help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0661
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow A correction has been published
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Marcus, C.
Right arrow Articles by Gustafsson, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Marcus, C.
Right arrow Articles by Gustafsson, J.
Related Collections
Right arrow Pediatric Endocrinology
Right arrow Metabolism
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 11 4080-4084
Copyright © 2007 by The Endocrine Society

CLINICAL CASE SEMINAR

Insufficient Ketone Body Use Is the Cause of Ketotic Hypoglycemia in One of a Pair of Homozygotic Twins

Claude Marcus, Jenny Alkén, Jens Eriksson, Leif Blom and Jan Gustafsson

Department for Clinical Science, Intervention and Technology (Clintec), Division of Pediatrics, (C.M., J.A., J.E.), Karolinska University Hospital, Karolinska Institutet, Huddinge SE-141 86 Stockholm, Sweden; Department of Pediatrics (L.B.), University of Lund, SE-221 84 Lund, Sweden; and Department of Women’s and Children’s Health (J.G.), Uppsala University, SE-751 05 Uppsala, Sweden

Address all correspondence and requests for reprints to: Claude Marcus, M.D., Ph.D., Professor of Pediatrics, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. E-mail: claude.marcus{at}ki.se.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Childhood ketotic hypoglycemia (KH) is a disease characterized by fasting hypoglycemia and increased levels of ketone bodies. The cause is unknown.

Objective: The objective of the study was to study a pair of homozygotic twin boys, one of whom had severe KH from the age of 14 months, whereas the other boy was apparently healthy.

Design and Results: At the age of 6 yr, the boys were thoroughly investigated. During a 24-h fasting tolerance test, the twin with KH showed hypoglycemia (blood glucose 2.0 mmol/liter) after 18 h. Three h before the occurrence of hypoglycemia, he had had 10 times higher ß-hydroxybutyrate levels than his brother, who showed no signs of hypoglycemia. Their glucose production rates were normal and similar (23.3 and 21.7 µmol/kg body weight per minute in the healthy and KH twin, respectively) as well as their lipolysis rates (5.8 and 6.8 µmol/kg body weight per minute, respectively). During repeated 60-min infusions of ß-hydroxybutyrate, the plasma level of ß-hydroxybutyrate increased 5–10 times more in the twin with KH (mean 1.1 mmol/liter in the healthy and 10.8 mmol/liter in the KH twin), indicating a disturbed clearance or metabolism of ß-hydroxybutyrate. No mutations were found in genes involved in ketone body metabolism or transport.

Conclusion: In the affected boy, KH seems to be the result of a reduced capacity to use ketone bodies, leading to increased peripheral metabolism of glucose that cannot be met by hepatic glucose production. Because the boys are homozygotic twins and only one of them is affected, the ketotic hypoglycemia is most likely caused by an altered imprinting of gene(s) involved in regulating metabolic pathways.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CHILDHOOD HYPOGLYCEMIA, a condition that often presents with alarming symptoms, may have a variety of underlying causes, such as inborn errors of metabolism, hyperinsulinemia, and hypopituitarism. However, the most frequent cause after the neonatal period is idiopathic ketotic hypoglycemia. This is characterized by symptomatic hypoglycemia after insufficient food intake and/or increased physical activity in otherwise healthy children.

The condition, which rarely is manifested before 6 months of age, is recurrent in nature but seems to disappear spontaneously before adolescence. Neurological damage and other sequelae are rare, and the condition is therefore considered benign (1, 2). However, long-term follow-up studies of cognitive function in subjects who have suffered from idiopathic ketotic hypoglycemia are lacking.

There are no specified endocrine or metabolic abnormalities associated with idiopathic ketotic hypoglycemia. The diagnosis is established from the occurrence of a combination of hypoglycemia and ketonemia/ketonuria without any evidence of metabolic or endocrine abnormalities during a spontaneous episode of hypoglycemia or during a fasting tolerance test.

