Cholecystokinin-33 inhibits meal size and prolongs the subsequent intermeal interval

There are various forms of the satiety gut-brain peptide cholecystokinin (CCK), a short, widely utilized form or CCK-8, and a long, putatively more effective form or CCK-33. The issue of which of these forms is a more effective satiety peptide is not resolved. Here, we compared the satiety responses, including the sizes of the first three meals (MS) and intermeal intervals (IMI) as well as their calculated satiety ratios (SR), evoked by both peptides. CCK-8 and 33 (1, 3 and 5 nmol/kg, i.p) reduced the size of the first meal similarly, only CCK-33 prolonged the first IMI and increased SR and both peptides failed to affect second and third MS and IMI. As such, CCK-33 is a more effective satiety peptide than CCK-8. The current results confirm previous findings which showed that both peptides reduce food intake by inhibiting meal size, whereas only CCK-33 reduces food intake by prolonging the intermeal interval.     

Comparison and recalculation of the very different QTc interval durations in young healthy women

The aim was to use some simple way for easier comparison, other expression or recalculation of the QTc duration from one formula to another in order to remove the large QTc differences.Methods and Results: The QT interval duration in 138 young healthy women was taken from our archive. The measured QT interval was corrected for heart rate (QTc) according to nine published regression equations (Bazett, Fridericia, Hodges, Sarma, Lecocq, Rautaharju, Sagie=Framingham, Arrowood, Malik) and compared mathematically by the Pearson correlation coefficient R and graphically by linear correlation.Correlation between two different QTc durations can be of three kinds: small (e.g. Bazett's versus Malik's formulas, R=0.0525, p=0.5405, the QTc values are much dispersed in the graph), larger (Malik's versus Sarma's formulas, R=0.939, p<0.01, the values are less dispersed), and identical (the Rautaharju's versus Arrowood's formulas, R=1.000, p<0.01, all QTc points are situated on one line). The linear correlation QTc1 = a+b·QTc2 enables recalculation from one QTc formula into another, if necessary.In conclusion, the QTc interval durations are differently long according to the QTc formula used. The correlations with the large Pearson R coefficient indicate the QTc pairs inappropriate for recalculation, the small R values indicate the appropriate pairs for recalculation.     

Metabolomic patterns associated to QTc interval in shiftworkers: an explorative analysis

Objectives: ¹H NMR-metabolomic approach was used to investigate QTc interval correlation with plasma metabolic profiles in shiftworkers.

Methods: Socio-demographic data, electrocardiographic QTc interval and plasma metabolic profiles from 32 male shiftworkers, were correlated by multivariate regression analysis.

Results: We found a positive correlation between QTc interval values, body mass index, glycemia and lactate level and a negative correlation between QTc interval and both pyroglutamate and 3-hydroxybutyrate plasma level.

Conclusions: Our analysis provides evidence of the association between clinical, metabolic profiles and QTc interval values. This could be used to identify markers of early effects and/or susceptibility in shiftworkers.     

The relationship between QTc interval and cardiac autonomic neuropathy in diabetes mellitus

Methylxanthines are widely consumed because of their stimulating effect primarily on the central nervous system. Their diuretic and respiratory stimulant action is used in clinical medicine. L-Arginine metabolism in the brain is very important for normal brain function. In addition to brain protein synthesis, arginine is a substrate for the production of urea, creatine, nitric oxide, agmatine, glutamic acid, ornithine, proline and polyamines. As known, many of these compounds are very important in brain function. There is no information relating to effects of caffeine on arginine metabolism in the brain, however, there is a lot of new information about arginine metabolism and caffeine action on the central nervous system. So, we have hypothesized the existence of a relationship that may be of interest in understanding mechanisms of caffeine effects on the central nervous system that may have utility in the clinical applications.In our experiment protocol we used male Wistar rats weighing about 200 g. Caffeine was added to the drinking water in gradually increasing amounts, from 2 g/l over the first 3 days, to 4 g/l over the last 7 days. A control group was given drinking water without caffeine. The level of lipid peroxidation, arginase and diamine oxidase (DAO) activity in the brain was measured. The results of our study show that arginase and diamine oxidase were decreased in animals treated with caffeine. The level of lipid peroxidation (MDA) was decreased also.The inhibitory effect of caffeine on arginase activity indicates that caffeine provides more arginine for consumption in other metabolic pathways. Considering the central stimulant effects of caffeine and the decreased lipid peroxidation level, it can be assumed that moderate short-term consumption of caffeine may be beneficial for brain function.     

