Ketone body production and disposal: effects of fasting, diabetes, and exercise

Turnover studies performed during progressive fasting in normal subjects indicate that the production rate and the concentration of KB rise markedly during the early phase of fasting and start reaching a plateau after about 5 days. In addition to increased production, a reduction in the metabolic clearance rate of KB contributes to the hyperketonemia. This reduced metabolic clearance rate reflects essentially the progressive saturation of muscular ketone uptake that occurs with increasing ketonemia. The hormonal and metabolic environment of fasting plays only a minor role in this process, since a fall in KB metabolic clearance similar to that observed during fasting is observed if hyperketonemia is artificially induced in the postabsorptive state by the infusion of exogenous ketones. As extraction of KB by muscle becomes limited during ongoing fasting, KB are preferentially taken up by the brain to serve as a substrate replacing glucose. The remarkable stability of ketonemia during prolonged fasting is maintained through the operation of a negative feedback mechanism whereby KB tend to restrain their own production rate. The antilipolytic and insulinotropic effects of KB are instrumental in this process. This homeostatic mechanism maintains ketogenesis only slightly above the maximal metabolic disposal rate, the difference corresponding to urinary excretion, which is always below 10% of total turnover under physiologic conditions. When type I insulin-deprived diabetic patients are compared at the same KB concentration with control subjects with fasting ketosis, the characteristics of KB kinetics are comparable in the two groups. The maximal KB removal capacity is identical in the two situations, and it is not possible to identify a ketone removal defect specific to diabetes. Thus, these data favor the concept that excessive production of KB represent the main factor leading to uncontrolled hyperketonemia. It should be realized that a production exceeding only slightly that prevailing during prolonged fasting is sufficient to cause a progressive build-up in concentration, leading to uncontrolled diabetic ketosis. In the overnight-fasted state, a prolonged exercise (2 h) performed at moderate intensity (50% VO2 max) stimulates the capacity of muscle to extract ketones from blood as evidenced by a stimulation of the metabolic clearance rate.(ABSTRACT TRUNCATED AT 400 WORDS)