Pathological ketosis

The major example of pathological ketosis is of course insulin-dependent or type 1 diabetes. Essentially the changes in this condition are similar to those that occur during fasting, but they are more pronounced. Insulin is absent or very low in the plasma and therefore there is no antagonistic action to restrain the opposing hormones, adrenaline, nor-adrenaline, and glucagon. Consequently, lipolysis in adipose tissue is greatly stimulated and plasma fatty acids increase to high levels.

The lack of insulin and the large flux of fatty acids to the liver means that lipognesis is inhibited at the level of acetyl-CoA carboxylase and there is the expected decrease in malonyl-CoA concentration. In addition, the sensitivity of CAT I to inhibition by malonyl-CoA is considerably decreased. The level of expression of hepatic CAT I and II proteins also increases several-fold in diabetes. Thus the liver is in the ideal mode for producing excessive amounts of ketone bodies.

It has been suggested that diversion of oxaloace-tate to hepatic glucose synthesis (which is also increased in insulin deficiency) may also play a role in the increased rate of ketogenesis by diverting acetyl-CoA from the tricarboxylate cycle. However, present evidence suggests that this makes a minor contribution. Although the excessive output of ketone bodies by the liver undoubtedly makes the major contribution to their high levels in the blood, it is likely that there is also a degree of underutiliza-tion by peripheral tissues. The net result is ketoaci-dosis and excretion of large amounts of energy as ketone bodies in the urine.

A rare, but intriguing, example of pathological ketosis (ketone bodies up to 10mmoll_1) is the inborn error of hepatic glycogen synthase deficiency (Figure 8). Here glycogen is virtually absent from the liver so that after short-term fasting (5-10 h) the glucose falls to hypoglycemic levels, plasma insulin is decreased, plasma fatty acids increase, and

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Diurnal metabolite profile Figure 8 Diurnal blood metabolite profile of a child with glycogen synthetase deficiency. Values taken from Aynsley-Green A, Williamson DH and Gitzelmann R (1977) Archives of Disease in Childhood 52: 573-579. (With permission from BMJ Publishing Group.)

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Diurnal metabolite profile Figure 8 Diurnal blood metabolite profile of a child with glycogen synthetase deficiency. Values taken from Aynsley-Green A, Williamson DH and Gitzelmann R (1977) Archives of Disease in Childhood 52: 573-579. (With permission from BMJ Publishing Group.)

ketogenesis is switched on. On consuming a meal the pattern is reversed until the blood glucose falls again. This case illustrates the importance of hepatic glycogen (and its mobilization) in the smooth transition of substrate supply from the fed to the fasted state. Treatment in this case was to recommend the consumption of more frequent high-carbohydrate snacks. It is of interest that this particular child suffered no ill effects from the daily exposure to high concentrations of ketone bodies, underlining their role as normal substrates for the brain when available.

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