Thioredoxin deficiency in yeast prolongs S phase and shortens the G1 interval of the cell cycle

Two thioredoxin genes from the yeast Saccharomyces cerevisiae were cloned using synthetic oligonucleotide probes. The DNA sequences of the two genes were found to be 74% identical. The two genes, designated TRX1 and TRX2, were mutagenized in vitro and used to construct a set of thioredoxin deletion mutants. The loss of either thioredoxin gene alone has no effect on cell growth or morphology. However, the simultaneous deletion of both thioredoxin genes profoundly affects the cell cycle. S phase is 3-fold longer, and G1 is virtually absent. In addition, the thioredoxin double mutant shows a 33% increase in generation time, a significant increase in cell size, and a greater proportion of large budded cells. The results suggest that in the absence of TRX1 and TRX2, a slow rate of DNA replication inhibits the normal progress of cellular reproduction. Surprisingly, the loss of both thioredoxins also leads to methionine auxotrophy. Thus yeast glutaredoxin is unable to substitute for thioredoxin in sulfate assimilation. As a first step in studying the cell cycle control mechanisms that respond to the thioredoxin deficiency, it was shown that cell viability does not require the function of RAD9, a known cell cycle checkpoint.     

Prolonged ventricular repolarization measured by corrected QT interval (QTc) in subclinical hyperthyroidism.

Overt hyperthyroidism and hypothyroidism exert a major effect on cardiac function and on ECG. The influence of subclinical hyperthyroidism on the circulatory system is still under debate. Few studies examined the effect of thyroid hormones on ventricular repolarization measured by corrected QT interval (QTc). Longer QTc is associated with increased risk of arrhythmia and cardiac mortality. The aim of this study was to examine the influence of subclinical hyperthyroidism on ventricular repolarization measured by corrected QTc in a standard 12-lead electrocardiogram. The examined group consisted of thirty-two patients with subclinical hyperthyroidism; the controls were thirty-nine healthy individuals. In the group with subclinical hyperthyroidism, we observed a significant increase in heart rate (80.3 +/- 10.59 vs. 73.7 +/- 11.37 bpm, p < 0.05). The mean corrected QTc was 0.434 +/- 0.0207 seconds and 0.414 +/- 0.0208 in the examined groups and in controls, respectively (p < 0.001). QTc did not correlate with free thyroxin concentrations (p = 0.5084). Conclusion: Corrected QT intervals were significantly longer in patients with subclinical hyperthyroidism.     

Insulin resistance and the metabolism of branched-chain amino acids in humans

Peripheral resistance to insulin action is the major mechanism causing the metabolic syndrome and eventually type 2 diabetes mellitus. The metabolic derangement associated with insulin resistance is extensive and not restricted to carbohydrates. The branched-chain amino acids (BCAAs) are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in conditions featuring insulin resistance, insulin deficiency, or both. Obesity, the metabolic syndrome and diabetes mellitus display a gradual increase in the plasma concentration of BCAAs, from the obesity-related low-grade insulin-resistant state to the severe deficiency of insulin action in diabetes ketoacidosis. Obesity-associated hyperinsulinemia succeeds in maintaining near-normal or slightly elevated plasma concentration of BCAAs, despite the insulin-resistant state. The low circulating levels of insulin and/or the deeper insulin resistance occurring in diabetes mellitus are associated with more marked elevation in the plasma concentration of BCAAs. In diabetes ketoacidosis, the increase in plasma BCAAs is striking, returning to normal when adequate metabolic control is achieved. The metabolism of BCAAs is also disturbed in other situations typically featuring insulin resistance, including kidney and liver dysfunction. However, notwithstanding the insulin-resistant state, the plasma level of BCAAs in these conditions is lower than in healthy subjects, suggesting that these organs are involved in maintaining BCAAs blood concentration. The pathogenesis of the decreased BCAAs plasma level in kidney and liver dysfunction is unclear, but a decreased afflux of these amino acids into the blood stream has been observed.     