The underlying mechanism has been considered to be an impairment of hepatic glucose production during fasting (3, 4). The condition is more frequent in children born small for gestational age and in those who are thin, i.e. children who have a low body mass index for age (5). Therefore, and because muscle protein serves as a major source of amino acids for gluconeogenesis (6), it has been suggested that the impaired glucose production could be due to reduced muscle mass (5). In accordance, it has been suggested that these children have no metabolic abnormalities but rather represent the end of the Gaussian curve for fasting tolerance in children due to accelerated starvation (7, 8). In contrast, it has been reported that children born small for gestational age who develop transient neonatal hyperinsulinemic hypoglycemia can present later in childhood with ketotic hypoglycemia (9). This indicates a more complex metabolic or endocrine underlying cause, at least in some patients. There also are recently identified subgroups of children with ketotic hypoglycemia and reduced glucose production due to other defined inborn errors of metabolism (10), and it is possible that the remaining subjects with ketotic hypoglycemia without any specified cause also represent a heterogenic entity.

Ketone bodies may to some extent serve as an alternative energy substrate to glucose, and the pronounced ketonemia during ketotic hypoglycemia is at least partly a result of an increased production of ketone bodies in the liver after pronounced stimulation of lipolysis in adipose tissue.

Here we describe a pair of monozygotic twins, of whom one developed ketotic hypoglycemia, whereas the other was healthy. The data provide evidence that an alternative mechanism, involving impaired metabolism of ß-hydroxybutyrate, may underlie ketotic hypoglycemia of childhood.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Case presentation

The twin boys were born by cesarean section after 36 wk of uncomplicated pregnancy. The parents are unrelated and healthy and there is no family history of metabolic or endocrine disorders. Birth weight and length of the healthy boy were 2400 g and 45 cm. His twin brother, who later developed ketotic hypoglycemia, had a birth weight of 2240 g and a birth length of 44 cm. He also had an episode of hypothermia without hypoglycemia, but the neonatal period was otherwise uneventful for both twins. The boys had similar and satisfactory weight and height gain throughout the first year of life.

At 1 yr of age, the twin who was later diagnosed with ketotic hypoglycemia was examined at the local hospital because of severe fatigue. This fatigue episode was repeated several times without any detectable hypoglycemia on arrival at the emergency ward. A fasting tolerance test, performed at 21 months of age, showed that the symptoms were associated with hypoglycemia. Blood glucose (B-glucose) decreased to 2.3 mmol/liter after 12 h, concomitantly with pronounced ketonuria.

Despite dietary counseling, including frequent meals and energy enrichment with cornstarch, several episodes of symptoms associated with hypoglycemia, such as fatigue, headache, and paleness occurred. The boy was hospitalized for an extended examination at 5.5 yr of age. Again, hypoglycemia (p-glucose 2.2 mmol/liter) in combination with pronounced ketonuria was found after a 15-h fast. No pathological organic aciduria was noted. Nor was any defect in the metabolism of fatty acids diagnosed. The patient had normal serum levels of amino acids, cortisol, TSH, insulin, and GH. Because of the frequency and severity of the symptoms, the boy was referred to Karolinska University Hospital for further investigation and treatment.

Methods

The twins were tested twice for monozygosity, on two different occasions, at the Department of Forensic Medicine, Linköping University Hospital, and at the Department of Clinical Genetics of Karolinska University Hospital by means of haplotype testing of 13 different markers of polymorphic loci. Subcutaneous glycerol levels were measured by microdialysis as an index of lipolysis (11). After a 12-h fast, rates of glucose and glycerol production were measured during the last 2 h of a 3-h constant rate infusion of 6.6-2H2-glucose and 1.1.2.3.3-2H5-glycerol by analysis of isotope dilution by gas chromatography-mass spectrometry during approximate steady-state (12). The 6.6-2H2-glucose (isotopic purity 98%) and 1.1.2.3.3-2H5-glycerol (isotopic purity 98%) were purchased from Cambridge International Laboratory (Woburn, MA).

To test the elimination/metabolism of ketone bodies, ß-hydroxybutyrate, 2 mmol/kg body weight per hour, was infused over 60 min after a 10- to 11-h fast. The infusion had been tested on three healthy adult volunteers before the investigation. The concentration of p-ß-hydroxybutyrate never exceeded 0.5 mmol/liter, and the conversion to acetoacetate was minimal in the control subjects. B-glucose was measured by Hemocue (Hemocue AB, Ángelholm, Sweden) (13). For the sequencing of the genes encoding for the two enzymes involved in ketone body metabolism, succinyl-CoA-3-oxoacid CoA-transferase [OXCT/SCOT (14)] and acetoacetyl-CoA thiolase [ACAT1/AAT (15)], as well as for three monocarboxylate transporters (MCTs) involved in ketone body cellular transport, MCT1, MCT2, and MCT4 (16), genomic DNA was obtained from whole blood, and the genes were amplified by PCR with specific primers. The PCR products were sequenced using cycle sequencer Big Dye terminator chemistry (Applied Biosystems, Foster City, CA) and analyzed on an ABI 377 automated sequence (PerkinElmer Biosystems, Foster City, CA). All other analyses were performed at the certified laboratory at the Department of Clinical Chemistry of Huddinge University Hospital.

