Ketogenesis

The keto acids relevant to DKA are P-hydroxybutyric acid and acetoacetic acid (2,3,6). The primary mode of keto acid generation is from free fatty acids (FFAs). Released from triglycerides in adipose tissue, FFAs are transported to the liver, where they are converted to acyl-CoA derivatives in the cytosol of hepatocytes. These acyl-CoA derivatives enter the mitochondria as carnitine esters via a process catalyzed by carnitine acyl transferase I (CAT I) (see Fig. 1). In the mitochondria, acyl-CoA is regenerated and subsequently oxidized to acetyl-CoA. Acetyl-CoA condenses with acetoacetyl-CoA to form P-hydroxy-P-methylglutaryl-CoA (HMGCoA), which then splits to form acetoacetate and acetyl-CoA. Acetoacetate is converted to P-hydroxybu-tyrate in the presence of NADH. The net metabolic effect of ketone formation is the accumulation of keto anions and the formation of three hydrogen ions for every triglyceride molecule metabolized to ketones (3).

Low insulin and elevated glucagon concentrations facilitate the release of FFA from adipose stores; the opposite hormonal milieu of elevated insulin and low glucagon concentrations inhibits keto acid production. In the whole animal, keto acid generation is, to the greatest extent, regulated by the substrate, (i.e., FFA availability) (3). The rate of accumulation of keto acids is dependent on the ability of the tricarboxylic acid (TCA) cycle to utilize acetyl-CoA and the rate at which acetyl-CoA is generated. Evidence indicates that overproduction of acetyl-CoA and not reduced TCA cycle activity is the major mechanism for the increase in keto acids in DKA (3).

Acetone is a neutral compound with no effect on blood pH; it is formed by the nonenzymatic decarboxylation of acetoacetate. Acetone is metabolically of little importance, but it provides an important bedside clinical clue to the diagnosis of DKA because of its characteristic odor and excretion via expired air and urine. In the normal fasting state, the ratio of serum P-hydroxybutyrate to acetoacetate is of the order of 3 : 1. The rate of interconversion of acetoacetate and P-hydroxybutyrate depends on the cellular redox state (see Fig. 2). A reduced redox state, as encountered in DKA, favors the formation of P-hydroxybutyrate, whereas an increase in the redox state associated

Acylcarnitine

Fig. 1. Fatty acid oxidation system in the liver. The inner mitochondrial membrane is impermeable to long-chain fatty acyl-CoA but permeable to fatty acylcarnitine. Formation of the carnitine ester is catalyzed by carnitine palmitoyltransferase I (CPT I), the rate-limiting step in the sequence. This enzyme is inhibited by malony-CoA. The transesterification reaction is reversed inside mitochondria by CPT II. the majority of fatty acid molecules entering the mitochondria are converted to ketones, only a small amount of the acetyl-CoA generated being oxidized in the tricarboxylic acid cycle. (From Unger RH, Foster DW. Diabetes mellitus. In: Wilson JD, Foster DW, eds., Williams Textbook of Endocrinology, 7th ed. WB Saunders, Philadelphia, 1985.)

Fig. 1. Fatty acid oxidation system in the liver. The inner mitochondrial membrane is impermeable to long-chain fatty acyl-CoA but permeable to fatty acylcarnitine. Formation of the carnitine ester is catalyzed by carnitine palmitoyltransferase I (CPT I), the rate-limiting step in the sequence. This enzyme is inhibited by malony-CoA. The transesterification reaction is reversed inside mitochondria by CPT II. the majority of fatty acid molecules entering the mitochondria are converted to ketones, only a small amount of the acetyl-CoA generated being oxidized in the tricarboxylic acid cycle. (From Unger RH, Foster DW. Diabetes mellitus. In: Wilson JD, Foster DW, eds., Williams Textbook of Endocrinology, 7th ed. WB Saunders, Philadelphia, 1985.)

Cycle Ketogenesis

Fig. 2. Generation of ketone bodies. Simplified schema of the formation of the major ketone bodies: acetoacetate (AA). P-hydroxybutyrate (BHOB), and acetone. Note the preferential formation of BHOB from AA with acidosis and, conversely, the dissociation of BHOB to AA when acidosis resolves. The nitroprusside reaction commonly used to detect ketone bodies reacts strongly with AA, weakly with acetone, and not at all with BHOB. See text for significance.

Fig. 2. Generation of ketone bodies. Simplified schema of the formation of the major ketone bodies: acetoacetate (AA). P-hydroxybutyrate (BHOB), and acetone. Note the preferential formation of BHOB from AA with acidosis and, conversely, the dissociation of BHOB to AA when acidosis resolves. The nitroprusside reaction commonly used to detect ketone bodies reacts strongly with AA, weakly with acetone, and not at all with BHOB. See text for significance.

with recovery from DKA favors the conversion of P-hydroxybutyric acid to acetoacetic acid. Thus, in severe DKA the ratio of P-hydroxybutyric acid to acetoacetic acid is usually about 7 : 1 and may even increase to 15 : 1 (1-6). The nitroprusside reaction used in the semiquantitative and qualitative tests (Acetest, Ketostix, Chemstrips UGK) for ketonemia and ketonuria does not measure P-hydroxybutyric acid, reacts weakly with acetone, and predominantly measures acetoacetic acid. About 80% of the color reaction in the nitroprusside test is a result of acetoacetate, and acetoacetate comprises only one-third to one-fifteenth of the total ketone bodies in the circulation during DKA (2). Thus, the usual bedside tests for ketones provide a gross underestimation of the total ketone body concentration. This laboratory artifact has important implications for the management of patients with DKA. First, the absence of a positive nitroprusside reaction does not necessarily imply the absence of ketoacidosis. Conversely, the persistence or even an increase in the color reaction of the nitroprusside test should not be assumed to be the result of a deteriorating metabolic response to treatment. This is because with improvement in the metabolic status of the patient, the concomitant increase in the cellular redox state results in the conversion of the "unmeasured" P-hydroxybutyric acid to "measured" acetoacetate and an apparent worsening of the ketonemic state. False-positive reactions for ketones with the nitroprusside reaction, although rare, can occur as a result of the presence of drugs such as captopril in the urine (2,3).

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