Hepatic fructose-1,6-diphosphatase deficiency

Pagliara, Anthony S.; Karl, Irene E.; Keating, James P.; Brown, Barbara I.; Kipnis, David

doi:10.1172/jci107018

Cited by 96 publications

(13 citation statements)

References 22 publications

(16 reference statements)

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“…It is now recognized that the coinetiologic mechanism has been identified. The subjects cidence of ketosis with hypoglycemia may occur in a of the present study conform to the clinical pattern of number of disorders due to specific enzyme defects such a syndrome although homogeneity of age is not as [27]. However, in the majority of cases, no such specific great as when compared with other studies [26].…”

Section: Discussionsupporting

confidence: 79%

Response to 2-Deoxy-D-glucose and to Glucagon in “Ketotic Hypoglycemia” of Childhood: Evidence for Epinephrine Deficiency and Altered Alanine Availability

et al. 1973

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ExtractThe commonest clinical type of hypoglycemia in childhood presents as "ketotic hypoglycemia," a syndrome which typically remits spontaneously before adolescence. In young children with the severe form of this syndrome, deficient catecholamine secretion and, recently, decreased mobilization of gluconeogenic substrate (alanine) have been shown. The present study concerns five children with ketotic hypoglycemia, aged 2.5 to 9.5 years, and six control children, of similar ages. Each received (7) an infusion of 2-deoxy-D-glucose (2-DG) to test the catecholamine response and (2) intravenous glucagon before and after a 26-28-hr fast, to define possible difference in the response of substrates and hormones, with particular reference to alanine. In the control group, the infusion of 2-DG, 50 mg/kg body wt over 30 min, induced anxiety, hunger or thirst and sweating, as well as a sustained rise in plasma glucose from 78 ± 5 (mean ± SEM) to 156 ± 13.5 mg/100 ml from 1-3 hr after beginning the infusion. There was a transient rise in renin activity in plasma (PRA) from 2.0 ± 0.5 to a peak of 5.8 ± 1.2 ng/ml/hr. By contrast, in the children with hypoglycemia, no clinical response was observed, and there was no change in either glucose in plasma, which remained at 77 ± 6 mg/100 ml, or in PRA (1.3 ± 0.3 to 1.0 ± 0.5 ng/ml/hr). After a period of unrestricted diet, and after an overnight fast, values of plasma glucose, insulin, glucagon, /3-hydroxybutyrate, and alanine were the same in the two groups. In both groups intravenous glucagon, 30 yug/kg, was followed by a comparable rise in glucose in plasma and immunoreactive insulin and a comparable fall in alanine in plasma. During the subsequent fast, glucose and insulin in plasma declined similarly. Ketonuria appeared at the same time and /S-hydroxybutyrate in plasma rose to equivalent values. The response to a second glucagon infusion was smaller after fasting both as to glucose in blood and plasma insulin, but once again similar for control and hypoglycemia groups. However, the fall in alanine in plasma was significantly greater in the hypoglycemic group during fasting (to 200 ± 13 /*M for the control group compared with 151 ± 13 ^Mforthe hypoglycemia group, P < 0.05) and at five time points (10,30, 60, 90, and 120 min) after the second glucagon administration. Absence of hyperglycemic response to 2-DG in ketotic hypoglycemia suggests 983 984 SlZONENKO ET AL. impaired catecholamine response. Further, after provocation by fasting and subsequent glucagon administration, the hypoalaninemia which resulted was more marked. Because epinephrine has been shown to raise alanine levels in plasma in man, it is hypothesized that a connection may exist between defective catechol secretion and alanine mobilization in ketotic hypoglycemia. SpeculationDecreased availability of alanine in so-called ketotic hypoglycemia probably represents a defective metabolic system by which neoglucogenic substrates are not readily mobilized, rather than an absolute absence of substrate. One of the poss...

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Section: Discussionsupporting

confidence: 79%

Response to 2-Deoxy-D-glucose and to Glucagon in “Ketotic Hypoglycemia” of Childhood: Evidence for Epinephrine Deficiency and Altered Alanine Availability

et al. 1973

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“…The gradual rise in glycerol particularly during the second study indicates active lipolysis. Plasma ,f3-hydroxybutyrate was also within normal limits (20, 34, 38, 40) when the children were normoglycemic but remained essentially unchanged when the subjects became hypoglycemic; thus, there was a n inappropriate hypoketonemia for the level of glycemia (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34).…”

