Ketone body metabolism: A physiological and clinical overview

Nosadini, R.; Avogaro, Angelo; Doria, Alessandro; Fioretto, Paola; Trevisan, Roberto; Morocutti, Anna

doi:10.1002/dmr.5610050307

Cited by 26 publications

(15 citation statements)

References 84 publications

(20 reference statements)

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“…Also, it is calculated under the assumption that all substrates taken up by the myocardium undergo complete oxidation in the steady state. Recent isotope-labeled substrate studies have shown that this is not exactly true (41,53,54). OER overestimates the glucose utilization because -13% is released as lactate (41), whereas lactate and fatty acid utilizations are underestimated.…”

Section: Discussionmentioning

confidence: 99%

Myocardial Carbohydrate, Ketone, and Fatty Acid Uptake in Conscious Lambs with Aortopulmonary Shunts1

et al. 1992

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ABSTRACT. A left to right shunt increases myocardial work and is often accompanied by increased catecholamine levels. Because both increased myocardial work and increased catecholamine levels may induce increased fatty acid utilization, which could increase resting myocardial oxygen consumption and therefore unfavorably affect coronary reserve, we studied myocardial uptake of glucose, pyruvate, lactate, &OH-butyrate, acetoacetate, FFA, and triglycerides in 12 7-wk-old lambs with aortopulmonary left to right shunts (58 f 2% of left ventricular output, mean f SEM) and in 10 control lambs 2 wk after surgery. Despite the shunt, systemic blood flow in the shunt lambs was maintained at the same level as in the control lambs. This was accomplished by an increased heart rate and stroke volume. Furthermore, the shunt was accompanied by an increased myocardial oxygen consumption in the shunt lambs (834 f 70 versus 528 f 43 pmol 02-mine' -100 g-I; p c 0.05). There were no significant differences in arterial substrate concentrations between the two groups. The same was true for arteriovenous differences across the myocardium, with the exception of lactate, which was substantially higher in shunt than in control lambs (72 f 25 versus 18 f 23 pmol/L; p < 0.05). As a consequence, myocardial lactate uptake in the shunt lambs was increased 15-fold (18 2 6 versus 1 f 2 pmol. min-I. 100 g-I; p c 0.02), whereas uptake of the other substrates merely paralleled the increased myocardial blood flow. Our data demonstrate that myocardial substrate uptake is not substantially different between shunt and control lambs, with the exception of lactate, of which the extraction is 10-fold higher than in control lambs. We speculate that the increased myocardial lactate utilization may reflect an increase of lactate and pyruvate dehydrogenase activities. A left to right shunt through a ventricular septa1 defect or ductus arteriosus imposes an increased work load on the heart because of its effect on left ventricular wall stress, external work, contractility, and heart rate (1-3). This effect is accompanied by an increased myocardial oxygen consumption (3), which reflects increased oxidation of substrates to meet the increased ATP demand (4). Often, an increased work load leads not only to increased substrate uptake, but also to a change in the pattern of myocardial substrate utilization (5), as has been shown in hearts with increased afterload (6), contractility (7), and thyroxineinduced volume load (8, 9) and during exercise (5,(10)(11)(12). Furthermore, catecholamines are often increased in the presence of a substantial left to right shunt (13), and they are also known to affect myocardial metabolism (14,15). Through their effect on myocardial performance, catecholamines stimulate glucose and fatty acid utilization by the myocardium, and, through activation of lipoprotein lipase, they enhance fatty acid utilization (5, [14][15][16].These considerations suggest that a left to right shunt could lead to a change in myocardial substrate metabolism....

