Effect of acute hyperketonemia on the cerebral uptake of ketone bodies in nondiabetic subjects and IDDM patients.

Using R-beta-[1-(11)C]hydroxybutyrate and positron emission tomography, we studied the effect of acute hyperketonemia (range 0.7-1.7 micromol/ml) on cerebral ketone body utilization in six nondiabetic subjects and six insulin-dependent diabetes mellitus (IDDM) patients with average metabolic control (HbA(1c) = 8.1 +/- 1.7%). An infusion of unlabeled R-beta-hydroxybutyrate was started 1 h before the bolus injection of R-beta-[1-(11)C]hydroxybutyrate. The time course of the radioactivity in the brain was measured during 10 min. For both groups, the utilization rate of ketone bodies was found to increase nearly proportionally with the plasma concentration of ketone bodies (1.0 +/- 0.3 micromol/ml for nondiabetic subjects and 1.3 +/- 0.3 micromol/ml for IDDM patients). No transport of ketone bodies from the brain could be detected. This result, together with a recent study of the tissue concentration of R-beta-hydroxybutyrate in the brain by magnetic resonance spectroscopy, indicate that, also at acute hyperketonemia, the rate-limiting step for ketone body utilization is the transport into the brain. No significant difference in transport and utilization of ketone bodies could be detected between the nondiabetic subjects and the IDDM patients.

Effect of valproate, sodium 2-propyl-4-pentenoate and sodium 2-propyl-2-pentenoate on renal substrate uptake and ammoniagenesis in the rat.

Experiments were carried out in the intact functioning rat kidney to study the effect of valproate (VPA), a widely used antiepileptic drug and an hyperammonemic agent, but usually without clinical relevance, and of two of its metabolites, sodium 2-propyl-4-pentenoate (4-en-VPA) and sodium 2-propyl-2-pentenoate (2-en-VPA), on the renal production of ammonia and on the renal uptake of glutamine, glutamate and of inhibitors of renal ammoniagenesis; mainly lactate, fatty acids, ketone bodies and alpha-ketoglutarate. Administration of VPA and 4-en-VPA stimulated the uptake of glutamine and glutamate and the production of ammonia by the rat kidney, resulting in an increase in the renal venous release of ammonia and in a hyperammonemia. By contrast, no hyperammonemia was observed after the administration of 2-en-VPA which stimulated renal ammoniagenesis to a lesser extent than VPA and 4-en-VPA, resulting in no stimulation of the renal venous release of ammonia. The three compounds tested caused, in a qualitatively different but, in terms of substrate carbons, in a quantitatively similar manner, a significant diminution of the renal uptake of fatty acids, ketone bodies and alpha-ketoglutarate. These results suggest that, in the rat kidney, VPA, 4-en-VPA and 2-en-VPA stimulate the production of ammonia at least in part by reducing the renal uptake and metabolism of ammoniagenesis inhibitors; the more potent stimulation of renal ammoniagenesis caused by VPA and 4-en-VPA also suggest that these compounds exert their stimulatory effect by an additional mechanism.

V-A and A-V modes in whole body and regional kinetics: domain of validity from a physiological model.

In turnover studies, both at whole body and regional level, sources of tracer and tracee are in general nonidentical thus resulting in nonuniformity of specific activity (SA). Guidelines are available in literature to deal with the heterogeneous SA problem, and either the V-A or A-V modes, based on the arterial and mixed venous blood SA, respectively, have been recommended for different substrates. In particular, the A-V mode is considered the method of choice for studying lactate, amino acids, free fatty acid, etc. Guidelines are based on specific models chosen to describe kinetic and circulatory events of the substance under study but are often conflicting. A unitary physiological framework to understand assumptions of various models is also lacking. In this paper, we first review these models to assess their domain of validity. In particular, we point out major drawbacks that relate to the tissue compartment being treated as a lumped well-mixed pool with a single SA value. We then attempt to handle the nonuniform tissue SA by employing a more physiological model. The tissue system is thought to be made up of elementary units connected in parallel and categorized according to their functional ability to affect incoming SA. Potential changes of SA within individual units are examined. Thus each tissue unit may provide a different contribution to the overall change in SA, as measured in mixed venous blood. A spatial profile of SA is also identified both along the direction of blood flow and transversely toward the inner cellular space. This distributed model allows assessment of the domain of validity of V-A and A-V modes. We show that, in general, the V-A mode underestimates the production rate both at whole body and regional level, whereas the A-V mode can either under- or overestimate it.

Regional blood-brain barrier transport of ketone bodies in portacaval-shunted rats.

The permeability of the blood-brain barrier to ketone bodies, substrates of the monocarboxylic acid carrier, was measured in individual brain structures of control and portacaval-shunted rats. The measurements were made 5-7 wk after the shunt or sham operation by quantitative autoradiography. Portacaval shunting caused the permeability to ketone bodies to decrease throughout the brain by approximately 70%. There was a striking change in the transport pattern in the cerebral cortex; deeper cortical layers were affected more than superficial layers. Ketone body consumption by brain is limited by the transport capacity of the monocarboxylic acid system. Therefore, in portacaval-shunted rats the very low activity of this system makes it unlikely that ketone bodies can make a substantial contribution during situations such as fasting. Likewise, other substrates of the monocarboxylic acid system, e.g., lactate and pyruvate, will have greatly restricted access to the brain after portacaval shunting. If the carrier is symmetrical, another consequence will be that exit of endogenously produced lactate will be retarded.

Effect of exercise on the disposal of infused ketone bodies in humans.

We previously reported that the stimulatory effect of exercise on the metabolic clearance of ketone bodies in postabsorptive subjects is abolished when plasma ketone body concentrations are elevated above 4 mmol/L by prior fasting. In this study we determined whether this process is related to fasting or to hyperketonemia itself. Eight normal postabsorptive subjects were rendered artificially hyperketonemic (approximately 6 mmol/L) by a constant infusion of acetoacetate and exercised moderately for 2 h. The kinetics of ketone bodies were determined with [14C]acetoacetate or beta-[14C]hydroxybutyrate. The metabolic clearance was slightly increased (approximately 25%) at the beginning of exercise, but this phenomenon was subsequently amplified by the progressive fall in ketonemia, which decreased to about 4 mmol/L at the end of exercise. Taking into account the fact that the metabolic clearance of ketones is inversely related to their concentration, it could be estimated that the direct effect of exercise on the metabolic clearance is negligible. Thus, the inability of exercise to enhance the metabolic clearance of ketones at high physiological plasma ketone levels is a general phenomenon that applies to both endogenous and exogenous ketosis.