Kinetics of ketone body metabolism in fasting humans

Abstract

The rates of production of total ketone bodies (acetoacetate + beta-hydroxybutyrate) were determined using an isotope tracer technique in 23 obese subjects submitted to a fast of variable duration (15 hr--23 days). Constant infusions of 14C-acetoacetate were used in most studies, but similar results were obtained with pulse injections of this tracer or with constant infusions of 14C-D(-)-beta-hydroxybutyrate. Blood concentration, production rate, and urinary elimination of total ketones rose during approximately the first 3 days of fast and plateaued thereafter at values amounting, respectively, to 7.09 +/- 0.32 mumole/ml, 1908 +/- 80 mumole/min and 167 +/- 14 mumole/min. The rates of ketogenesis are significantly higher than those usually reported in the literature. Ketonemia was an exponential function of production rate suggesting that tissue uptake becomes progressively saturated as inflow rate rises. The same type of relationship between concentration and inflow rate was observed in nine control overnight fasted obese subjects rendered hyperketonemic with infusions of variable amounts of unlabeled acetoacetate. The comparison between the fasted and the control subjects at ketone concentrations of 3--10 mumole/ml showed that on an average, starvation is associated with a 35% decrease in the metabolic clearance rate of ketones. These data suggest that fasting is associated with an impairment of mechanisms for utilizing ketones, this defect contributing to the hyperketonemia of food deprivation.