The Ethics Committee at Karolinska Institutet approved the study. Informed consent was obtained from the parents, and the twin boys gave their assent. Oral and written information was given to the parents and the boys were informed orally.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The investigations were carried out when the twins were 6 yr old. They had almost identical body proportions (Table 1Go) and had reached their developmental milestones at normal and similar times. On the basis of genetic testing in two different laboratories on separate occasions, it was found that the twins were monozygotic (P << 0.001).


View this table:
[in this window]
[in a new window]

  		TABLE 1. Auxological data and rates of glucose and glycerol production in the monozygotic twin boys

 
Because genetically identical twins tend to have similar metabolism, it was questioned whether the healthy twin could have had episodes of hypoglycemia without any apparent symptoms. Furthermore, it was considered that a comparison of their response to fasting might increase the understanding of the cause of ketotic hypoglycemia in the twin boy with symptomatic hypoglycemia. Both twins were therefore subjected to a 24-h fasting tolerance test.

The twin with ketotic hypoglycemia displayed hypoglycemic symptoms (B-glucose 2.0 mmol/liter) after 18 h of fasting, and the fast was therefore discontinued. The apparently healthy twin showed no symptoms of hypoglycemia and was normoglycemic throughout the 24-h fast (B-glucose 3.4 mmol/liter at the end of the fast). The levels of GH, cortisol, glucagon, and insulin were almost identical during the first 15 h of the fasting period (Table 2Go), but the hypoglycemia then induced a pronounced cortisol and glucagon rise in the hypoglycemic twin. This was not observed in the healthy twin. The microdialysis glycerol levels were similar, indicating that the twins had the same rate of lipolysis. Despite this, a rise in the ß-hydroxybutyrate concentration was observed much earlier in the hypoglycemic twin (Fig. 1Go). Three hours before any signs of hypoglycemia, the twin with ketotic hypoglycemia had a plasma ß-hydroxybutyrate level that was 10 times higher than that of his brother.


View this table:
[in this window]
[in a new window]

  		TABLE 2. Laboratory findings in the twin boys after 12 h of fasting

 

Figure 1
View larger version (11K):
[in this window]
[in a new window]

  		FIG. 1. Effect of fasting on plasma glucose and ß-hydroxybutyrate in monozygotic twins. Squares, Healthy twin; triangles, the twin with ketotic hypoglycemia.

 
The rate of glucose production measured during 2 h after 13 h of overnight fast was similar and stable in the two boys (Table 1Go). In addition, their rates of glycerol production were similar, indicating almost identical total body lipolysis (Table 1Go). To study the question whether a difference in elimination of ketone bodies could explain the differences between the ketone body levels in the twins during fasting, a ß-hydroxybutyrate tolerance test was performed after an overnight fast (11 h). In the healthy twin, neither a rise in ß-hydroxybutyrate nor increased conversion into acetoacetate was observed, findings similar to observations in control adults (data not shown). In the twin with ketotic hypoglycemia, a dramatic increase in the plasma level, up to 16.6 mmol/liter, of ß-hydroxybutyrate (Fig. 2Go) was observed soon after the initiation of the infusion. When the test was repeated 7 months later, the maximum increase in the twin with ketotic hypoglycemia was 5.0 mmol/liter and in the healthy twin boy 1.3 mmol/liter. The conversion of ß-hydroxybutyrate into acetoacetate was low in both boys but slightly higher in the boy with ketotic hypoglycemia (1.5 mmol/liter vs. 0.3 mmol/liter).


Figure 2
View larger version (8K):
[in this window]
[in a new window]

  		FIG. 2. Effect of ß-hydroxybutyrate infusion in the healthy twin (squares) and the twin boy with ketotic hypoglycemia (triangles).

