Abstract
In order to study the pathophysiology of hypoglycemia in idiopathic ketotic hypoglycemia (KH), glucose kinetics during fasting in patients with KH were determined. A fasting test was performed in 12 children with previously documented KH. Besides determination of glucoregulatory hormones, plasma ketones, FFA and alanine, the rates of endogenous glucose production (EGP), glucose uptake, gluconeogenesis (GNG) and glycogenolysis (GGL) were quantified using the [6,6-2H2] glucose isotope dilution method and the deuterated water method. The five youngest subjects (age 2.5–3.9 years) became hypoglycemic (glucose <3.0 mmol/l) during the test. Mean differences in glucose kinetics between overnight fasting and the end of the test in the hypoglycemic vs. the normoglycemic subjects were: EGP: −31.9% vs. −17.9% (p = 0.007), GGL: −66.2% vs. −50.8% (p = 0.465) and GNG 6.8% vs. 19.5% (p = 0.465). Plasma alanine levels were significantly lower (p = 0.028) at the end of the test in the hypoglycemic subjects. Plasma ketones and FFA levels were in the normal range for fasting duration in all subjects. We conclude that hypoglycemia in KH is caused by the inability to sustain an adequate EGP during fasting in view of the higher glucose requirement in young children. The decrease in GGL is not accompanied by a significant increase in GNG, possibly because of a limitation in the supply of alanine. Our results support the hypothesis that KH represents the lower tail of the Gaussian distribution of fasting tolerance in children.
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Abbreviations
- KH:
-
ketotic hypoglycemia
- EGP:
-
endogenous glucose production
- Ra glucose:
-
rate of appearance of glucose in plasma
- Rd glucose:
-
rate of disappearance of glucose from plasma
- GNG:
-
rate of appearance of glucose from gluconeogenesis in plasma
- GGL:
-
rate of appearance of glucose from glycogenolysis in plasma
- GSD-0:
-
glycogen storage disease type 0
References
Ackermans MT, Pereira Arias AM, Bisschop PH, Endert E, Sauerwein HP, Romijn JA (2001) The quantification of gluconeogenesis in healthy men by 2H2O and [2-13C]glycerol yields different results: rates of gluconeogenesis in healthy men measured with 2H2O are higher than those measured with [2-13C]glycerol. J Clin Endocrinol Metab 86:2220–2226
Amiel SA (1995) Organ fuel selection: brain. Proc Nutr Soc 54:151–155
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
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
Boden G (2004) Gluconeogenesis and glycogenolysis in health and diabetes. J Investig Med 52:375–378
Bonnefont JP, Specola NB, Vassault A, Lombes A, Ogier H, de Klerk JB, Munnich A, Coude M, Paturneau-Jouas M, Saudubray JM (1990) The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states. Eur J Pediatr 150:80–85
Chang TW, Goldberg AL (1978) The origin of alanine produced in skeletal muscle. J Biol Chem 253:3677–3684
Chaussain JL (1973) Glycemic response to 24 hour fast in normal children and children with ketotic hypoglycemia. J Pediatr 82:438–443
Chaussain JL, Georges P, Olive G, Job JC (1974) Glycemic response to 24-hour fast in normal children and children with ketotic hypoglycemia: II. Hormonal and metabolic changes. J Pediatr 85:776–781
Colle E, Ulstrom RA (1964) Ketotic Hypoglycemia. J Pediatr 64:632–651
Corssmit EP, Romijn JA, Sauerwein HP (2001) Review article: Regulation of glucose production with special attention to nonclassical regulatory mechanisms: a review. Metabolism 50:742–755
Dahlquist G, Gentz J, Hagenfeldt L, Larsson A, Low H, Persson B, Zetterstrom R (1979) Ketotic hypoglycemia of childhood–a clinical trial of several unifying etiological hypotheses. Acta Paediatr Scand 68:649–656
