Timing matters: diurnal variation of maximal fat oxidation and substrate oxidation rates in metabolic syndrome-a randomized crossover study.

PURPOSE: The aim of this study was to investigate if diurnal oscillation in maximal fat oxidation (MFO) and substrate oxidation rates during exercise exists in subjects with metabolic syndrome (MetS). METHODS: In a randomized crossover design, 14 MetS patients were assigned to two graded exercise tests conditions performed in the morning (between 7:00 and 9:00 a.m) and in the afternoon (between 4:00 and 5:00 p.m). MFO was defined as the highest absolute value of fat oxidation obtained from the average of last 2-min stages during an indirect calorimetry test. RESULTS: MFO increased by 20.6% from morning to afternoon (p = 0.0002, Cohen's d = 0.52). There was a significant time of day, (p < 0.0001, η2p = 0.76) and intensity effect (p = 0.002, η2p = 0.32) in fat oxidation (Fatox) rates indicating that Fatox was higher in the afternoon than in the morning. CONCLUSION: Our study extends previous findings on the existence of diurnal variation in maximal fat oxidation to MetS patients, highlighting the afternoon as a more favorable time for fat utilization during exercise. These findings have practical implications for optimizing training timing in MetS patients. TRIAL REGISTRATION NUMBER: PACTR202306776991260.

Which sub-compartments of fat mass and fat-free mass are related to blood viscosity factors?

The size of body compartments is a determinant of several factors of blood viscosity. Red cell aggregation is proportional to fat mass while hematocrit is proportional to both fat-free mass and abdominal adiposity, but which parts of these body components are involved in this relationship is not known. Segmental bioelectrical impedance analysis (sBIA) provides a possibility to delineate the relationships more precisely between various subdivisions of the body and blood viscosity factors, going farther than preceding studies using non segmental BIA. In this study we investigated in 38 subjects undergoing a standardized breakfast test with mathematical modelling of glucose homeostasis and a segmental bioelectrical impedance analysis (sBIA) the relationships between the various compartments of the body and viscosity factors. Blood and plasma viscosity were measured with the Anton Paar rheometer and analyzed with Quemada's model. The parameters better correlated to hematocrit are fat free mass (r = 0.562) and its two components muscle mass (r = 0.516) and non-muscular fat-free mass (r = 0.452), and also trunk fat mass (r = 0.383) and waist-to hip ratio (r = 0.394). Red cell aggregation measurements were correlated with both truncal and appendicular fat mass (r ranging between 0.603 and 0.728). Weaker correlations of M and M1 are found with waist circumference and hip circumference. This study shows that the correlation between lean mass and hematocrit involves both muscle and non-muscle moieties of lean mass, and that both central and appendicular fat are determinants of red cell aggregation.

Toward Exercise Guidelines for Optimizing Fat Oxidation During Exercise in Obesity: A Systematic Review and Meta-Regression.

BACKGROUND: Exercise training performed at maximal fat oxidation (FATmax) is an efficient non-pharmacological approach for the management of obesity and its related cardio-metabolic disorders. OBJECTIVES: Therefore, this work aimed to provide exercise intensity guidelines and training volume recommendations for maximizing fat oxidation in patients with obesity. METHODS: A systematic review of original articles published in English, Spanish or French languages was carried out in EBSCOhost, PubMed and Scopus by strictly following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Those studies that analyzed maximal fat oxidation (MFO) and FATmax in patients with obesity (body fat > 25% for men; > 35% for women) by calculating substrate oxidation rates through indirect calorimetry during a graded exercise test with short-duration stages (< 10 min) were selected for quantitative analysis. The accuracy of relative oxygen uptake (% peak oxygen uptake [%[Formula: see text]O2peak]) and relative heart rate (% peak heart rate [%HRpeak]) for establishing FATmax reference values was investigated by analyzing their intra-individual and inter-study variation. Moreover, cluster analysis and meta-regression were used for determining the influence of biological factors and methodological procedures on MFO and FATmax. RESULTS: Sixty-four manuscripts were selected from 146 records; 23 studies only recruited men (n = 465), 14 studies only evaluated women (n = 575), and 27 studies included individuals from both sexes (n = 6434). The majority of the evaluated subjects were middle-aged adults (aged 40-60 y; 84%) with a poor cardiorespiratory fitness (≤ 43 mL·kg-1·min-1; 81%), and the reported MFO ranged from 0.27 to 0.33 g·min-1. The relative heart rate at FATmax (coefficient of variation [CV]: 8.8%) showed a lower intra-individual variation compared with relative oxygen uptake (CV: 17.2%). Furthermore, blood lactate levels at FATmax ranged from 1.3 to 2.7 mmol·L-1 while the speed and power output at FATmax fluctuated from 4 to 5.1 km·h-1 and 42.8-60.2 watts, respectively. Age, body mass index, cardiorespiratory fitness, FATmax, the type of ergometer and the stoichiometric equation used to calculate the MFO independently explained MFO values (R2 = 0.85; p < 0.01). The MFO in adolescents was superior in comparison with MFO observed in young and middle-aged adults. On the other hand, the MFO was higher during treadmill walking in comparison with stationary cycling. Body fat and MFO alone determined 29% of the variation in FATmax (p < 0.01), noting that individuals with body fat > 35% showed a heart rate of 61-66% HRpeak while individuals with < 35% body fat showed a heart rate between 57 and 64% HRpeak. Neither biological sex nor the analytical procedure for computing the fat oxidation kinetics were associated with MFO and FATmax. CONCLUSION: Relative heart rate rather than relative oxygen uptake should be used for establishing FATmax reference values in patients with obesity. A heart rate of 61-66% HRpeak should be recommended to patients with > 35% body fat while a heart rate of 57-64% HRpeak should be recommended to patients with body fat < 35%. Moreover, training volume must be higher in adults to achieve a similar fat oxidation compared with adolescents whereas exercising on a treadmill requires a lower training volume to achieve significant fat oxidation in comparison with stationary cycling.