 
Two enzymes are known to be involved in ketone body metabolism, OXCT/SCOT and ACAT1/AAT (17, 18), and three monocarboxylate transporters are known in different tissues to be involved in ketone body transport, MCT 1, MCT2, and MCT 4 (16). Sequencing of these genes revealed identical patterns in the twin boys, and no polymorphisms associated with altered protein function were found.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present investigation has shown that one of the genetically identical twins fulfilled the criteria for the diagnosis of ketotic hypoglycemia, whereas the other boy was healthy and performed a 24-h fast without any signs of hypoglycemia. Comparison of the metabolism of the boys during fasting provides new information concerning the etiology of ketotic hypoglycemia. Our data indicate that the tendency for the affected twin to develop hypoglycemia was not due to a decreased glucose production. After an overnight fast, the affected twin had a rate of glucose production within the range reported for healthy children (19, 20, 21). Furthermore, the rate of glucose production was almost identical in the healthy twin boy, indicating that the ketotic hypoglycemia in the affected boy had another primary cause.

The similar rates of lipolysis, reflected by both rates of glycerol production and sc microdialysis glycerol levels, show that the early rise in the plasma levels of ketone bodies, which preceded hypoglycemia by several hours in the ketotic hypoglycemic twin, was not due to a difference in the production of ketone body precursors. On the contrary, the ketone body infusion test indicates that the difference between the boys is due to a disturbed ketone body clearance in the affected twin.

Hypoglycemia may occur as a result of either a reduced rate of production of glucose or increased glucose use. The former is known to be the case in children with low levels of counterregulatory hormones or mitochondrial dysfunction. In hyperinsulinemic conditions, there is a combination of both reduced glucose production and increased use (22). In the present case, no signs of hormonal or metabolic dysfunction associated with these conditions were detected. Instead, we suggest that the hypoglycemia in the affected twin is due to a reduced capacity to use ketone bodies as energy substrates. During prolonged fasting, this will lead to increased peripheral glucose consumption, resulting in a risk of hypoglycemia. Reduced use of ketone bodies will also result in an early increase of ketone body levels in plasma.

The nature of the defect causing the reduced metabolism of ketone bodies is at present unknown. We found no mutations in OXCT/SCOT or ACAT1/AAT genes, i.e. the two genes in which mutations affecting ketone body metabolism have previously been reported (18, 23). Furthermore, in contrast to patients with OXCT/SCOT deficiency, the ketone body level in the affected twin is not constantly elevated, indicating only a moderate reduction of the capacity of ketone body metabolism or transport (24). However, no mutations were found in monocarboxylate transporters known to be involved in ketone body transport (16). An uneven distribution of a heteroplasmic mitochondrial DNA mutation is also unlikely. There is no indication of any phenotype consistent with a mitochondrial DNA disease in their mother or maternal relatives, and plasma lactate levels were normal in both boys.

Idiopathic ketotic hypoglycemia is probably a heterogeneous disease. Although a genetic predisposition is probably a prerequisite, the finding of ketotic hypoglycemia in one of a pair of genetically identical twins indicates that other mechanisms are also of importance for the development of the disease. Such a distinct difference in morbidity between monozygotic twins has been reported before for other diseases (25, 26).

It has previously been observed that children with ketotic hypoglycemia often have a low body mass index and are born small for gestational age (5). This has led to the assumption that hypoglycemia in these children is due to a diminished amount of substrates for gluconeogenesis, resulting in a reduced rate of glucose production during prolonged fasting (4). Bodamer et al. (3) recently reported reduced glucose production rates in children with ketotic hypoglycemia. However, these rates were similar to those found in healthy children by Sunehag et al. (21). Thus, it is still unclear whether children with ketotic hypoglycemia in general have a decreased rate of glucose production. In the present study, the affected twin had a somewhat lower birth weight than his twin brother, but the boys did not differ with regard to their rates of glucose production after 13–15 h of fasting. Thus, it was not shown that the glucose production was unchanged during a prolonged fast, but in neither healthy adults (27) nor children with ketotic hypoglycemia (3) does a prolonged fast seem to be associated with a decline in the glucose production rate. Therefore, it can be assumed that the glucose production measured after 13–15 h of fasting reflects the situation also after a prolonged fast.

The importance of the intrauterine environment for metabolic adaptation later in life has been highlighted in many studies (28, 29). Disturbances of the metabolic status during fetal life may cause epigenetic changes by covalent modifications of the genome. These may in turn result in permanently altered metabolic patterns (30). Epigenetic modification of metabolism is thought to occur among children born small for gestational age (31), and epigenetic differences between monozygotic twins have recently been demonstrated (32).

