Glucose production in type I glycogen storage disease

Kalhan, Satish C.; Gilfillan, Carol; Tserng, Kou‐Yi; Savin, Samuel M.

doi:10.1016/s0022-3476(82)80218-7

Cited by 23 publications

(11 citation statements)

References 2 publications

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“…Gl-6-Pase-β has been shown to have structural and functional properties in muscle comparable with glucose-6-phosphatase-α expressed in liver, kidney, and intestine (EC 3.1.3.9; Glc-6-Pase-α) (Shieh et al 2004). As patients with glycogen storage disease 1a (GSD-1a; OMIM #232200) are deficient for Glc-6-Pase-α, resulting in defective hepatic and renal GNG and GGL, Gl-6-Pase-β activity in muscle might explain the residual EGP previously observed in these patients (Kalhan et al 1982; Schwenk et al 1986; Tsalikian et al 1984; Weghuber et al 2007). In order to investigate the potential role of extrahepatic and extrarenal tissue in glucose homeostasis during fasting in vivo, we performed whole-body kinetic studies in a patient with GSD-1a and a patient with fructose-1,6-bisphosphatase (FBPase) deficiency (OMIM #229700), an inborn error of hepatic and renal GNG.…”

Section: Introductionmentioning

confidence: 99%

A potential role for muscle in glucose homeostasis: in vivo kinetic studies in glycogen storage disease type 1a and fructose‐1,6‐bisphosphatase deficiency

Huidekoper

Visser

Ackermans

et al. 2010

J of Inher Metab Disea

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BackgroundA potential role for muscle in glucose homeostasis was recently suggested based on characterization of extrahepatic and extrarenal glucose-6-phosphatase (glucose-6-phosphatase-β). To study the role of extrahepatic tissue in glucose homeostasis during fasting glucose kinetics were studied in two patients with a deficient hepatic and renal glycogenolysis and/or gluconeogenesis.DesignEndogenous glucose production (EGP), glycogenolysis (GGL), and gluconeogenesis (GNG) were quantified with stable isotopes in a patient with glycogen storage disease type 1a (GSD-1a) and a patient with fructose-1,6-bisphosphatase (FBPase) deficiency. The [6,6-2H2]glucose dilution method in combination with the deuterated water method was used during individualized fasting tests.ResultsBoth patients became hypoglycemic after 2.5 and 14.5 h fasting, respectively. At that time, the patient with GSD-1a had EGP 3.84 μmol/kg per min (30% of normal EGP after an overnight fast), GGL 3.09 μmol/kg per min, and GNG 0.75 μmol/kg per min. The patient with FBPase deficiency had EGP 8.53 μmol/kg per min (62% of normal EGP after an overnight fast), GGL 6.89 μmol/kg per min GGL, and GNG 1.64 μmol/kg per min.ConclusionEGP was severely hampered in both patients, resulting in hypoglycemia. However, despite defective hepatic and renal GNG in both disorders and defective hepatic GGL in GSD-1a, both patients were still able to produce glucose via both pathways. As all necessary enzymes of these pathways have now been functionally detected in muscle, a contribution of muscle to EGP during fasting via both GGL as well as GNG is suggested.

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Section: Introductionmentioning

confidence: 99%

A potential role for muscle in glucose homeostasis: in vivo kinetic studies in glycogen storage disease type 1a and fructose‐1,6‐bisphosphatase deficiency

Huidekoper

Visser

Ackermans

et al. 2010

J of Inher Metab Disea

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“…2C), in order to keep this alternative fuel available in case of sudden hypoglycemia. The simplest and safest way to maintain this lactate level would seem to restrict the glucose content of the night drip feeding to the basic production rate of glucose, as found in normal children (2), which is higher than the glucose production found in one G6Pase-deficient patient (17). This covers the brain's requirement for glucose, which is estimated to be 60-80% of the normale production rate (2).…”

Section: Resultsmentioning

confidence: 98%

Lactate as a Cerebral Metabolic Fuel for Glucose-6-Phosphatase Deficient Children

1984

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SummaryThe main substrates for brain energy metabolism were measured in blood samples taken from the carotid artery and the internal jugular bulb of four children with glycogen storage disease caused by deficiency of glucose-6-phosphatase. Multiple paired arterial and venous blood samples were analyzed for glucose, lactate, pyruvate, D-b-hydroxybutyrate, acetoacetate, glycerol and 02, and the arteriovenous differences of the concentrations were calculated. In the first three patients the substrates were measured in two successive conditions with lower and higher glucose-intake, respectively, inducing reciprocally higher and lower concentrations of blood lactate. In the fourth patient medium chain triglycerides were administered simultaneously with the glucose-containing gastric drip feeding.Lactate appeared to be taken up significantly. It consumed, if completely oxidized, between 40-50% of the total O2 uptake in most cases. Only once in one patient the uptake of lactate switched to its release, when the blood lactate level decreased to normal. D-B-hydroxybutyrate and acetoacetate arteriovenous (A-V) differences were small to negligible and these ketone bodies, therefore, did not contribute substantially to the brain's energy expenditure. Glycerol was not metabolized by the brain. Lactate thus appeared to be the second brain fuel next to glucose. It may protect the brain against fuel depletion in case of hypoglycemia. AbbreviationsA-V, arteriovenous AcAc, acetoacetate G6Pase, glucose-6-phosphatase GDF, gastric drip feeding MCT, medium chain triglycerides &OHB, Bhydroxybutyrate P, priming dose Some children with hepatic glycogenosis caused by G6Pase deficiency show a striking tolerance for hypoglycemia. Their brain function remains unimpaired even when the blood glucose concentration is very low. Remarkably, those of our patients who show the most pronounced metabolic disturbances and the highest lactate levels in the blood, appear to be the least suscep tible to clinical symptoms of hypoglycemia. On the other hand, patients with a less abnormal metabolic state and only moderately elevated lactate levels show cerebral symptoms as soon as their blood glucose drops to even moderately low levels. We, therefore, wondered whether in some patients, besides glucose, lactate might be utilized as an energy substrate by the brain and thus protect the child against the deleterious effects of glucose depletion. This would be opposite to the situation in normal children (18, 22, 24, 25, 26) and normal adults (4, 9, 23), in whom the brain releases lactate and consumes ketone bodies (P-OHB and AcAc) as soon as glucose, the preferential fuel, becomes insufficiently available. In G6Pase-deficient children, however, this is impossible because there is no physiologic hyperketosis during fasting. Their fasting hypoglycemia is accompanied by hypoketosis (5) and hyperlactacidemia (6).The ability to utilize lactate instead of ketone bodies would fierefore be a useful mechanism. If, indeed, substantial cerebral utilization of lactate we...

