Focus: Clinical case study, carbohydrate metabolism, cell signaling (review of m
ID: 31726 • Letter: F
Question
Focus: Clinical case study, carbohydrate metabolism, cell signaling (review of material from CHEM 441A) Description The patient was a 2 year old boy who presented with fasting hypoglycemia and acidosis. The liver was enlarged three-fold and kidneys two-fold. Hypoglycemia responded to oral doses of glucose but not to administered glucagon or epinephrine. During hypoglycemic episodes, lactic acid in the blood increased almost 10-fold higher than normal. Unlike the response in normal individuals, administration of oral galactose did not increase blood glucose concentrations but blood lactate levels were increased. Urine contained high levels of lactate. A glucose tolerance test showed normal insulin responses with a corresponding increase in blood glucose and decrease in blood lactate levels, liver glycogen stores were elevated three-fold but muscle glycogen levels were normal. Liver glycogen structure was normal. Assays for liver glucose-4 phosphatase activity showed a 20-fold lower activity per mg liver protein compared to control using either glucose-6-phosphate or glucose- I -phosphate as a substrate. 1. What enzyme in the infant is lacking? Explain your answer. 2. What is the metabolic reason for elevated levels of blood lactate in this patient? What are the biochemical sources of lactate? 3. What evidence suggests that phosphoglucomutase levels in the patient were normal? 4. Why were glycogen levels elevated in liver but normal in skeletal muscle? What symptoms. if any, would appear for this patient under exercise? S. What is the biochemical basis for the increase in blood glucose following oral galactose administration, and why was this response not observed in the patient? 6. Successful treatment of the patient?s symptoms was through frequent daytime feedings and administration of high-glucose formula via nocturnal nasogastric infusion. Why is this treatment successful in maintaining blood glucose concentrations and reducing blood lactate levels?Explanation / Answer
The infant is lacking the enzyme hepatic glucose-6-phosphatase. This enzyme is responsible for release of free glucose units from glucose-6-phosphate (glu-6-phosphate is released from glycogen). The enzyme is mainly present in liver and kidneys, and to a lesser extent in the intestines. Deficiency of this enzyme causes glycogen storage disease called type I GSD or von Gierke disease. The disease is characterized by poor tolerance to fasting. The liver fails to release free glucose to blood.
Since free glucose is not produced from glucose-6-phosphate, g-6-P is diverted to glycolysis. The end product of glycolysis cannot be used in TCA cycle to completely oxidize it since the release of pyruvate is above the capacity of TCA cycle to oxidize the pyruvate generated. Therefore, pyruvate is reduced to lactate, causing lactate academia. Also, conversion of lactate to pyruvate does not occur in the absence of the enzyme glu-6-phosphatease.
Utilization of glucose-1-phosphate as a substrate is normal. When glu-1-phosphate is given as substrate, the levels of phosphatase activity are low. If phosphoglucomutase is not functional, glu-6-p is not synthesized, reduced enzyme activity is not seen. During exercise, the patient shows reduced blood glucose levels and recovery of blood glucose levels are very slow. The patient shows increased fatigue.
Glycogen levels are elevated in liver only since the defective enzyme is produced in the liver. The liver enzyme expression is restricted as liver glycogen serves as a pool to maintain blood glucose. The enzyme is not expressed in muscles. In muscles, the enzyme responsible for glycogenolysis is phosphorylase a or glycogen phosphorylase a.
Galactose should be first converted into galactose-1-phosphate, which is further epimerized to glucose-1-phosphate.Glucose-1-phosphate should be converted into glucose-6-phosphate which is then converted into free glucose. Since the person is deficient in the enzyme which converts glu-6-p to free glucose, administration of galactose does not increase blood glucose levels. Instead, it leads to glycogen synthesis.
Nasogastric infusion is given so that the glucose absorbed is supplied to the tissues.Nocturnal nasogastric infusion of glucose prevents hypoglycemia.