous mutation (p.Q392H) in the ABCC8 gene
- Short communications
- Polyglandular autoimmune syndrome type I – a novel AIRE mutation in a North American patient
- Post-hemorrhagic hydrocephalus and diabetes insipidus in preterm infants
- Two novel mutations in acid α-glucosidase gene in two patients with Pompe disease
- Letter to the Editor
- And what about septin 9 (SEPT9) as a binding partner of survivin in heart regeneration?
Articles in the same Issue
- Frontmatter
- Highlight: Cushing syndrome
- Fundamental principles of clinical and biochemical evaluation underlie the diagnosis and therapy of Cushing’s syndrome
- Cushing syndrome secondary to CRH-producing Wilms tumor in a 6 year old
- Cushing’s disease presenting as cholestatic hepatitis
- How early can one diagnose Cushing’s disease? An early diagnosis in a case of prepubertal Cushing’s disease
- Review article
- Subclinical hypothyroidism in childhood and adolescense
- Original articles
- Energy substrate metabolism in pyruvate dehydrogenase complex deficiency
- Chromosome 6q24 transient neonatal diabetes mellitus and protein sensitive hyperinsulinaemic hypoglycaemia
- Measures of pituitary gland and stalk: from neonate to adolescence
- Are preterm newborns who have relative hyperthyrotropinemia at increased risk of brain damage?
- Pseudohypoparathyroidism vs. tricho-rhino-phalangeal syndrome: patient reclassification
- Association of serum 25-hydroxyvitamin D with race/ethnicity and constitutive skin color in urban schoolchildren
- A nonsense thyrotropin receptor gene mutation (R609X) is associated with congenital hypothyroidism and heart defects
- Acanthosis nigricans, vitamin D, and insulin resistance in obese children and adolescents
- Clinical characteristics and chromosome 11p15 imprinting analysis of Silver-Russell syndrome – a Chinese experience
- Change in reference body mass index percentiles and deviation in overweight and obesity over 3 years in Turkish children and adolescents
- Long-term outcomes of pediatric Graves’ disease
- Accessibility of the reference center as a protective factor against ketoacidosis at the onset of diabetes in children
- Vitamin D, parathormone, and insulin resistance in children born large for gestational age
- Prevalence of vitamin D deficiency in apparently healthy children in north India
- Prevalence of autoantibodies in type 1 diabetes patients and its association with the clinical presentation – UAE Eastern Region experience
- Clinical and molecular studies related to bone metabolism in patients with congenital adrenal hyperplasia
- Islet neogenesis-associated protein-related pentadecapeptide improves the function of allograft after islets transplantation
- Anti-Mullerian hormone may be a useful adjunct in the diagnosis of polycystic ovary syndrome in nonobese adolescents
- Early infant feeding practice and childhood obesity: the relation of breast-feeding and timing of solid food introduction with childhood obesity
- Late onset X-linked adrenal hypoplasia congenita with hypogonadotropic hypgonadism due to a novel 4-bp deletion in exon 2 of NR0B1
- The correlation between GnRH stimulation testing and obstetric ultrasonographic parameters in precocious puberty
- The DATAC study: a new growth database. Description of the epidemiology, diagnosis and therapeutic attitude in a group of Spanish children with short stature
- Concentrations of tumour necrosis factor-α and its soluble receptors in the serum of teenagers with atherosclerosis risk factors: obesity or obesity combined with hypertension
- Are HDL levels lower in children with type 1 diabetes and concurrent celiac disease compared with children with type 1 diabetes only?
- Patient reports
- Hereditary vitamin D rickets: a case series in a family
- Two heterozygous mutations of the AMH gene in a Japanese patient with persistent Müllerian duct syndrome
- Two case reports of severe pediatric hyperosmolar hyperglycemia and diabetic ketoacidosis accompanied with rhabdomyolysis and acute renal failure
- Acquired hypothyroidism due to iodine deficiency in an American child
- Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome
- Amylase/creatinine clearance ratio in diabetic ketoacidosis: a case report
- Worsening hypertriglyceridemia with oral contraceptive pills in an adolescent with HIV-associated lipodystrophy: a case report and review of the literature
- Congenital hyperinsulinism in a newborn with a novel homozygous mutation (p.Q392H) in the ABCC8 gene
- Short communications
- Polyglandular autoimmune syndrome type I – a novel AIRE mutation in a North American patient
- Post-hemorrhagic hydrocephalus and diabetes insipidus in preterm infants
- Two novel mutations in acid α-glucosidase gene in two patients with Pompe disease
- Letter to the Editor
- And what about septin 9 (SEPT9) as a binding partner of survivin in heart regeneration?