Section: Resultsmentioning

confidence: 93%

Hypoglycemia, Hepatic Dysfunction, Muscle Weakness, Cardiomyopathy, Free Carnitine Deficiency and Long-Chain Acylcarnitine Excess Responsive to Medium Chain Triglyceride Diet

et al. 1983

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SummaryFraternal twins who had fasting hypoglycemia, hypoketonemia, muscle weakness, and hepatic dysfunction are reported. The hepatic dysfunction occurred only during periods of caloric deprivation. The surviving patient developed a cardiomyopathy. In this sibling, muscle weakness and cardiomyopathy were markedly improved by a diet high in medium chain triglycerides. There was a marked deficiency of muscle total carnitine and a mild deficiency of hepatic total carnitine. Unlike patients with systemic carnitine deficiency, serum and muscle long-chain acylcarnitine were elevated and renal reabsorption of carnitine was normal. It was postulated that the defect in long-chain fatty acid oxidation in this disorder is caused by an abnormality in the mitochondria1 acylcarnitine transport.Detailed studies of the cause of the hypoglycemia revealed that insulin, growth hormone, cortisol, and glucagon secretion were appropriate and that it is unlikely that there was a major deficiency of a glycolytic or gluconeogenic enzyme. Glucose production and alanine conversion to glucose were in the low normal range when compared to normal children in the postabsorptive state. The hypoglycemia in our patients was probably due to a modest increase in glucose consumption, secondary to the decreased oxidation of fatty acids and ketones, alternate fuels which mare glucose utilization, plus a modest decrease in hepatic glucose production secondary to decreased available hepatic energy substrates. AbbreviationsAla, alanine ALT, alanine aminotransferase AST, aspartate aminotransferase CPK, creatine kinase hGH, human growth hormone LA, left atrium LPEP/LVET, left pre-ejection period/left ventricular ejection time P-OHB, beta-hydroxybutyrate RPEP/RVET, right pre-ejection period/right ventricular ejection time LVED, left ventricular end diastolic dimension LVES, left ventricular end systolic dimension MCT, medium chain triglyceride PC, pyruvate carboxylase PEPCK, phosphoenol phosphate carboxykinase U, units Hepatic long-chain acyl CoA carnitine transferase deficiency (4), multiple acyl CoA dehydrogenase deficiency (glutaric aciduria type 11) (18), and systemic carnitine deficiency (3,9,12,17,24,37,43), all of which are associated with impaired fatty acid oxidation, have hypoglycemia as a major clinical manifestation.The purpose of this paper is twofold: (1) to report fraternal twins with free carnitine deficiency and long-chain acylcarnitine excess in whom hypoglycemia, hepatic dysfunction, muscle weakness, and in the surviving patient cardiomyopathy were major problems and (2) to discuss results of studies to evaluate the etiology of the disorder. CASE REPORTSPatient I . The patient was the 1.8-kg product of 7% month uncomplicated twin pregnancy. He did well until 9 months of age. After a respiratory infection (parainfluenza 3 virus recovered from nasopharynx), he developed an illness characterized by vomiting, listlessness, and hypotonia. Progressive hepatomegaly (span 6 cm on admission, span 12 cm, 2 wk later) and more abnormal liver functi...

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“…Inherited enzyme deficiencies that have been identified as a causative factor in the development of lacticacidaemia are those belonging either to the gluconeogenic pathway; i.e., glucose-6-phosphatase [6], fructose-l,6-diphosphatase [8], phosphoenolpyruvate carboxykinase [12] and pyruvate carboxylase [1,5]; or to the pyruvate dehydrogenase complex; i.e., pyruvate decarboxylase [2], lipoamide dehydrogenase [11], pyruvate dehydrogenase phosphatase [10]. In some cases, deficiencies have been proposed to exist at undefined points in the Krebs cycle [12], and in two cases, the deficiency has been located at cytochrome oxidase [15].…”

Section: Introductionmentioning

confidence: 99%

Lacticacidosis, neurological deterioration and compromised cellular pyruvate oxidation due to a defect in the reoxidation of cytoplasmically generated NADH

et al. 1983

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Two patients, one dying at 25 days and one at 20 months had 'chronic' lactic acidaemia with a high lactate to pyruvate ratio. Both showed EEG abnormalities and seizure activity and both died of respiratory failure. Investigation of cultured skin fibroblasts from these patients revealed normal pyruvate dehydrogenase and pyruvate carboxylase activities but the cells showed a decreased ability to oxidase pyruvate which was returned to normal on the addition of methylene blue. Subsequent investigations revealed that the mitochondria from the patients' cells could oxidase pyruvate normally but that the cells had an abnormal NAD to NADH ratio under standard conditions of incubation. It was concluded that both children had a redox disequilibrium in the cytoplasmic compartment due to a problem in transporting reducing equivalents from the cytoplasmic to the mitochondrial compartments.

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Hepatic fructose-1,6-diphosphatase deficiency

Cited by 96 publications

References 22 publications

Response to 2-Deoxy-D-glucose and to Glucagon in “Ketotic Hypoglycemia” of Childhood: Evidence for Epinephrine Deficiency and Altered Alanine Availability

Response to 2-Deoxy-D-glucose and to Glucagon in “Ketotic Hypoglycemia” of Childhood: Evidence for Epinephrine Deficiency and Altered Alanine Availability

Hypoglycemia, Hepatic Dysfunction, Muscle Weakness, Cardiomyopathy, Free Carnitine Deficiency and Long-Chain Acylcarnitine Excess Responsive to Medium Chain Triglyceride Diet

Lacticacidosis, neurological deterioration and compromised cellular pyruvate oxidation due to a defect in the reoxidation of cytoplasmically generated NADH

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