Glucose and ketone body metabolism : with emphasis on ketotic hypoglycemia

Sammanfattning: Idiopathic ketotic hypoglycemia is characterized by hypoglycemia and elevated levels of ketone bodies (beta-hydroxybutyrate and acetoacetate) during fasting. The affected children are otherwise healthy and they usually present with the condition before 5 years of age. Hypoglycemia usually develops in the morning after a period of reduced energy intake. The presenting symptoms are the classical signs of hypoglycemia: paleness, tachycardia, sweatiness, tremor, headache, vomiting, etc. The underlying mechanisms have not yet been clarified. The aim of this thesis was to investigate ketone body turnover and fasting tolerance in children and adults with previous symptoms of hypoglycemia and in patients with suspected defects in ketolysis. In Paper I, a pair of homozygotic twin boys were studied, one of whom had severe ketotic hypoglycemia while the other one was apparently healthy. A 24-hour fasting tolerance test confirmed the diagnosis in the affected twin. The rates of glucose and glycerol production were measured and were similar in both boys. During infusions of beta-hydroxybutyrate, the plasma level of beta-hydroxybutyrate increased 5 10 times more in the twin with idiopathic ketotic hypoglycemia, indicating disturbed clearance or metabolism of beta-hydroxybutyrate. No mutations were found in the genes involved in ketone body metabolism or transport. In Paper II we studied whether an altered ketone body turnover might be the cause of idiopathic ketotic hypoglycemia. Twenty-two children with previous symptoms of hypoglycemia underwent investigations similar to those of the boys in Paper I. The results of the rate of glucose production were compared with those of 9 healthy age-matched controls. Nine children developed idiopathic ketotic hypoglycemia and their ketone body turnover differed from that of the normoglycemic children. The rate of glucose production was within the low normal range, and no mutations were found. The enzyme succinyl CoA-3:ketoacid-CoA transferase (SCOT) is involved in the metabolism of ketone bodies. In Paper III we investigated a child and an adult with suspected deficiencies in this enzyme and showing symptoms resembling those of idiopathic ketotic hypoglycemia. In total, 5 novel mutations were identified in the SCOT gene. Despite this, the analysis of the enzyme showed only a 30 35% decrease in activity, probably due to a nonspecific assay. A fasting tolerance test was terminated prematurely in both cases due to acidosis. During the test and also during the beta-hydroxybutyrate infusion, both patients showed high levels of ketone bodies. None of them developed hypoglycemia, and the glucose production rate was normal. Finally, in Paper IV, a group of adults who had had symptoms of hypoglycemia during fasting were investigated. None of them developed hypoglycemia, and, compared to a control group, no differences were found in the ketone body level or hormonal response. Conclusion: The results suggest that neither a low rate of glucose production nor a reduced metabolism of ketone bodies alone can explain idiopathic ketotic hypoglycemia. Instead, the combination of a disturbed ketone body metabolism and a glucose production rate within the low normal range seems to cause idiopathic ketotic hypoglycemia. The cause of the disturbed ketone body metabolism is unknown. No adults with idiopathic ketotic hypoglycemia were identified.