In conclusion, we suggest that ketotic hypoglycemia is caused by impaired ketone body metabolism and that the disease may be a result of fetal nutritional alterations causing permanent metabolic imprinting.


   Acknowledgments
 
The skillful technical assistance of Elisabeth Söderberg is gratefully acknowledged.


   Footnotes
 
This work was supported by grants from the Swedish Research Councils, projects 9941 and 11282.

Disclosure Statement: The authors have nothing to declare.

First Published Online August 7, 2007

Abbreviations: ACAT1/AAT, Acetoacetyl-CoA thiolase; B-glucose, blood glucose; MCT, monocarboxylate transporter; OXCT/SCOT, succinyl-CoA-3-oxoacid CoA-transferase.

Received March 22, 2007.

Accepted August 1, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Mitchell GA, Fukao T 2001 Inborn errors of ketone metabolism. In: Scriver CR, Baudet AL, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol. 2. Chap. 102. New York: McGraw-Hill Co. Inc.; 2327–2356
  2. Wets B, Milot JA, Polomeno RC, Letarte J 1982 Cataracts and ketotic hypoglycemia. Ophthalmology 89:999–1002[Medline]
  3. Bodamer OA, Hussein K, Morris AA, Langhans CD, Rating D, Mayatepek E, Leonard JV 2006 Glucose and leucine kinetics in idiopathic ketotic hypoglycaemia. Arch Dis Child 91:483–486[Abstract/Free Full Text]
  4. Haymond MW, Karl IE, Pagliara AS 1974 Ketotic hypoglycemia: an amino acid substrate limited disorder. J Clin Endocrinol Metab 38:521–530[Abstract/Free Full Text]
  5. Daly LP, Osterhoudt KC, Weinzimer SA 2003 Presenting features of idiopathic ketotic hypoglycemia. J Emerg Med 25:39–43[CrossRef][Medline]
  6. Berg JM, Tymoczko JL, Stryer L 2002 Glycolysis and Gluconeogenesis. In: Julet M, ed. Biochemistry. 5th ed. Chap. 16. New York: W. H. Freeman and Co.; 425–464
  7. Senior B 1973 Ketotic hypoglycemia. A tale (tail) of Gauss? J Pediatr 82:555–556[CrossRef][Medline]
  8. Stanley CA 2006 Parsing ketotic hypoglycaemia. Arch Dis Child 91:460–461[Free Full Text]
  9. Kochar IS, Hussain K, 2007 From hyperinsulinaemic hypoglycaemia to ketotic hypoglycaemia: the range of glucose abnormalities in patients born with intrauterine growth retardation. Eur J Pediatr, 166: 1003–1007
  10. Weinstein DA, Correia CE, Saunders AC, Wolfsdorf JI 2006 Hepatic glycogen synthase deficiency: an infrequently recognized cause of ketotic hypoglycemia. Mol Genet Metab 87:284–288[CrossRef][Medline]
  11. Kamel A, Norgren S, Persson B, Marcus C 1999 Insulin induced hypoglycaemia: comparison of glucose and glycerol concentrations in plasma and microdialysate from subcutaneous adipose tissue. Arch Dis Child 80:42–45[Abstract/Free Full Text]
  12. Diderholm B, Stridsberg M, Norden-Lindeberg S, Gustafsson J 2006 Decreased maternal lipolysis in intrauterine growth restriction in the third trimester. BJOG 113:159–164[CrossRef][Medline]
  13. Elimam A, Horal M, Bergstrom M, Marcus C 1997 Diagnosis of hypoglycaemia: effects of blood sample handling and evaluation of a glucose photometer in the low glucose range. Acta Paediatr 86:474–478[Medline]
  14. Fukao T, Mitchell GA, Song XQ, Nakamura H, Kassovska-Bratinova S, Orii KE, Wraith JE, Besley G, Wanders RJ, Niezen-Koning KE, Berry GT, Palmieri M, Kondo N 2000 Succinyl-CoA:3-ketoacid CoA transferase (SCOT): cloning of the human SCOT gene, tertiary structural modeling of the human SCOT monomer, and characterization of three pathogenic mutations. Genomics 68:144–151[CrossRef][Medline]
  15. Song XQ, Fukao T, Yamaguchi S, Miyazawa S, Hashimoto T, Orii T 1994 Molecular cloning and nucleotide sequence of complementary DNA for human hepatic cytosolic acetoacetyl-coenzyme A thiolase. Biochem Biophys Res Commun 201:478–485[CrossRef][Medline]
  16. Halestrap AP, Meredith D 2004 The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch 447:619–628[CrossRef][Medline]