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Section: Discussionmentioning

confidence: 99%

Myocardial Carbohydrate, Ketone, and Fatty Acid Uptake in Conscious Lambs with Aortopulmonary Shunts1

et al. 1992

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“…It has been speculated that products of ketoacidosis present in poorly controlled type 1 diabetes subjects could induce g-globin gene expression, thus increasing HbF levels. Although type 2 diabetes patients are ketosis-resistant (16), several reports have shown that type 2 diabetes patients with poor metabolic control present increased circulating levels of short-chain fatty acids (17)(18)(19)(20)(21). Clearly, these mechanisms must be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Fetal hemoglobin levels are related to metabolic control in diabetic subjects

Pardini¹,

Victoria

Pieroni

et al. 1999

Braz J Med Biol Res

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We have investigated the relationship between fetal hemoglobin (HbF) levels and metabolic control in subjects with insulin-dependent (N = 79) and non-insulin-dependent diabetes mellitus (N = 242). HbF and hemoglobin A1c (HbA1c) levels were increased in subjects with type 1 and type 2 diabetes as compared to levels in nondiabetic individuals (P<0.0001), and were significantly higher in type 1 than in type 2 diabetes subjects. Lower levels of HbA1c and HbF were observed in type 2 diabetes subjects treated by diet, intermediate levels in those treated with oral hypoglycemic agents, and higher levels in those treated with insulin. HbF and HbA1c levels were correlated in type 1 diabetes (R 2 = 0.57, P<0.0001) and type 2 diabetes (R 2 = 0.58, P<0.0001) subjects. Following intense treatment, twelve diabetic patients showed significant improvement both in HbA1c and HbF values. We conclude that increased HbF levels reflect poor metabolic control in subjects with diabetes mellitus.

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“…Literature reported processes for elimination of ketones include (1) irreversible conversion of AcAc to acetone (via decarboxylation) in the blood and the liver, to be excreted from the lungs, (2) renal elimination of unchanged BHB and AcAc, which escape tubular reabsorption in the kidneys (18) and (3) uptake and consumption to produce energy (ATP) via the citric acid cycle in peripheral tissues such as the brain, skeletal muscle and heart (40). These known mechanisms of consumption and elimination support the quantitatively different mechanisms of elimination that were observed for BHB here.…”

Section: In This Study We Have Developed a Population Pk M O D E L Tmentioning

confidence: 99%

The Population Pharmacokinetics of d-β-hydroxybutyrate Following Administration of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate

Shivva

Cox

Clarke

et al. 2016

AAPS J

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Abstract. The administration of ketones to induce a mild ketosis is of interest for the alleviation of symptoms associated with various neurological disorders. This study aimed to understand the pharmacokinetics (PK) of D-β-hydroxybutyrate (BHB) and quantify the sources of variability following a dose of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (ketone monoester). Healthy volunteers (n = 37) were given a single drink of the ketone monoester, following which, 833 blood BHB concentrations were measured. Two formulations and five dose levels of ketone monoester were used. A nonlinear mixed effect modelling approach was used to develop a population PK model. A one compartment disposition model with negative feedback effect on endogenous BHB production provided the best description of the data. Absorption was best described by two consecutive first-order inputs and elimination by dual processes involving first-order (CL = 10.9 L/h) and capacity limited elimination (V max = 4520 mg/h). Covariates identified were formulation (on relative oral bioavailable fraction and absorption rate constant) and dose (on relative oral bioavailable fraction). Lean body weight (on first-order clearance) and sex (on apparent volume of distribution) were also significant covariates. The PK of BHB is complicated by complex absorption process, endogenous production and nonlinear elimination. Formulation and dose appear to strongly influence the kinetic profile following ketone monoester administration. Further work is needed to quantify mechanisms of absorption and elimination of ketones for therapeutic use in the form of ketone monoester.

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Ketone body metabolism: A physiological and clinical overview

Cited by 26 publications

References 84 publications

Myocardial Carbohydrate, Ketone, and Fatty Acid Uptake in Conscious Lambs with Aortopulmonary Shunts1

Myocardial Carbohydrate, Ketone, and Fatty Acid Uptake in Conscious Lambs with Aortopulmonary Shunts1

Fetal hemoglobin levels are related to metabolic control in diabetic subjects

The Population Pharmacokinetics of d-β-hydroxybutyrate Following Administration of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate

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