Daly LP, Osterhoudt KC, Weinzimer SA (2003) Presenting features of idiopathic ketotic hypoglycemia. J Emerg Med 25:39–43
Dekker E, Hellerstein MK, Romijn JA, Neese RA, Peshu N, Endert E, Marsh K, Sauerwein HP (1997) Glucose homeostasis in children with falciparum malaria: precursor supply limits gluconeogenesis and glucose production. J Clin Endocrinol Metab 82:2514–2521
Friis-Hansen B (1961) Body water compartments in children: changes during growth and related changes in body composition. Pediatrics 28:169–181
Haymond MW, Karl IE, Pagliara AS (1974) Ketotic hypoglycemia: an amino acid substrate limited disorder. J Clin Endocrinol Metab 38:521–530
Haymond MW, Pagliara AS (1983) Ketotic hypoglycaemia. Clin Endocrinol Metab 12:447–462
Landau BR, Wahren J, Chandramouli V, Schumann WC, Ekberg K, Kalhan SC (1996) Contributions of gluconeogenesis to glucose production in the fasted state. J Clin Invest 98:378–385
Odessey R, Khairallah EA, Goldberg AL (1974) Origin and possible significance of alanine production by skeletal muscle. J Biol Chem 249:7623–7629
Owen OE, Reichard GA Jr, Patel MS, Boden G (1979) Energy metabolism in feasting and fasting. Adv Exp Med Biol 111:169–188
Pagliara AS, Kari IE, De Vivo DC, Feigin RD, Kipnis DM (1972) Hypoalaninemia: a concomitant of ketotic hypoglycemia. J Clin Invest 51:1440–1449
Previs SF, Hazey JW, Diraison F, Beylot M, David F, Brunengraber H (1996) Assay of the deuterium enrichment of water via acetylene. J Mass Spectrom 31:639–642
Redies C, Hoffer LJ, Beil C, Marliss EB, Evans AC, Lariviere F, Marrett S, Meyer E, Diksic M, Gjedde A, Hakim AM (1989) Generalized decrease in brain glucose metabolism during fasting in humans studied by PET. Am J Physiol 256:E805–E810
Reinauer H, Gries FA, Hubinger A, Knode O, Severing K, Susanto F (1990) Determination of glucose turnover and glucose oxidation rates in man with stable isotope tracers. J Clin Chem Clin Biochem 28:505–511
Roden M (2004) How free fatty acids inhibit glucose utilization in human skeletal muscle. News Physiol Sci 19:92–96
Roden M, Petersen KF, Shulman GI (2001) Nuclear magnetic resonance studies of hepatic glucose metabolism in humans. Recent Prog Horm Res 56:219–237
Senior B (1973) Ketotic hypoglycemia. A tale (tail) of Gauss? J Pediatr 82:555–556
Senior B, Loridan L (1969) Gluconeogenesis and insulin in the ketotic variety of childhoofd hypoglycemia and in control children. J Pediatr 74:529–539
Steele R (1959) Influences of glucose loading and of injected insulin on hepatic glucose output. Ann N Y Acad Sci 82:420–430
Vassault A, Bonnefont JP, Specola N, Saudubray JM (1991) Lactate, pyruvate, and ketone bodies. In: Hommes FA (ed) Techniques in diagnostic human biochemical genetics: a laboratory manual. Wiley-Liss, New York, pp 285–308
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
Wolfe RR, Chinkes DL (2005) Glucose metabolism. In: Wolfe RR, Chinkes DL (eds) Isotope tracers in metabolic research. Wiley Inc, Hoboken, pp 215–257
Acknowledgements
We would like to thank Thessa Westphal for technical assistance with the experiments, and An Ruiter and Barbara Voermans for their excellent analytical support.
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Huidekoper, H.H., Duran, M., Turkenburg, M. et al. Fasting adaptation in idiopathic ketotic hypoglycemia: a mismatch between glucose production and demand. Eur J Pediatr 167, 859–865 (2008). https://doi.org/10.1007/s00431-007-0598-5
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DOI: https://doi.org/10.1007/s00431-007-0598-5