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“…Some adult patients with type 1 GSD developed less severe disease and no longer had hypoglycemia 14,15 . Data suggested that these patients presumably had near normal glucose production rate.…”

Section: Discussionmentioning

confidence: 99%

“…Data suggested that these patients presumably had near normal glucose production rate. The increase in glycogen cycle in the liver via glycogenosis and glycogenolysis results in free glucose release by the debrancher enzyme 14 . The adult patients also had higher body mass indices than the children 15 .…”

Section: Discussionmentioning

confidence: 99%

Obesity and Reversed Growth Retardation in a Child with Type Ia Glycogen Storage Disease

Karnsakul

Gillespie

Skitarelic³

et al. 2010

Journal of Pediatric Endocrinology and Metabolism

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Type Ia Glycogen storage disease is an autosomal recessive hepatic metabolic disease due to a lack of glucose-6-phosphatase (G-6-Pase) activity presenting with growth retardation, lactic acidosis, fasting hypoglycemia with hypoinsulinemia, hyperuricemia, hepatomegaly, and hepatic adenoma with a risk of malignancy. The gene that encodes G-6-Pase was mapped to 17q21. There are some genotype-phenotype correlations. We report a case with delF327 mutation which is devoid of G-6-Pase activity; however clinical presentation in this case differs somewhat. Although correction of hypoglycemia and lactic acidosis with nocturnal intragastric feeding and uncooked starch therapy improves growth failure, mean height of the patients is often less than the target. Normal height and obesity in this case with hepatic steatosis and low hepatic glycogen storage requires clinical reevaluation since there are some overlapping phenotypes between type Ia GSD and metabolic syndrome. The phenomenon may be related to insulin resistance as a consequence of early aggressive nutrition therapy with frequent low glycemic index meals. KEY WORDSglycogen storage disease type 1, obesity, insulin resistance, reversed growth retardation, hepatic steatosis Corresponding author: Wikrom Karnsakul wkarnsa1@jhmi.edu PATIENT REPORTA 16-year-old Caucasian male was diagnosed with type Ia GSD from age 9 months of age. Since diagnosis he received nocturnal intragastric feeding until age 2; then he consumed uncooked cornstarch with a current dosage of 12 teaspoons three times a day along with snacks, which was noted to have low glycemic index when he had symptoms of hypoglycemia. He has no family history of metabolic liver disease, diabetes, nonalcoholic fatty liver disease, and obesity. Starch intake and nocturnal intragastric feeding have significantly improved his failure to thrive and biochemical profiles such as hypoglycemia, hyperuricemia, lactic acidosis and hepatomegaly without splenomegaly. His growth parameters reversed from failure to thrive to obesity at approximately age 2 (Figure 1). Physical examination demonstrated a height of 178 cm, weight of 120 kilograms (obesity with BMI of 38 (>95 th percentile), waist circumference not performed at the time), systolic hypertension, hepatomegaly, presence of grade 1 acanthosis nigricans and a papulosquamous rash without scale on the extensor surface of extremities consistent with psoriasis.A blood test demonstrated WBC 7900/mm 3 , hemoglobin 13.6 g/dL, hematocrit 40.1%, platelet 421,000/mm 3 , MCV 79, neutrophil 59%, lymphocyte 31%, eosinophil 1%, monocytes 8%, and basophil 1%, AST 26 U/L (13-58), ALT 25 U/L (4-40), LDH 136 U/L (98-192), total bilirubin 0.5 mg/dL (0.2-1.3), direct bilirubin 0 mg/dl (0.0-0.3), uric acid 5.9 mg/dL (4.0-8.6) while on allopurinol, alkaline phosphatase 121 U/L (65-260), gamma GT 57 U/L (7-26), cholesterol 247 mg/dL (125-170), HDLcholesterol 33 mg/dL (35-65), LDL-cholesterol 144, triglyceride 398 mg/dL (<150), lactic Acid Brought to you by |

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Glucose production in type I glycogen storage disease

Cited by 23 publications

References 2 publications

A potential role for muscle in glucose homeostasis: in vivo kinetic studies in glycogen storage disease type 1a and fructose‐1,6‐bisphosphatase deficiency

A potential role for muscle in glucose homeostasis: in vivo kinetic studies in glycogen storage disease type 1a and fructose‐1,6‐bisphosphatase deficiency

Lactate as a Cerebral Metabolic Fuel for Glucose-6-Phosphatase Deficient Children

Obesity and Reversed Growth Retardation in a Child with Type Ia Glycogen Storage Disease

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