Relationship between plasma and muscle concentrations of ketone bodies and free fatty acids in fed, starved and alloxan-diabetic states

Abstract

1. Concentrations of ketone bodies, free fatty acids and chloride in fed, 24-120h-starved and alloxan-diabetic rats were determined in plasma and striated muscle. Plasma glucose concentrations were also measured in these groups of animals. 2. Intracellular metabolite concentrations were calculated by using chloride as an endogenous marker of extracellular space. 3. The mean intracellular ketone-body concentrations (+/-s.e.m.) were 0.17+/-0.02, 0.76+/-0.11 and 2.82+/-0.50mumol/ml of water in fed, 48h-starved and alloxan-diabetic rats, respectively. Mean (intracellular water concentration)/(plasma water concentration) ratios were 0.47, 0.30 and 0.32 in fed, 48h-starved and alloxan-diabetic rats respectively. The relationship between ketone-body concentrations in the plasma and intracellular compartments appeared to follow an asymptotic pattern. 4. Only intracellular 3-hydroxybutyrate concentrations rose during starvation whereas concentrations of both 3-hydroxybutyrate and acetoacetate were elevated in the alloxan-diabetic state. 5. During starvation plasma glucose concentrations were lowest at 48h, and increased with further starvation. 6. There was no significant difference in the muscle intracellular free fatty acid concentrations of fed, starved and alloxan-diabetic rats. Mean free fatty acid intramuscular concentrations (+/-s.e.m.) were 0.81+/-0.08, 0.98+/-0.21 and 0.91+/-0.10mumol/ml in fed, 48h-starved and alloxan-diabetic states. 7. The intracellular ketosis of starvation and the stability of free fatty acid intracellular concentrations suggests that neither muscle membrane permeability nor concentrations of free fatty acids per se are major factors in limiting ketone-body oxidation in these states.

Rapid Intravenous Sodium Acetoacetate Infusion in Man METABOLIC AND KINETIC RESPONSES

“…The failure to correlate ketone body volumes of distribution with anatomical spaces (volumes) implies that these substrates are not homogenously distributed in the various water compartments of the body. Thus, our human studies support the experimental findings observed in tissue fragments (25)(26)(27) and in whole animals (38). However, the operational volume of distribution calculated here for ketone bodies is equal to that fluid volume in which these substrates would be dispersed if their concentrations were homogenous.…”

“…Although animal studies have shown concentration differences for ketone bodies between blood and various tissues (25)(26)(27), recent investigations have shown that for the bulk of the body the ketone body gradient between intracellular and extracellular water is constant (27). Since ketone bodies are not uniformly distributed in the body, actual volumes of distribution cannot be obtained by extrapolating the blood ketone body disappearance curves to time zero and calculating volumes of distribution.…”

Hepatic Ketogenesis and Gluconeogenesis in Humans

“…that remove ketone bodies from the blood (1-3). However, unlike kidney and brain, the utilization of ketone bodies by skeletal muscle is not dependent solely upon the arterial concentrations of these substrates (2,4). After a 3-and 24-day fast, total ketone-body (AcAc plus P-OHB) venous blood concentrations in obese subjects were about 2.5 and 7.5 mmolAiter, respectively (1,2,5).…”

Mechanism of Normochloremic and Hyperchloremic Acidosis in Diabetic Ketoacidosis

“…For example, if an individ ual retained 600 iriEq of a solute and its serum concentra tion increased by 20 mEq/1, the volume of distribution would be put at 600/20 = 30 liters. Since organic anions are distributed between cell and extracellular fluid ac cording to pH gradient, and since extracellular pH is higher than intracellular pH, the extracellular concentra tion of ketone anions is higher than the intracellular concentration, and hence the volume of distribution of ketone anions tends to be smaller than total body water [7][8][9], The volume of distribution of bicarbonate in meta bolic acidosis usually exceeds total body water, because (much of the H C 03 that enters the cells is titrated by cellular buffers [10]). The proportion of bicarbonate ti trated by cellular buffers increases progressively as aci dosis worsens, and hence its volume of distribution in creases progressively with decreasing concentrations of bicarbonate; the more severe the acidosis, the smaller the increase in serum H C03 for a given dose of H C03.…”