The short term satiety peptide cholecystokinin reduces meal size and prolongs intermeal interval

Camostat mesilate (or mesylate) releases endogenous cholecystokinin (CCK) or CCK-58, the only detectable endocrine form of CCK in the rat, and reduces cumulative food intake by activating CCK₁ receptor. However, the literature lacks meal pattern analysis and an appropriate dose-response curve for this peptide. Therefore, the current study determines meal size (MS), intermeal interval (IMI) and satiety ratio (SR) by orogastric gavage of camostat (0, 12.5, 25, 50, 100, 200, 300, 400, 800 mg/kg) and compares them to those previously reported by a single dose of CCK-8 (1 nmol/kg, i.p), the most utilized form of CCK. We found that camostat (200, 300, 400 and 800 mg/kg) and CCK-8 reduced cumulative food intake and the size of the first meal, but only camostat prolonged IMI and increased SR. There was no change in the duration of the first two meals or in rated behaviors such as feeding, grooming, standing and resting in response to camostat and CCK-8, but there was more resting during the IMI in response to camostat. This study provides meal pattern analysis and an appropriate dose-response curve for camostat and CCK-8. Camostat reduces food intake by decreasing MS and prolonging IMI, whereas CCK-8 reduces food intake by reducing only meal size.     

Insulin action and secretion in endurance-trained and untrained humans

To evaluate insulin sensitivity and responsiveness, a two-stage hyperinsulinemic euglycemic clamp procedure (insulin infusions of 40 and 400 mU.m-2.min-1) was performed on 11 endurance-trained and 11 untrained volunteers. A 3-h hyperglycemic clamp procedure (plasma glucose approximately 180 mg/dl) was used to study the insulin response to a fixed glycemic stimulus in 15 trained and 12 untrained subjects. During the 40-mU.m-2.min-1 insulin infusion, the glucose disposal rate was 10.2 +/- 0.5 mg.kg fat-free mass (FFM)-1.min-1 in the trained group compared with 8.0 +/- 0.6 mg.kg FFM-1.min-1 in the untrained group (P less than 0.01). In contrast, there was no significant difference in maximally stimulated glucose disposal: 17.7 +/- 0.6 in the trained vs. 16.7 +/- 0.7 mg.kg FFM-1.min-1 in the untrained group. During the hyperglycemic clamp procedure, the incremental area for plasma insulin was lower in the trained subjects for both early (0-10 min: 140 +/- 18 vs. 223 +/- 23 microU.ml-1.min; P less than 0.005) and late (10-180 min: 4,582 +/- 689 vs. 8,895 +/- 1,316 microU.ml-1.min; P less than 0.005) insulin secretory phases. These data demonstrate that 1) the improved insulin action in healthy trained subjects is due to increased sensitivity to insulin, with no change in responsiveness to insulin, and 2) trained subjects have a smaller plasma insulin response to an identical glucose stimulus than untrained individuals.     

Insulin modulates early-phase noradrenaline response to glucose ingestion in humans

To clarify the relationship between the early-phase insulin response and the early-phase noradrenaline (NA) response to glucose ingestion in humans, serum NA, adrenaline, immunoreactive insulin (IRI), C-peptide immunoreactivity, potassium, nonesterified fatty acid and plasma glucose levels were measured in 8 non-diabetics and 10 diabetics without autonomic disturbance after oral 75 g glucose load. Following results were obtained: 1) In non-diabetics, the maximal NA response was observed at 30 min after glucose ingestion, but in diabetics, mean serum NA levels remained unchanged. The effect of glucose ingestion on the NA response was significantly different between non-diabetics and diabetics by the repeated measurements analysis of variance (F ratio = 5.72, P less than 0.05). 2) In total group (n = 18), at early-phase after glucose ingestion (at 30 min), positive correlation was found between dIRI level and dNA level (r = 0.52, P less than 0.05), between dIRI level and %dNA level (r = 0.56, P less than 0.05), between dIRI/dglucose ratio (insulinogenic index) and dNA level (r = 0.70, P less than 0.01). 3) In four diabetics, NA responses to glucose ingestion were studied again after mild energy restriction for 2 wk. In three of them, both early-phase IRI response and early-phase NA response to glucose ingestion improved after diet therapy, but in the remainder, early-phase NA response to glucose ingestion remained unchanged in accordance with sustained impaired early-phase insulin response to glucose ingestion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin sensitivity is not associated with palmitoleate availability in obese humans

