[The ketogenic diet: an underappreciated therapeutic option?]. / La dieta chetogenica: un'opportunità terapeutica ignorata?

Obesity is reaching epidemic proportions in Western countries and is a strong risk factor for cardiovascular disease. Despite the constant recommendations of health care organizations regarding the importance of weight control, this goal often fails. Although there is a common agreement about the concept that exercise and diet are two key factors for the control of body weight, the ideal amount and type of exercise and also the ideal diet for weight control are still under debate. A widely accepted nutritional regime is the Mediterranean diet that has evident health benefits although less attention has been paid to see if the effects are due to other lifestyle factors which may contribute to the health benefits perhaps as much as specific food choices. There are several other options available to the physician that may produce good weight loss results in the short/medium term and also for maintenance of the goal achieved. One of these strategies is the ketogenic diet or VLCKD (very low carbohydrate ketogenic diet) that has been widely studied in recent years. Most studies show that this diet has a solid physiological and biochemical basis which is able to induce effective weight loss and improvement of several parameters of cardiovascular risk. This review discusses the physiological basis of VLCKD and the main applications together with its strengths and weaknesses compared to common dietary recommendations.

Effects of three distinct protocols of fitness training on body composition, strength and blood lactate.

AIM: Circuit training is a very popular methodology in fitness program because it allows to join together cardiovascular and strength training. The purpose of this study was to determine the physiological effects of circuit training performed at different intensities on body composition, strength and blood lactate in middle-aged subjects who had recently undergone only minimum physical training. METHODS: Forty participants (aged 50-65) were assigned to a control group (CG) or to one of the three exercise treatment groups: Endurance Group (EG), Circuit-Low Intensity Group (CLG), Circuit-High Intensity Group (CHG). The three groups exercised three times per week, 50 min per session for 12 wk using EG (N.=10), CLG (N.=10) or CHG (N.=10). Pre- and post-training, participants RESULTS: Among the three groups, CHG showed the greatest reductions in body weight (BW), percentage of fat mass (FM), waistline, blood lactate (produced at 100 Watt during submaximal test) and greater improvement in 6RM in horizontal leg press and underhand cable pulldowns. CONCLUSION: The results obtained favored the conclusion that high-intensity exercise combined with endurance training in the circuit training technique is more effective than endurance training alone or low intensity circuit training in improving body composition, blood lactate, moreover CHG results in significantly greater strength increase compared to traditional circuit training.

Effect of ubidecarenone oral treatment on aerobic power in middle-aged trained subjects.

BACKGROUND: Coenzyme Q10 (CoQ10) plays an important role in oxidative mithocondrial phosphorylation and prevents lipid peroxidation in biological membranes. During sustained physical exercise, reactive oxygen species (ROS) production increase through several mechanism; one of them is the purine nucleotide cycle activation by shifting xanthine-dehydrogenase to xanthine-oxidase during AMP breakdown. The aim of this study was to evaluate the effect of CoQ10 treatment on aerobic power. EXPERIMENTAL DESIGN: according to a single blind study design, 28 health male cyclists were randomized into two groups (CoQ10 or placebo) and remained on treatments for eight weeks; there were 5 drop-outs and only 23 subjects were completely evaluated. Before and at the end of the eight weeks, cyclists underwent cardiopulmonary exercise testing. MEASURES: a software system performed the necessary calculations to obtain the following parameters: oxygen uptake, CO2 production, minute ventilation, oxygen ventilatory equivalent, carbon dioxide ventilatory equivalent, oxygen pulse. Finally oxygen peak and anaerobic threshold were determined. Moreover blood inosine, hypoxanthine, xanthine, lactate and CoQ10 levels were measured before and immediately after each test. RESULTS: The results of this study showed that at the end of the eight weeks there was no difference between the two groups concerning physiological and metabolic parameters, but muscular exhaustion was reached at higher workloads in the CoQ10 group. CONCLUSIONS: In our experience ubidecarenone oral treatment does not improve aerobic power. The little improvement of tolerance to higher workloads may be due to the antioxidant activity of CoQ10.

Elevated plasma homocysteine levels in centenarians are not associated with cognitive impairment.

BACKGROUND: Previous reports have shown elevated plasma total homocysteine (tHcy) levels in elderly person with impaired cognition. OBJECTIVE: To study the association between cognitive status and plasma tHcy levels in centenarians. DESIGN: Cross-sectional survey. SETTING: Centenarians living in two northern Italian provinces. PARTICIPANTS: Thirteen cognitively normal centenarians, ten cognitively impaired not-demented centenarians, and 34 demented centenarians with a clinical diagnosis of Alzheimer's disease (AD). MEASUREMENTS: Blood levels of homocysteine's biological determinants vitamin B12, folate, and vitamin B6. RESULTS: Elevated plasma tHcy levels (>17 micromol/l) were common in the general population (77% of normal centenarians, 100% of cognitively impaired not-demented centenarians, 82% of AD centenarians). Demented centenarians had the lowest folate serum levels. Low or borderline vitamin B12 serum levels (<221 pmol/l) and low vitamin B6 plasma levels (<11.7 nmol/l) were found in 33 and 66% of all centenarians independently of cognitive status. Among demented centenarians only plasma tHcy correlated inversely with both serum vitamin B12 and folate. No significant difference was found for plasma tHcy levels among the three diagnostic groups, even after adjusting for B vitamin levels. CONCLUSIONS: Hyperhomocysteinemia is very common among centenarians, probably due to vitamin deficiencies, but does not seem to be associated with cognitive impairment.

Oxidative stress and anti-oxidant metabolites in patients with hyperthyroidism: effect of treatment.

OBJECTIVE: Oxygen free radicals (OFR) play a role in the pathogenesis of tissue damage in many pathological conditions via the peroxidation of membrane phospholipids. Experimental studies showed an elevated oxidative stress during hyperthyroidism, which is reduced by treatment. Therapy per se might decrease oxidative stress. DESIGN: Fasting plasma levels of thiobarbituric acid reacting substances (TBARS), vitamin E and coenzyme Q10 were measured in 22 hyperthyroid patients, before treatment for their thyroid disease, after 13.9 [SD 9.2] weeks, when they achieved an euthyroid state on thyrostatic drugs, and again after 47.7 [21.0] weeks, off therapy. No patient presented additional risk factors for increased lipoperoxidation and/or increased OFR levels. Smokers were asked to abstain from smoking overnight. METHODS: All analytes were measured by HPLC. RESULTS: In hyperthyroidism, plasma levels of TBARS were increased, whereas vitamin E and coenzyme Q10 were reduced. Average levels of TBARS and antioxidant agents returned to normal in euthyroid patients, without differences in relation to stop of thyrostatic therapy. CONCLUSIONS: Our data confirm the presence of oxidative stress and decreased anti-oxidant metabolites in hyperthyroid patients, which are corrected in euthyroidism, without any influence of thyrostatic drugs per se. Nutritional support with antioxidant agents, which are defective during hyperthyroidism, is warranted.

Can oxypurines plasma levels classify the type of physical exercise?

BACKGROUND: A laboratory-based model able to describe muscle energy status during physical exercise and changes in myofibrillar composition in response to training would be desirable. Lactate and ammonia concentrations are not sufficient for a comprehensive knowledge of these systems. All muscle fibres, irrespective of the type, show ATP depletion and IMP accumulation following exhausting muscular exercise with quantitative differences due to the different concentrations of deaminase. We studied the plasma concentration of metabolites of oxypurine cascade to test their reliability to classify different exercises. METHODS: We studied 52 athletes, measuring plasma metabolites at the beginning and at the end of their specific field exercise (cycle pursuers, 8 cases; soccer players, 19; marathon runners, 25). K3EDTA-blood samples were assayed for plasma hypoxanthine, xanthine, and inosine, using an HPLC technique, as well as ammonia and lactate by means of enzymatic methods. RESULTS AND CONCLUSIONS: Basal oxypurines levels were not different in relation to any specific physical exercise. Post-exercise oxypurines, namely hypoxanthine, were more precise predictors of muscle energy exhaustion than strain intensity or duration. Plasma levels of hypoxanthine may be elevated also in the presence of normal xanthine and uric acid concentrations, due to an exhaustion of the enzymatic pathway, to a reduced activity of xanthine-oxidase or finally to a substrate-dependent inhibition of the process.

Plasma catecholamines in pre- and in postmenopausal women with mild to moderate essential hypertension.

The sympathetic nervous system (SNS) is thought to play an important role in the pathogenesis of essential hypertension and many studies have established a relationship between plasma levels of norepinephrine (NE) and epinephrine (E) and sympathetic nervous activity (SNA). Furthermore, it has been suggested that climacteric women are more exposed to psychosocial stress which can produce a transient rise in blood pressure (BP) and, with time, determine a hypertensive state. Plasma NE and E levels were measured at rest and after physiological stimulation (head-up tilt test) in 20 hypertensive (BP: 146 +/- 13/101 +/- 4 mm Hg) and in 20 normotensive women (BP: 132 +/- 7/85 +/- 4 mm Hg). Women in each of these two groups were further subdivided according to their climacteric status (10 premenopausal and 10 postmenopausal women). No difference in NE values at rest was found between groups and subgroups. During head-up tilt test, Ln NE plasma values increased in normotensive and hypertensive groups; the rise was significantly higher in hypertensive than in normotensive women (P < 0.01). In climacteric subgroups, Ln NE appeared markedly increased above resting levels in pre- and postmenopausal hypertensive women when their position was changed from supine to upright (P < 0.01). Since high plasma NE levels after stimulation (head-up tilt) are associated with sympathetic overactivity, we conclude that SNA is involved in the pathogenesis of essential hypertension in climacteric women.

May peripheral and central fatigue be correlated? Can we monitor them by means of clinical laboratory tools?

BACKGROUND: A laboratory-based model which links regional and central fatigue during physical exercise has not yet developed. Today we can assay the oxypurines, a specific and sensible marker of muscle cell-energy exhaustion during strenuous physical exercise, thus allowing us to insight in peripheral fatigue mechanisms. Prolonged physical exercise modifies plasma free amino acids and fatty acids levels, increases plasma free tryptophan (fTrp) and, conversely, probably serotonin, an amine involved in the genesis of central fatigue. We tried to verify if there is a correlation between central and peripheral fatigue. EXPERIMENTAL DESIGN: We studied 29 male marathon runners before marathon, at the arrival, one and three days after the run. MEASURES: Plasma samples were assayed for amino acids, fTrp serotonin, xanthine, hypoxanthine inosine, cortisol. Urine samples were assayed for serotonin and hydroxyin-doleacetic acid (5HIAA). RESULTS: After the competition we observed a decrease in plasma fTrp but an increased ratio fTrp/sum of neutral amino acids with a normalization after 24 hours. No significant changes were observed in plasma and urinary serotonin and 5HIAA. Hypoxanthine and inosine increased at the end of the trial and returned to basal levels the day after. Cortisol increased at the end of the run but was reduced after 24 and 72 hours. CONCLUSIONS: In our athletes we observed only indirect signs of fTrp involvement in the genesis of central fatigue. Oxypurines seem to be a good marker of regional muscular fatigue. Plasma cortisol expresses the stress reaction to the competition and its exhaustion after a prolonged physical exercise.

Reduced ubiquinone plasma levels in patients with liver cirrhosis and in chronic alcoholics.

Ubiquinone (CoQ10 coenzyme) is part of the respiratory chain in mitochondria, and acts as a scavenger in oxidative stress in cell membranes. Ubiquinone is mainly synthesized in the liver and partly derived from the diet; its plasma levels significantly correlate with tissue levels in experimental animals and in pathological states in man. By means of an original high-performance liquid chromatography technique, we measured ubiquinone plasma levels in 10 healthy subjects, in 27 patients with cirrhosis and in 22 chronic alcoholics with normal liver function. Ubiquinone levels were markedly reduced in cirrhosis (0.25 [SD 0.21] microgram/ml vs. 0.92 [0.38] in controls; P < 0.001), without any difference between alcohol- and non-alcohol-related disease. Also, in chronic alcoholics ubiquinone levels were nearly halved (0.49 [0.24]). In cirrhosis, ubiquinone plasma levels significantly correlated with cholesterol (P < 0.05), and with total bilirubin levels (P < 0.01). Our study highlights a remarkable deficiency in ubiquinone levels in patients with cirrhosis and in chronic alcoholics, to which both reduced hepatic synthesis and nutritional defects may contribute.

Exogenous CoQ10 preserves plasma ubiquinone levels in patients treated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

Ubiquinone is a carrier of the mitochondrial respiratory chain which regulates oxidative phosphorylation: it also acts as a membrane stabilizer preventing lipid peroxidation. In man the quinone ring originates from tyrosine, while the formation of the polyisoprenoid lateral chain starts from acetyl CoA and proceeds through mevalonate and isopentenylpyrophosphate; this biosynthetic pathway is the same as the cholesterol one. We therefore performed this study to evaluate whether statins (hypocholesterolemic drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase) modify blood levels of ubiquinone. Thirty unrelated outpatients with primary hypercholesterolemia (IIa phenotype) were treated with 20 mg of simvastatin for a 3-month period (group S) or with 20 mg of simvastatin plus 100 mg CoQ10 (group US). The following parameters were evaluated at time 0, and at 45 and 90 days: total plasma cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides, Apo A1, Apo B and CoQ10 in plasma and in platelets. In the S group, there was a marked decrease in total cholesterol low-density lipoprotein-cholesterol and in plasma CoQ10 levels from 1.08 mg/dl to 0.80 mg/dl. In contrast, in the US group we observed a significant increase of plasma CoQ10 (from 1.20 to 1.48 mg/dl) while the hypocholesterolemic effect was similar to that observed in the S group. Platelet CoQ10 also decreased in the S group (from 104 to 90 ng/mg) and increased in the US group (from 95 to 145 ng/mg).(ABSTRACT TRUNCATED AT 250 WORDS)

Exogenous CoQ10 supplementation prevents plasma ubiquinone reduction induced by HMG-CoA reductase inhibitors.

The biosynthetic pathway of the CoQ polyisoprenoid side chain, starting from acetyl-CoA and proceeding through mevalonate and isopentenylpyrophosphate, is the same as that of cholesterol. We performed this study to evaluate whether vastatins (hypocholesterolemic drugs that inhibit HMG-CoA reductase) modify blood levels of ubiquinone. Thirty-four unrelated outpatients with hypercholesterolemia (IIa phenotype) were treated with 20 mg of simvastatin for a 6-month period (group S) or with 20 mg of simvastatin plus 100 mg CoQ10 (group US). The following parameters were evaluated at time 0, 45, 90, 135 and 180 days: total plasma cholesterol (TC), HDL-cholesterol, LDL-cholesterol (LDL-C), triglycerides (TG), apo A1, apo B and CoQ10 in plasma and platelets. In the S group, there was a marked decrease in TC and LDL-C (from 290.3 mg/dl to 228.7 mg/dl for TC and from 228.7 mg/dl to 167.6 mg/dl for LDL-C) and in plasma CoQ10 levels from 1.08 mg/dl to 0.80 mg/dl. In contrast, in the US group we observed a significant increase of CoQ10 in plasma (from 1.20 to 1.48 mg/dl) while the hypocholesterolemic effect was similar to that observed in the S group. Platelet CoQ10 also decreased in the S group (from 104 to 90 ng/mg) and increased in the US group (from 95 to 145 ng/mg). This study demonstrates that simvastatin lowers both LDL-C and apo B plasma levels together with the plasma and platelet levels of CoQ10, and that CoQ10 therapy prevents both plasma and platelet CoQ10 decrease, without affecting the cholesterol lowering effect of simvastatin.

The use of phosphorus magnetic resonance spectroscopy to study in vivo the effect of coenzyme Q10 treatment in retinitis pigmentosa.

Phosphorus magnetic resonance spectroscopy (31P-MRS) has emerged as a noninvasive reliable tool for in vivo study of human tissue bioenergetics. It detects and quantifies some phosphorylated compounds present in millimolar concentration inside the cell, including ATP, phosphocreatine (PCr) and inorganic phosphate (Pi). By 31P-MRS we studied brain and skeletal muscle energy metabolism of three patients with retinitis pigmentosa before and after oral coenzyme Q10 (CoQ10) (100 mg/day). Before treatment we found a low PCr content in the brains of all patients, accompanied by a high [Pi] and high [ADP]. In two of three patients CoQ10 treatment resulted in a larger brain energy reserve mainly shown by an increased [PCr]. Abnormal muscle mitochondrial function was found only in one patient as shown by a reduced rate of PCr resynthesis after exercise. In this patient CoQ10 treatment resulted in an increased rate of PCr resynthesis. Our observations indicate that CoQ10 can improve mitochondrial functionality in the brain and skeletal muscle of patients with retinitis pigmentosa.

Improved high-performance liquid chromatographic method for the determination of coenzyme Q10 in plasma.

Coenzyme (Co) Q10 was dissociated from lipoproteins in plasma by treatment with methanol and extraction with n-hexane. Subsequent clean-up on silica gel and C18 solid-phase extraction cartridges with complete recovery (99 +/- 1.2%) produced a clean extract. High-performance liquid chromatographic (HPLC) separation was performed on a C18 reversed-phase column. Three simple, rapid procedures are presented: HPLC with final UV (275 nm) detection, a microanalysis utilizing a three-electrode electrochemical detector and a microanalysis with column-switching HPLC and electrochemical detection. The methods correlate very well with classical ethanol-n-hexane extraction with UV detection. The identity and purity of the Co Q10 peak were investigated and the resulting methods were concluded to be suitable for total plasma Co Q10 determination. The average level in healthy subjects was 0.80 +/- 0.20 mg/l; the minimum detectable Co Q10 plasma level was 0.05 and 0.005 mg/l for UV and electrochemical detection, respectively. The methods were applied to many samples and the plasma Co Q10 reference values for healthy subjects, athletes, hyperthyroid, hypothyroid and hypercholesterolaemic patients are given.

Improvements in automated analysis of catecholamine and related metabolites in biological samples by column-switching high-performance liquid chromatography.

Previously two fully automated methods based on column switching and high-performance liquid chromatography have been described, one for plasma and urinary catecholamines and the other for catecholamine urinary metabolites. Improvements in these methods, after 3 years of routine application, are now reported. The sample processing scheme was changed in order to eliminate memory effects and, in the procedure for plasma catecholamines, a pre-analytical deproteinization step was added which enhances the analytical column lifetime. The applied voltages for the electrochemical detector have been optimized, resulting in an automated method, suitable for the simultaneous determination of vanillylmandelic acid, 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid. The sensitivity of the methods allows the detection of 2-3 ng/l of plasma catecholamines and 0.01-0.06 mg/l of urinary metabolites. Also, it is possible to switch from one method to the other in only 30 min. The normal values obtained from 200 healthy people are reported, together with a list of 57 potential interfering substances tested.

Lipid abnormalities in insulin-dependent diabetic patients with albuminuria.

The relationship between serum lipid, lipoprotein, and apolipoprotein levels and abnormalities of renal function has been investigated in 112 insulin-dependent (type I) diabetic patients. They were subdivided into three matched groups according to the amount of albuminuria: group A (albuminuria less than 20 micrograms/min), group B (albuminuria between 20 and 150 micrograms/min; Albustix negative), and group C (albuminuria greater than 150 micrograms/min; Albustix positive). Twenty-one nondiabetic subjects with albuminuria above 150 micrograms/min but without nephrotic syndrome and/or renal failure and 77 healthy subjects were also studied. Mean total and LDL cholesterol, triglycerides, and apo B were higher, while HDL cholesterol and HDL/LDL cholesterol ratio were lower in group C than in groups A and B; the apo A/apo B ratio was lower in group C than in group A. Differences in apo B and in apo A/apo B ratio were found between groups A and B. No correlation between lipid parameters and amount of albuminuria was observed. Significant differences in lipid concentrations were also found in diabetic patients when compared with nondiabetic subjects with albuminuria and with healthy subjects. The present study confirmed previous reports of lipid disorders in insulin-dependent (type I) diabetes; however, the most important observation was the finding of albuminuria-related differences in lipid parameters in diabetic patients without renal failure. We think that the greater lipid abnormalities observed in diabetic patients with larger amounts of albuminuria might be the consequence both of impairment of glomerular permeability and of the diabetic state.