  17. Berry GT, Fukao T, Mitchell GA, Mazur A, Ciafre M, Gibson J, Kondo N, Palmieri MJ 2001 Neonatal hypoglycaemia in severe succinyl-CoA: 3-oxoacid CoA-transferase deficiency. J Inherit Metab Dis 24:587–595[Medline]
  18. Bennett MJ, Hosking GP, Smith MF, Gray RG, Middleton B 1984 Biochemical investigations on a patient with a defect in cytosolic acetoacetyl-CoA thiolase, associated with mental retardation. J Inherit Metab Dis 7:125–128[CrossRef][Medline]
  19. Sunehag AL, Treuth MS, Toffolo G, Butte NF, Cobelli C, Bier DM, Haymond MW 2001 Glucose production, gluconeogenesis, and insulin sensitivity in children and adolescents: an evaluation of their reproducibility. Pediatr Res 50:115–123[Medline]
  20. Bier DM, Leake RD, Haymond MW, Arnold KJ, Gruenke LD, Sperling MA, Kipnis DM 1977 Measurement of "true" glucose production rates in infancy and childhood with 6,6-dideuteroglucose. Diabetes 26:1016–1023[Abstract]
  21. Sunehag AL, Toffolo G, Treuth MS, Butte NF, Cobelli C, Bier DM, Haymond MW 2002 Effects of dietary macronutrient content on glucose metabolism in children. J Clin Endocrinol Metab 87:5168–5178[Abstract/Free Full Text]
  22. Lteif AN, Schwenk WF1999 Hypoglycemia in infants and children. Endocrinol Metab Clin North Am 28:619–646, vii
  23. Baric I, Sarnavka V, Fumic K, Maradin M, Begovic D, Ruiter JP, Wanders RJ 2001 A new case of succinyl-CoA:acetoacetate transferase deficiency: favourable course despite very low residual activity. J Inherit Metab Dis 24:81–82[CrossRef][Medline]
  24. Martin PM, Gopal E, Ananth S, Zhuang L, Itagaki S, Prasad BM, Smith SB, Prasad PD, Ganapathy V 2006 Identity of SMCT1 (SLC5A8) as a neuron-specific Na+-coupled transporter for active uptake of L-lactate and ketone bodies in the brain. J Neurochem 98:279–288[CrossRef][Medline]
  25. Ilicki A, Marcus C, Karlsson FA 1990 Hyperthyroidism and hypothyroidism in monozygotic twins: detection of stimulating and blocking TSH receptor antibodies using the FRTL5-cell line. J Endocrinol Invest 13:327–331[Medline]
  26. Cimaz R, Borghi MO, Gerosa M, Biggioggero M, Raschi E, Meroni PL 2006 Transforming growth factor ß1 in the pathogenesis of autoimmune congenital complete heart block: lesson from twins and triplets discordant for the disease. Arthritis Rheum 54:356–359[CrossRef][Medline]
  27. Katz J, Tayek JA 1998 Gluconeogenesis and the Cori cycle in 12-, 20-, and 40-h-fasted humans. Am J Physiol 275:E537–E542
  28. Fleming TP, Kwong WY, Porter R, Ursell E, Fesenko I, Wilkins A, Miller DJ, Watkins AJ, Eckert JJ 2004 The embryo and its future. Biol Reprod 71:1046–1054[Abstract/Free Full Text]
  29. Budge H, Gnanalingham MG, Gardner DS, Mostyn A, Stephenson T, Symonds ME 2005 Maternal nutritional programming of fetal adipose tissue development: long-term consequences for later obesity. Birth Defects Res C Embryo Today 75:193–199[CrossRef][Medline]
  30. Waterland RA, Jirtle RL 2004 Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition 20:63–68[CrossRef][Medline]
  31. Holness MJ, Sugden MC 2006 Epigenetic regulation of metabolism in children born small for gestational age. Curr Opin Clin Nutr Metab Care 9:482–488[Medline]
  32. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M 2005 Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102:10604–10609[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow A correction has been published
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Marcus, C.
Right arrow Articles by Gustafsson, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Marcus, C.
Right arrow Articles by Gustafsson, J.
Related Collections
Right arrow Pediatric Endocrinology
Right arrow Metabolism

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals