Ketone body production

McGarry, J. D., and Foster, D. W., 1980. Regulation of hepatic fatty acid oxidation and ketone body production. Annual Review of Biochemistry 49 395-420. 

Increased fatty acid oxidation is a characteristic of starvation and of diabetes meUims, leading to ketone body production by the Ever (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal. Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia. This occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, eg, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, eg, hypoglycin. 

In moderate ketonemia, the loss of ketone bodies via the urine is only a few percent of the total ketone body production and utilization. Since there are renal threshold-like effects (there is not a true threshold) that vary between species and individuals, measurement of the... 

There is a small fall in plasma glucose upon starvation, then little change as starvation progresses (Table 27-2 Figure 27-2). Plasma free fatty acids increase with onset of starvation but then plateau. There is an initial delay in ketone body production, but as starvation progresses the plasma concentration of ketone bodies increases markedly. 

Three compounds acetoacetate, P-hydroxybutyrate, and acetone, are known as ketone bodies. They are suboxidized metabolic intermediates, chiefly those of fatty acids and of the carbon skeletons of the so-called ketogenic amino acids (leucine, isoleucine, lysine, phenylalanine, tyrosine, and tryptophan). The ketone body production, or ketogenesis, is effected in the hepatic mitochondria (in other tissues, ketogenesis is inoperative). Two pathways are possible for ketogenesis. The more active of the two is the hydroxymethyl glutarate cycle which is named after the key intermediate involved in this cycle. The other one is the deacylase cycle. In activity, this cycle is inferior to the former one. Acetyl-CoA is the starting compound for the biosynthesis of ketone bodies. 

The increased oxidation of fatty acids decreases the rate of glucose utilisation and oxidation by muscle, via the glucose/fatty acid cycle, which accounts for some of the insulin resistance in trauma. An additional factor may be the effect of cytokines on the insulin-signalling pathway in muscle. An increased rate of fatty acid oxidation in the liver increases the rate of ketone body production the ketones will be oxidised by the heart and skeletal muscle, which will further reduce glucose utilisation. This helps to conserve glucose for the immune and other cells. 

Pilon D, Charbonneau M, Brodeur J, et al. 1986. Metabolites and ketone body production following methyl n-butyl ketone exposure as possible indices of MnBK potentiation of carbon tetrachloride hepatotoxicity. Toxicol AppI Pharmacol 85 49-59. 

FIGURE 21-19 Regulation of triacylglycerol synthesis by insulin. Insulin stimulates conversion of dietary carbohydrates and proteins to fat. Individuals with diabetes mellitus lack insulin in uncontrolled disease, this results in diminished fatty acid synthesis, and the acetyl-CoA arising from catabolism of carbohydrates and proteins is shunted instead to ketone body production. People in severe ketosis smell of acetone, so the condition is sometimes mistaken for drunkenness (p. 909). 

Physical therapists and occupational therapists may help reinforce the importance of patient compliance during pharmacologic management of diabetes mellitus. Therapists can question whether patients have been taking their medications on a routine basis. Regular administration of insulin is essential in preventing a metabolic shift toward ketone body production and subsequent ketoacidosis, especially in patients with type 1 diabetes. In addition, therapists can help explain that adequate control of blood glucose not only prevents acute metabolic problems but also seems to decrease the incidence of the neurovascular complications. 

High gluconeogenesis activity means a high blood glucagon and/or epinephrine levels. Of the four choices, only ketone body production can coexist with gluconeogenesis. 

Understand the biosynthesis of cholesterol compare this process with that of ketone body production know what controls cholesterol biosynthetic reactions. 

Because insulin normally inhibits lipolysis, a diabetic has an extensive lipolytic activity in the adipose tissue. As is seen in Table 21.4, plasma fatty acid concentrations become remarkably high. /3-Oxidation activity in the liver increases because of a low insulin/glucagon ratio, acetyl-CoA carboxylase is relatively inactive and acyl-CoA-camitine acyltransferase is derepressed. /3-Oxidation produces acetyl-CoA which in turn generates ketone bodies. Ketosis is perhaps the most prominent feature of diabetes mellitus. Table 21.5 compares ketone body production and utilization in fasting and in diabetic individuals. It may be seen that, whereas in the fasting state ketone body production is roughly equal to excretion plus utilization, in diabetes this is not so. Ketone bodies therefore accumulate in diabetic blood. 

Table 21.5 Ketone Body Production and Utilization in Fasting and Diabetes Mellitus (g/24 h) ...

Figure 32-5. P-oxidation and ketogenesis in the liver. The rate-limiting step in fatty acid oxidation and subsequent ketone body production is the activity of carnitine acyltrans-ferase I (CAT I).The activity of CAT I is inhibited by malonyl-CoA. Insulin deficiency results in inhibition of acetyl-CoA carboxylase, decreased levels of maloyl-CoA, and thus increased activity of CAT-I.Adapted from Foster and McGarry (1983).

A major factor in stinoulating ketone body production is increased availability of FTAs. An increased rate of FFA mobilisation from the adipose tissue, with the consequent increase in FFA levels in the liver, may be sufficient to enhance ketone body formation. Increased release of FFAs occurs when the glucagon/insulin ratio... 

Fery, F., and Balasse, E. O. (1985). Ketone body production and disposal in diabetic ketosis. Diiiiwles 34, 326-332. 

B) An insulin injection would decrease her ketone body production... 

Ketone body production and utilization. Ketone bodies are produced in the liver from fatty acids derived from adipocyte lipolysis. They are released and used as fuel in peripheral tissues. The initial step in acetoacetate metabolism is activation to acetoacetyl-CoA by succinyl-CoA. HMG-CoA, /S-hydroxy-y3-methylglutaryl-CoA HB, /i-hydroxybutyrate. 

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