We evaluated whether insulin resistance in obese people is associated with decreased plasma palmitoleate availability. Palmitoleate content (percentage and absolute concentrations) in FFA and VLDL was measured in obese subjects who were either insulin resistant (IR) or insulin sensitive (IS), based on assessment of multiorgan (skeletal muscle, liver, and adipose tissue) insulin sensitivity by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with infusion of stable isotopically labeled tracers. Plasma palmitoleate concentration and the relative contribution of palmitoleate to total plasma FFA concentration in the IS group (0.018 ± 0.002 mmol/l and 4.4% ± 0.2%, respectively) were not significantly different than values in the IR group (0.023 ± 0.003 mmol/l and 4.4% ± 0.4%, respectively). Plasma VLDL-triglyceride palmitoleate concentration and the proportion of VLDL fatty acids as palmitoleate in the IS group (0.09 ± 0.02 mmol/l and 5.7 ± 0.3%, respectively) were also not significantly different than those in the IR group (0.16 ± 0.04 mmol/l and 5.0% ± 0.4%, respectively). These data demonstrate that decreased palmitoleate in plasma and in VLDL is not associated with insulin resistance in skeletal muscle, liver, or adipose tissue in obese people.     

Change in spontaneous baroreflex control of pulse interval during heat stress in humans.

Spontaneous baroreflex control of pulse interval (PI) was assessed in healthy volunteers under thermoneutral and heat stress conditions. Subjects rested in the supine position with their lower legs in a water bath at 34 degrees C. Heat stress was imposed by increasing the bath temperature to 44 degrees C. Arterial blood pressure (Finapres), PI (ECG), esophageal and skin temperature, and stroke volume were continuously collected during each 5-min experimental stage. Spontaneous baroreflex function was evaluated by multiple techniques, including 1) the mean slope of the linear relationship between PI and systolic blood pressure (SBP) with three or more simultaneous increasing or decreasing sequences, 2) the linear relationship between changes in PI and SBP (deltaPI/DeltaSBP) derived by using the first differential equation, 3) the linear relationship between changes in PI and SBP with simultaneously increasing or decreasing sequences (+deltaPI/+deltaSBP or -deltaPI/-deltaSBP), and 4) transfer function analysis. Heat stress increased esophageal temperature by 0.6 +/- 0.1 degrees C, decreased PI from 1,007 +/- 43 to 776 +/- 37 ms and stroke volume by 16 +/- 5 ml/beat. Heat stress reduced baroreflex sensitivity but increased the incidence of baroreflex slopes from 5.2 +/- 0.8 to 8.6 +/- 0.9 sequences per 100 heartbeats. Baroreflex sensitivity was significantly correlated with PI or vagal power (r2 = 0.45, r2 = 0.71, respectively; P < 0.05). However, the attenuation in baroreflex sensitivity during heat stress appeared related to a shift in autonomic balance (shift in resting PI) rather than heat stress per se.     

Effects of interval training at the ventilatory threshold on clinical and cardiorespiratory responses in elderly humans

This study assessed clinical and cardiorespiratory responses after an interval training programme in sedentary elderly adults using the ventilatory threshold (V _th) as the index of exercise training intensity. A selection of 22 subjects were randomized into two groups: 11 subjects served as the training group (TG) and the others as controls (CG). Maximal exercise tests were performed on a treadmill before (T₀), each month (T₁, T₂) and after the 3-month interval training programme period (T₃). The TG subjects were individually trained at the heart rate corresponding to V _th measured at T₀, T₁ and T₂ as the breakpoint in the oxygen uptake-carbon dioxide production relationship. Their training programme consisted of walking/jogging sessions on a running track twice a week. The sessions consisted of varying durations of exercise alternating with active recovery in such a way that the subjects slowly increased their total exercise time from an initial duration of 30 min to a final duration of 1 h. During training the heart rate was continuously monitored by a cardiofrequency meter. Compared with the daily activities of the controls, no training programme-related injuries were observed in TG. Moreover, programme adherence (73%) and attendance (97.3%) were high. The maximal oxygen uptake and V _th were increased in TG, by 20% (P<0.05) and 26% (P<0.01), respectively. Interval training at V _th also significantly increased maximal O₂ pulse (P<0.05) and maximal ventilation (P<0.01). A significant decrease in submaximal ventilation (P<0.05) and heart rate (P<0.01) was also noted. These results would suggest that for untrained elderly adults, an interval training programme at the intensity of V _th may be well-tolerated clinically and may significantly improve both maximal aerobic power and submaximal exercise tolerance. Accepted: 6 January 1998     

Incidence and risk of QTc interval prolongation among cancer patients treated with vandetanib: a systematic review and meta-analysis

Background

Vandetanib is a multikinase inhibitor that is under assessment for the treatment of various cancers. QTc interval prolongation is one of the major adverse effects of this drug, but the reported incidence varies substantially among clinical trials. We performed a systematic review and meta-analysis to obtain a better understanding in the risk of QTc interval prolongation among cancer patients administered vandetanib.

Methodology and Principal Findings

Eligible studies were phase II and III prospective clinical trials that involved cancer patients who were prescribed vandetanib 300 mg/d and that included data on QTc interval prolongation. The overall incidence and risk of QTc interval prolongation were calculated using random-effects or fixed-effects models, depending on the heterogeneity of the included studies. Nine trials with 2,188 patients were included for the meta-analysis. The overall incidence of all-grade and high-grade QTc interval prolongation was 16.4% (95% CI, 8.1–30.4%) and 3.7% (8.1–30.4%), respectively, among non-thyroid cancer patients, and 18.0% (10.7–28.6%) and 12.0% (4.5–28.0%), respectively, among thyroid cancer patients. Patients with thyroid cancer who had longer treatment duration also had a higher incidence of high-grade events, with a relative risk of 3.24 (1.57–6.71), than patients who had non-thyroid cancer. Vandetanib was associated with a significantly increased risk of all-grade QTc interval prolongation with overall Peto odds ratios of 7.26 (4.36–12.09) and 5.70 (3.09–10.53) among patients with non-thyroid cancer and thyroid cancer, respectively, compared to the controls.

Conclusions/Significance

Treatment with vandetanib is associated with a significant increase in the overall incidence and risk of QTc interval prolongation. Different cancer types and treatment durations may affect the risk of developing high-grade QTc interval prolongation.     

Insulin in methionine and homocysteine kinetics in healthy humans: plasma vs. intracellular models

Methionine is a sulfur-containing amino acid that is reversibly converted into homocysteine. Homocysteine is an independent cardiovascular risk factor frequently associated with the insulin resistance syndrome. The effects of insulin on methionine and homocysteine kinetics in vivo are not known. Six middle-aged male volunteers were infused with L-[methyl-2H3,1-13C]methionine before (for 3 h) and after (for 3 additional hours) an euglycemic hyperinsulinemic (150 mU/l) clamp. Steady-state methionine and homocysteine kinetics were determined using either plasma (i.e., those of methionine) or intracellular (i.e., those of plasma homocysteine) enrichments. By use of plasma enrichments, insulin decreased methionine rate of appearance (Ra; both methyl- and carbon Ra) by 25% (P < 0.003 vs. basal) and methionine disposal into proteins by 50% (P < 0.0005), whereas it increased homocysteine clearance by approximately 70% (P < 0.025). With intracellular enrichments, insulin increased all kinetic rates, mainly because homocysteine enrichment decreased by approximately 40% (P < 0.001). In particular, transmethylation increased sixfold (P < 0.02), transsulfuration fourfold (P = 0.01), remethylation eightfold (P < 0.025), and clearance eightfold (P < 0.004). In summary, 1) physiological hyperinsulinemia stimulated homocysteine metabolic clearance irrespective of the model used; and 2) divergent changes in plasma methionine and homocysteine enrichments were observed after hyperinsulinemia, resulting in different changes in methionine and homocysteine kinetics. In conclusion, insulin increases homocysteine clearance in vivo and may thus prevent homocysteine accumulation in body fluids. Use of plasma homocysteine as a surrogate of intracellular methionine enrichment, after acute perturbations such as insulin infusion, needs to be critically reassessed.     

Insulin and C-peptide secretion and kinetics in humans: direct and model-based measurements during OGTT

To directly evaluate prehepatic secretion of pancreatic hormones during a 3-h oral glucose tolerance test (OGTT), we measured insulin and C-peptide in six healthy control, six obese, and six type 2 diabetic subjects in the femoral artery and hepatic vein by means of the hepatic catheterization technique. Hypersecretion in obesity was confirmed (309 +/- 66 nmol in obese vs. 117 +/- 22 in control and 79 +/- 13 in diabetic subjects, P 0.3, r(2) = 0.93), whereas estimation of hepatic insulin extraction and insulin clearance needs further investigation for improvement.     

Insulin, catecholamines, glucose and antioxidant enzymes in oxidative damage during different loads in healthy humans

Exercise, insulin-induced hypoglycemia and oral glucose loads (50 g and 100 g) were used to compare the production of malondialdehyde and the activity of antioxidant enzymes in healthy subjects. Twenty male volunteers participated in the study. Exercise consisted of three consecutive work loads on a bicycle ergometer of graded intensity (1.5, 2.0, and 2.5 W/kg, 6 min each). Hypoglycemia was induced by insulin (Actrapid MC Novo, 0.1 IU/kg, i.v.). Oral administration of 50 g and 100 g of glucose was given to elevate plasma glucose. The activity of superoxide dismutase (SOD) was determined in red blood cells, whereas glutathione peroxidase (GSH-Px) activity was measured in whole blood. The concentration of malondialdehyde (MDA) was determined by HPLC, catecholamines were assessed radioenzymatically and glucose was measured by the glucose-oxidase method. Exercise increased MDA concentrations, GSH-Px and SOD activities as well as plasma noradrenaline and adrenaline levels. Insulin hypoglycemia increased plasma adrenaline levels, but the concentrations of MDA and the activities of GSH-Px and SOD were decreased. Hyperglycemia increased plasma MDA concentrations, but the activities of GSH-Px and SOD were significantly higher after a larger dose of glucose only. Plasma catecholamines were unchanged. These results indicate that the transient increase of plasma catecholamine and insulin concentrations did not induce oxidative damage, while glucose already in the low dose was an important triggering factor for oxidative stress.     

Chloroquine-induced QTc prolongation in COVID-19 patients

In the battle against the SARS-CoV‑2 pandemic, chloroquine has emerged as a new potential therapeutic option for the treatment of infected patie     

Six sessions of sprint interval training increases muscle oxidative potential and cycle endurance capacity in humans.

Parra et al. (Acta Physiol. Scand 169: 157-165, 2000) showed that 2 wk of daily sprint interval training (SIT) increased citrate synthase (CS) maximal activity but did not change "anaerobic" work capacity, possibly because of chronic fatigue induced by daily training. The effect of fewer SIT sessions on muscle oxidative potential is unknown, and aside from changes in peak oxygen uptake (Vo(2 peak)), no study has examined the effect of SIT on "aerobic" exercise capacity. We tested the hypothesis that six sessions of SIT, performed over 2 wk with 1-2 days rest between sessions to promote recovery, would increase CS maximal activity and endurance capacity during cycling at approximately 80% Vo(2 peak). Eight recreationally active subjects [age = 22 +/- 1 yr; Vo(2 peak) = 45 +/- 3 ml.kg(-1).min(-1) (mean +/- SE)] were studied before and 3 days after SIT. Each training session consisted of four to seven "all-out" 30-s Wingate tests with 4 min of recovery. After SIT, CS maximal activity increased by 38% (5.5 +/- 1.0 vs. 4.0 +/- 0.7 mmol.kg protein(-1).h(-1)) and resting muscle glycogen content increased by 26% (614 +/- 39 vs. 489 +/- 57 mmol/kg dry wt) (both P < 0.05). Most strikingly, cycle endurance capacity increased by 100% after SIT (51 +/- 11 vs. 26 +/- 5 min; P < 0.05), despite no change in Vo(2 peak). The coefficient of variation for the cycle test was 12.0%, and a control group (n = 8) showed no change in performance when tested approximately 2 wk apart without SIT. We conclude that short sprint interval training (approximately 15 min of intense exercise over 2 wk) increased muscle oxidative potential and doubled endurance capacity during intense aerobic cycling in recreationally active individuals.