Cystatin C for kidney function assessment in patients with facioscapulohumeral muscular dystrophy.

BACKGROUND AND AIMS: Muscle mass (MM) impairment observed in facioscapulohumeral muscular dystrophy (FSHD) may bias estimated glomerular filtration rate (eGFR) based on creatinine (eGFRcreat). eGFR based on cystatin C (eGFRcys), produced by all nucleated cells, should be an interesting alternative. Main objectives were to compare eGFRcreat and eGRFcys for chronic kidney disease (CKD) staging and for annual eGFR evolution. Secondary objective was to analyse creatinine, cystatin C with measured MM. MATERIAL AND METHODS: During 4 years, 159 FSHD patients having one or more creatinine and cystatin C measurements (total samples: n = 379), with MM determination by bio-impedancemetry during their follow-up were included. eGFR were determined with CKD-Epi and EKFC equations. RESULTS: On first examination samples, mean eGFRcys was significantly lower than mean eGFRcreat of 25.5 and 17.9 ml/min/1.73 m2 using CKD-Epi and EKFC equations, respectively. 53.5% (CKD-Epi) and 59.1% (EKFC) of agreement were obtained when using eGFRcys instead of eGFRcreat with reclassifications occurring mainly towards more severe stages. Age was correlated with cystatin C but not with creatinine, MM was correlated with creatinine but not with cystatin C. eGFR decreases > 1 ml/min/1.73 m2 were more important when using eGFRcys instead of eGFRcreat (CKD-Epi: 37.5 vs 15.4%, p < 0.001; EKFC: 34.6 vs 20.2%, p < 0.01). CONCLUSION: Cystatin C which is independent of MM appears as a promising candidate biomarker for CKD diagnosis and follow-up in FSHD patient.

Beyond the Calorie Paradigm: Taking into Account in Practice the Balance of Fat and Carbohydrate Oxidation during Exercise?

Recent literature shows that exercise is not simply a way to generate a calorie deficit as an add-on to restrictive diets but exerts powerful additional biological effects via its impact on mitochondrial function, the release of chemical messengers induced by muscular activity, and its ability to reverse epigenetic alterations. This review aims to summarize the current literature dealing with the hypothesis that some of these effects of exercise unexplained by an energy deficit are related to the balance of substrates used as fuel by the exercising muscle. This balance of substrates can be measured with reliable techniques, which provide information about metabolic disturbances associated with sedentarity and obesity, as well as adaptations of fuel metabolism in trained individuals. The exercise intensity that elicits maximal oxidation of lipids, termed LIPOXmax, FATOXmax, or FATmax, provides a marker of the mitochondrial ability to oxidize fatty acids and predicts how much fat will be oxidized over 45-60 min of low- to moderate-intensity training performed at the corresponding intensity. LIPOXmax is a reproducible parameter that can be modified by many physiological and lifestyle influences (exercise, diet, gender, age, hormones such as catecholamines, and the growth hormone-Insulin-like growth factor I axis). Individuals told to select an exercise intensity to maintain for 45 min or more spontaneously select a level close to this intensity. There is increasing evidence that training targeted at this level is efficient for reducing fat mass, sparing muscle mass, increasing the ability to oxidize lipids during exercise, lowering blood pressure and low-grade inflammation, improving insulin secretion and insulin sensitivity, reducing blood glucose and HbA1c in type 2 diabetes, and decreasing the circulating cholesterol level. Training protocols based on this concept are easy to implement and accept in very sedentary patients and have shown an unexpected efficacy over the long term. They also represent a useful add-on to bariatric surgery in order to maintain and improve its weight-lowering effect. Additional studies are required to confirm and more precisely analyze the determinants of LIPOXmax and the long-term effects of training at this level on body composition, metabolism, and health.

Biomarkers of Redox Balance Adjusted to Exercise Intensity as a Useful Tool to Identify Patients at Risk of Muscle Disease through Exercise Test.

The screening of skeletal muscle diseases constitutes an unresolved challenge. Currently, exercise tests or plasmatic tests alone have shown limited performance in the screening of subjects with an increased risk of muscle oxidative metabolism impairment. Intensity-adjusted energy substrate levels of lactate (La), pyruvate (Pyr), ß-hydroxybutyrate (BOH) and acetoacetate (AA) during a cardiopulmonary exercise test (CPET) could constitute alternative valid biomarkers to select "at-risk" patients, requiring the gold-standard diagnosis procedure through muscle biopsy. Thus, we aimed to test: (1) the validity of the V'O2-adjusted La, Pyr, BOH and AA during a CPET for the assessment of the muscle oxidative metabolism (exercise and mitochondrial respiration parameters); and (2) the discriminative value of the V'O2-adjusted energy and redox markers, as well as five other V'O2-adjusted TCA cycle-related metabolites, between healthy subjects, subjects with muscle complaints and muscle disease patients. Two hundred and thirty subjects with muscle complaints without diagnosis, nine patients with a diagnosed muscle disease and ten healthy subjects performed a CPET with blood assessments at rest, at the estimated 1st ventilatory threshold and at the maximal intensity. Twelve subjects with muscle complaints presenting a severe alteration of their profile underwent a muscle biopsy. The V'O2-adjusted plasma levels of La, Pyr, BOH and AA, and their respective ratios showed significant correlations with functional and muscle fiber mitochondrial respiration parameters. Differences in exercise V'O2-adjusted La/Pyr, BOH, AA and BOH/AA were observed between healthy subjects, subjects with muscle complaints without diagnosis and muscle disease patients. The energy substrate and redox blood profile of complaining subjects with severe exercise intolerance matched the blood profile of muscle disease patients. Adding five tricarboxylic acid cycle intermediates did not improve the discriminative value of the intensity-adjusted energy and redox markers. The V'O2-adjusted La, Pyr, BOH, AA and their respective ratios constitute valid muscle biomarkers that reveal similar blunted adaptations in muscle disease patients and in subjects with muscle complaints and severe exercise intolerance. A targeted metabolomic approach to improve the screening of "at-risk" patients is discussed.

Metabolic Influences Modulating Erythrocyte Deformability and Eryptosis.

Many factors in the surrounding environment have been reported to influence erythrocyte deformability. It is likely that some influences represent reversible changes in erythrocyte rigidity that may be involved in physiological regulation, while others represent the early stages of eryptosis, i.e., the red cell self-programmed death. For example, erythrocyte rigidification during exercise is probably a reversible physiological mechanism, while the alterations of red blood cells (RBCs) observed in pathological conditions (inflammation, type 2 diabetes, and sickle-cell disease) are more likely to lead to eryptosis. The splenic clearance of rigid erythrocytes is the major regulator of RBC deformability. The physicochemical characteristics of the surrounding environment (thermal injury, pH, osmolality, oxidative stress, and plasma protein profile) also play a major role. However, there are many other factors that influence RBC deformability and eryptosis. In this comprehensive review, we discuss the various elements and circulating molecules that might influence RBCs and modify their deformability: purinergic signaling, gasotransmitters such as nitric oxide (NO), divalent cations (magnesium, zinc, and Fe2+), lactate, ketone bodies, blood lipids, and several circulating hormones. Meal composition (caloric and carbohydrate intake) also modifies RBC deformability. Therefore, RBC deformability appears to be under the influence of many factors. This suggests that several homeostatic regulatory loops adapt the red cell rigidity to the physiological conditions in order to cope with the need for oxygen or fuel delivery to tissues. Furthermore, many conditions appear to irreversibly damage red cells, resulting in their destruction and removal from the blood. These two categories of modifications to erythrocyte deformability should thus be differentiated.

Impact of a Mobile Telerehabilitation Solution on Metabolic Health Outcomes and Rehabilitation Adherence in Patients With Obesity: Randomized Controlled Trial.

BACKGROUND: Obesity is a major public health issue. Combining exercise training, nutrition, and therapeutic education in metabolic rehabilitation (MR) is recommended for obesity management. However, evidence from randomized controlled studies is lacking. In addition, MR is associated with poor patient adherence. Mobile health devices improve access to MR components. OBJECTIVE: The aim of this study is to compare the changes in body composition, anthropometric parameters, exercise capacity, and quality of life (QOL) within 12 weeks of patients in the telerehabilitation (TR) program to those of usual care patients with obesity. METHODS: This was a parallel-design randomized controlled study. In total, 50 patients with obesity (BMI>30 kg/m²) were included in a TR group (TRG) or a usual care group (UCG) for 12 weeks. Patients underwent biometric impedance analyses, metabolic exercise tests, actimetry, and QOL and satisfaction questionnaires. The primary outcome was the change in fat mass at 12 weeks from baseline. Secondary outcomes were changes in body weight, metabolic parameters, exercise capacity, QOL, patients' adhesion, and satisfaction. RESULTS: A total of 49 patients completed the study. No significant group × time interaction was found for fat mass (TRG: mean 1.7 kg, SD 2.6 kg; UCG: mean 1.2 kg, SD 2.4 kg; P=.48). Compared with the UCG, TRG patients tended to significantly improve their waist to hip ratios (TRG: -0.01 kg, SD 0.04; UCG: +0.01 kg, SD 0.06; P=.07) and improved QOL physical impact (TRG: +21.8, SD 43.6; UCG: -1.2, SD 15.4; P=.005). Significant time effects were observed for body composition, 6-minute walk test distance, exercise metabolism, sedentary time, and QOL. Adherence (95%) and satisfaction in the TRG were good. CONCLUSIONS: In adults with obesity, the TR program was not superior to usual care for improving body composition. However, TR was able to deliver full multidisciplinary rehabilitation to patients with obesity and improve some health outcomes. Given the patients' adherence and satisfaction, pragmatic programs should consider mobile health devices to improve access to MR. Further studies are warranted to further establish the benefits that TR has over usual care. TRIAL REGISTRATION: ClinicalTrials.gov NCT03396666; http://clinicaltrials.gov/ct2/show/NCT03396666.

Shear-dependency of the predicted ideal hematocrit.

 The ideal hematocrit is the hematocrit (Hct) value resulting in the highest value of Hct/viscosity (h/η) ratio and can thus be predicted from viscometric measurements with the use of equations such as Quemada's one which yield the determination of the bell-shaped curve of h/η as a function of Hct. In a series of recent papers we applied this approach to various populations, using viscometry at high shear rate (1000 s-1). However the shape of this curve has been reported to be dependent on the shear rate, resulting in a right-shift in this top value when Hct increase. We present here in 11 young recreative athletes the evolution of the predicted top of the h/η curve and optimal theoretical Hct and the discrepancy between theoretical and optimal values over the range of shear rates 1 to 6000 s-1. Results show that the predicted optimal value of both h/η and Hct increases when shear rate increases and that the discrepancy between predicted laquooptimalraquo and actual values decreases and becomes almost asymptotic at very high shear (500 s-1). It is minimal at 2720 s-1. The correlation between predicted laquooptimalraquo and actual values of both parameters describes the same evolution. Therefore, it is better for assessing h/η and its agreement with theoretical values, and for determining the theoretical ideal hematocrit, to measure blood viscosity at shear rates equal or superior to 500 s-1.

Fetal growth retardation and hemorheological predictors of oxygen delivery in hypertensive vs normotensive pregnant women.

Physiological modifications of blood rheology during pregnancy and their alterations in pregnant hypertensive women have been extensively studied in the 1980's. Since vascular resistance is higher in hypertensive pregnant women whose newborns are small-for gestational-age (SGA), we investigated in a personal database if growth retardation of newborns is related to the oxygen delivery index (ratio hematocrit/blood viscosity) and to the difference between hematocrit (Hct) and the prediction of its optimal valued based on Quemada's equation. A sample of 38 hypertensive pregnant women (age 29 yr±1) was compared with 64 controls matched for age and gestational age, studied at 35±1 weeks gestation, extracted from a larger series of 162 pregnant women. On the whole the hypertensive group gave birth to smaller children (p = 0.014). Plasma viscosity correlated with blood pressure (BP) only in hypertensive women (r = 0.403 p < 0.05). The bell-shaped curve of predicted optimal Hct of non hypertensive pregnant women was similar to that of non-pregnant women, but in hypertensive women it was shifted toward higher values (p = 0.07), and the predicted optimal Hct (but not the actual one) was correlated with systolic blood pressure (SBP) (r = 0.349 p < 0.001) and diastolic blood pressure (DBP) (r = 0.218 p < 0.05). The predicted optimal Hct/viscosity (h/η) ratio was higher in hypertensive women whose newborns exhibited a low birth weight (p = 0.03), resulting in a higher discrepancy between actual and model-predicted «ideal¼ values of h/η ratio (p = 0.03) and Hct (p = 0.02) compared with the subgroup with no growth retardation. Therefore, in hypertensive women whose newborns exhibited a low birth weight, hemorheological parameters predicting oxygen supply are shifted to lower values than predicted by the model.

Leg electrical resistance predicts venous blood viscosity and hematocrit.

 We previously reported that whole body bioelectrical impedance analysis (BIA) measurements are correlated to some hemorheologic factors, suggesting a relationship between viscosity factors and electric properties of flowing blood not only in vitro but also in vivo. Recently we reported that with segmental BIA (analyzing the body considered as composed of 5 cylinders) predictive equations for various determinants of blood viscosity were closer than for the wole body. Another widely used BIA technique uses leg-to-leg impedance measurements so that two cylinders (the two legs) are analyzed. We investigated whether impedance measured with this technique (Tanita TBF-300) is also a predictor of blood viscosity factors. From viscometric measurements performed on venous blood drawn in recreative athletes over the range of shear rates 1 to 6000 s-1 (RHEOMETRE Anton Paar CP 50-1), we found a correlation between leg-leg resistance at 50 kHz (Rx[50 kHz]) and blood viscosity at 1000 s-1 (η1000= 0.0051 Rx[50 kHz] + 1.3265; r = 0.521 p = 0.028 yielding a prediction of η1000 (Bland Altman plot: bias 0.05 [RANGE - 0.24; 0.34]. Neither plasma viscosity nor the red cell rheology index «k¼ of Quemada's model are correlated with Rx[50 kHz], but hematocrit (Hct) does (Hct (%) = 0.0217 Rx[50 kHz] + 33.783; r = 0.480 p = 0.044) yielding a prediction of Hct (Bland Altman plot: bias - 0.11, [range - 1.67; 1.45]. The discrepancy between actual and predicted Hct is also correlated with resistance at 50 kHz (r = 0.575 p = 0.031) as does the discrepancy between actual and predicted Hct/viscosity ratio (r = -0.651 p = 0.006). Therefore, as other previously studied methods, leg to leg BIA predicts viscosity, suggesting that blood rheology may influence the passage of an electric current in the legs.

Fine-scale haplotype mapping of MUT, AACS, SLC6A15 and PRKCA genes indicates association with insulin resistance of metabolic syndrome and relationship with branched chain amino acid metabolism or regulation.

Branched chain amino acids (BCAA) are essential elements of the human diet, which display increased plasma levels in obesity and regained particular interest as potential biomarkers for development of diabetes. To define determinants of insulin resistance (IR) we investigated 73 genes involved in BCAA metabolism or regulation by fine-scale haplotype mapping in two European populations with metabolic syndrome. French and Romanians (n = 465) were genotyped for SNPs (Affymetrix) and enriched by imputation (BEAGLE 4.1) at 1000 genome project density. Initial association hits detected by sliding window were refined (HAPLOVIEW 3.1 and PHASE 2.1) and correlated to homeostasis model assessment (HOMAIR) index, in vivo insulin sensitivity (SI) and BCAA plasma levels (ANOVA). Four genomic regions were associated with IR located downstream of MUT, AACS, SLC6A15 and PRKCA genes (P between 9.3 and 3.7 x 10-5). Inferred haplotypes up to 13 SNPs length were associated with IR (e.g. MUT gene with P < 4.9 x 10-5; Bonferroni 1.3 x 10-3) and synergistic to HOMAIR. SNPs in the same regions were also associated with one order of magnitude lower P values (e.g. rs20167284 in the MUT gene with P < 1.27 x 10-4) and replicated in Mediterranean samples (n = 832). In French, influential haplotypes (OR > 2.0) were correlated with in vivo insulin sensitivity (1/SI) except for SLC6A15 gene. Association of these genes with BCAA levels was variable, but influential haplotypes confirmed implication of MUT from BCAA metabolism as well as a role of regulatory genes (AACS and PRKCA) and suggested potential changes in transcriptional activity. These data drive attention towards new regulatory regions involved in IR in relation with BCAA and show the ability of haplotypes in phased DNA to detect signals complimentary to SNPs, which may be useful in designing genetic markers for clinical applications in ethnic populations.

Seeking the optimal hematocrit: May hemorheological modelling provide a solution?

Hematocrit increases during exercise and is usually decreased after regular training. However the interpretation of these facts is ambiguous since hematocrit is both a determinant of oxygen supply and the major determinant of blood viscosity. Classically hematocrit was assumed to impair blood flow, but it has been evidenced to exert a biphasic effect on it. In order to cope with these two apparently opposite effects of hematocrit, hemorheologists have proposed the concept hematocrit/viscosity ratio (h/η). This h/η ratio is related to tissue oxygenation in vascular diseases (eg, POAD) but not in healthy subjects. h/η displays a bell-shaped curve as a function of hematocrit and the hematocrit value corresponding to the maximal h/η can be assumed to be a theoretically optimal hematocrit. We propose to analyse exercise-related alterations in hematocrit according to this theoretical approach, viscosity at high shear rate being reconstructed with Quemada's equation from actual plasma viscosity and red cell rigidity at various hematocrit levels. While theoretical and actual h/η are fairly correlated in athletes both before and after exercise, actual hematocrit is lower at rest and higher after exercise compared to the theoretical one. The main statistic correlate of these discrepancies between actual and predicted hematocrit is red cell rigidity. Submaximal exercise acutely decreases the h/η ratio (despite increasing both hematocrit and viscosity). This change is well predicted by the model and there is a strong correlation between predicted and actual h/η ratio. Endurance training tends to increase h/η and to reduce the discrepancy between predicted and actual hematocrit. Accordingly trained athletes have a higher h/η (both model-predicted and actual) than sedentary subjects, and a lower hematocrit, this lowering being rather correlated to training volume than to fitness improvement. On the whole, this approach suggests that homeostatic "viscoregulation" in athletes results in a fine tuning of h/η which seems to be a closely regulated parameter. Hematocrit alterations in this context are an adaptation involved in this regulation.

The Second Phase of Insulin Secretion in Nondiabetic Islet-Grafted Recipients Is Altered and Can Predict Graft Outcome.

Context: Islet transplantation (IT) can treat patients with severely unstable type 1 diabetes. Prehepatic kinetics of insulin secretion (ISec) in two phases can be calculated by C-peptide levels during meal tests. We proposed to describe the ISec profile after a mixed-meal tolerance test (MMTT) in IT recipients and to determine whether the calculated ISec indexes can predict graft outcome. Methods: We analyzed 34 MMTT among 11 patients who underwent IT between 2011 and 2016 and compared them with healthy controls and patients with type 2 diabetes (T2D). ISec indexes and insulin sensitivity were calculated from models of Van Cauter, Breda, and Mari after MMTT. Graft success was defined by total insulin independence without any criteria for diabetes. Results: In patients with successful IT, the first- and second-phase ISec indexes were lower than those of controls (P < 0.001) and did not differ from those of the T2D group. Nevertheless, insulin sensitivity of IT recipients was similar to that of the control group and higher than that of the T2D group. The index of the second phase of ISec ɸS was correlated with total infused islet equivalents (IEQs), was a good predictor of diabetes (re)occurrence, and allowed us to calculate 9500 IEQ/kg as the minimum needed to reach insulin independence. Conclusion: We showed that indexes from the first and second phases of ISec are altered in insulin-independent IT recipients. Higher sensitivity distinguishes them from patients with T2D. Even in insulin-independent patients, IT remains a marginal mass model. Moreover, ɸS can estimate transplanted islet mass and predict IT recipient outcomes.

Blood rheology as a mirror of endocrine and metabolic homeostasis in health and disease1.

Rheological properties of plasma and blood cells are markedly influenced by the surrounding milieu: physicochemical factors, metabolism and hormones. Acid/base status, osmolality, lipid status, plasma protein pattern, oxidative stress induced by increased free radicals production, endothelium-derived factors such as nitric oxide (NO), achidonic acid derivatives modulate both red blood cell (RBC) and white cell mechanics. Therefore, regulatory axes involving liver, endothelium, kidney, pancreas, adrenal gland, endocrine heart, adipose tissue, pituitary gland, and surely other tissues play important roles in the regulation of blood fluidity. A comprehensive picture of all this complex network of regulatory loops is still unavailable but current progress of knowledge suggest that some attempts can currently be made.

Oxidative mechanisms at rest and during exercise.

Carbohydrates (CHO) and lipids provide the amount of energy required for physical and chemical reactions inside the human body. The various constraints the body has to resolve explain the use of these two substrates, catabolized via distinct pathways to one common final reaction. In the classic model, three main organs/tissues for substrate fluxes (liver, adipose tissue and skeletal muscle) and one organ regulating main reactions by adaptation of hormonal secretions (endocrine pancreas) are described. From this point of view, the only interactions between CHO and lipid metabolisms are mediated by glycaemic changes via insulin/glucagon ratio (IGR). However, according to recent advances, this concept seems to have a limited validity as it does take into account neither the many other interactions between CHO and lipid metabolism that are likely to occur in addition to the coarse control by IGR, nor the long-term regulation of energy balance, whose description began with the discovery of leptin. Moreover, it does not include the effects of energy expenditure. Therefore, this review focuses on three topics: (i) describe interactions between CHO and lipid metabolism at the level of each tissue and organ implied, via hormonal signaling as well as direct action of nutrients, (ii) integrate fluxes of substrates and signals between those tissues at rest in a global view of the metabolism taking into account short-term and long-term regulating factors and (iii) describe separately, to avoid confusion or extrapolation, the short-term and long-term influence of exercise on these regulation loops.

Maximal exercise and lactate do not change red blood cell aggregation in well trained athletes.

Exercise and lactate usually change blood rheology, particularly red blood cell (RBC) deformability. The effect of lactate on RBC aggregation is unknown. The present study tested the in vivo effects of exercise on both lactate and RBC aggregation and the in vitro effects of lactate on RBC aggregation. Thirteen well trained athletes performed a progressive and maximal exercise test during which blood was sampled at rest, at 50% of maximal exercise, and at maximal exercise. RBC aggregation was assessed with the Myrenne aggregometer which gives two indexes of RBC aggregation: "M" (aggregation during stasis after shearing at 600 s(-1)) and "M1" (facilitated aggregation at low shear rate after shearing at 600 s(-1)). A part of the resting blood sample was also reserved to test the in vitro effects of three lactate concentrations (2, 4 and 10 mM). The lactate solutions were described in a previous study (P. Connes, D. Bouix, G. Py, C. Préfaut, J. Mercier, J.F. Brun and C. Caillaud, Opposite effects of in vitro lactate on erythrocyte deformability in athletes and untrained subjects, Clin. Hemorheol. Microcirc. 31 (2004), 311-318). The results demonstrated that M and M1 were unchanged with exercise and lactate. Therefore, lactate is able to change RBC deformability but not RBC aggregation.

Evaluation of insulin sensitivity and glucose effectiveness during a standardized breakfast test: comparison with the minimal model analysis of an intravenous glucose tolerance test.

There is a need for reliable measurements of insulin sensitivity (SI) simpler than the euglycemic hyperinsulinemic clamp or the intravenous glucose tolerance test (IVGTT), which could be used when the simpler surrogates based on fasting insulin (Ib) and glucose (Gb) lose their validity. Several evaluations of SI derived from oral glucose tolerance test (OGTT) or its physiologic form, the standardized breakfast test (SBT), have been proposed. We aimed at determining which SBT-derived measurements of SI give the best prediction of the values obtained with the minimal model analysis of an IVGTT. Twenty-eight subjects (23 females and 5 males; age, 44.3+/-0.6 years) with a wide range of glucose tolerance randomly underwent a hyperglucidic SBT and an IVGTT with minimal model analysis. Correlations of 35 indices (converted if appropriated into similar units) with IVGTT-derived SI were calculated, and the accuracy of the empiric formulas obtained with the 11 best predictions were evaluated with Bland-Altman plots. Subjects covered all the spectrum of SI between 0.19 and 21.3 min-1/(microU.mL-1)x10(-4). Eight procedures yielded satisfactory predictions of minimal model SI: (1) SI (from Matsuda's composite index)=-1.24+65/(IbGbImGm)-0.5; (2) SI=1.89+2690/(IbGbImGm); (3) SI (from Bennett's index)=-2.93+5.16/(log Ibxlog Gb); (4) SI (from Sluiter's index)=0.2+2400/(IpGp); (5) SI=-8.54+38.4/(Belfiore's ISI index); (6) SI (from Cederholm's formula)=76/(Gm log Im); (7) SI=0.248+0.947/GbIm; (8) SI (from Mari's "oral glucose insulin sensitivity" index)=oral glucose insulin sensitivity/Ip; (9) Caumo's model. Glucose effectiveness Sg can also be accurately predicted by the following formula: Sg=2.921e-0.185(G60- Gb) (Ip=insulin peak; Gp=glucose peak; Ia=insulin area; Ga=glucose area; G60=glycemia at 60 minutes). The hyperglucidic SBT can provide accurate evaluations of SI and Sg, either by elaborated models or by simple empiric formulas.

Is plasma viscosity a predictor of overtraining in athletes?

There is a lack of consensus about the biological diagnosis of the overtraining syndrome (OTS). Recently, efforts have been made to standardize its clinical diagnosis (e.g., standardized questionnaires like that of the French consensus group on overtraining of the Société Française de Médecine du Sport-SFMS). We previously reported that the early signs of overtraining (= "overreaching") in elite sportsmen are associated with a hemorheologic pattern (raised hematocrit and plasma viscosity etap) that suggests some degree of reversal of the "autohemodilution" which characterizes fitness, and that the feeling of heavy legs in overtrained athletes is related to higher etap and higher red cell aggregation. We thus investigated on a sample of 48 athletes (age 24 +/- 1 yr), referred for possible diagnosis of overtraining to what extent plasma viscosity is a predictor of OTS. From those 48 athletes 10 had a value of etap in the highest quartile (etap > 1.44 pPa.s) and 8 of them had a diagnosis of overreaching, while in the 38 whose etap was < 1.44 mPa.s there were 20 cases of overreachings. Overt cases of OTS were found in 1 subject of the highest quintile and two in the lowest. Thus the predictive value of etap for early stages (overreaching) or chronicized stages (overtraining syndrome) is as follows: (a) prediction of overreaching: sensitivity 28.57%; specificity 90%; positive predictive value 80%; negative predictive value 47.37%; (b) prediction of chronicized overtraining: sensitivity 2.70%; specificity 18.18%; positive predictive value; 10.00%; negative predictive value 5.26%. These results show that etap is a rather specific, although poorly sensitive predictor of overreaching but has no interest in the diagnosis of the overtraining syndrome itself.

The hemorheological aspects of the metabolic syndrome are a combination of separate effects of insulin resistance, hyperinsulinemia and adiposity.

The metabolic syndrome which is at high risk for diabetes and atherothrombosis is associated with hemorheologic abnormalities. Initially, insulin resistance was considered as the core of the syndrome. However, it becomes clear that the syndrome is a cluster in which the combined effects of obesity, insulin resistance, and hyperinsulinemia can be inconstantly associated, contributing to a various extent to a global impairment of blood rheology. We previously reported in 157 nondiabetic subjects that both obesity and insulin resistance increase red cell rigidity (Dintenfass's Tk) and plasma viscosity (eta p), and that whole blood viscosity at high shear rate (eta b 1000 s(-1)) reflects rather obesity than insulin resistance. In this study we aimed at defining the specific hemorheologic profile of insulin resistance and hyperinsulinemia by separating a sample of 81 subjects into 4 subgroups according to quartiles of insulin sensitivity (SI) (measured with the minimal model of an intravenous glucose tolerance test) and baseline insulin. Results show that (1) values of SI within the upper quartile are associated with low eta b due to low eta p; (2) low SI regardless insulinemia is associated with increased aggregation indexes; (3) when low SI is associated with hyperinsulinemia (insulin the upper quartile and SI in the lower) there is a further increase in eta b due to an increase in eta p; (4) neither SI nor insulinemia modify Hct. Thus hyperinsulinemia and insulin resistance induce hyperviscosity syndromes which are somewhat different, although they are associated most of the time. Low SI increases RBC aggregation while hyperinsulinemia increases eta p.