Metabolic response to oral glucose tolerance test performed in neutral and warm environmental temperature.

Objective: Hot environments are associated with impaired glucose metabolism at rest in healthy humans. The purpose of this study was to explore the contribution of key glucoregulatory hormones and biomarkers to this altered glucose tolerance. Methods: The effects of ambient temperature on glucose tolerance and its determinants were assessed with a 3-hr oral glucose tolerance test (OGTT) administered to 19 healthy young men and women at 22 °C and 31 °C. Results: The glucose response amplitude was greater in warm environment (AUC 904 ± 151 vs. 721 ± 89 mmol/l·180 min at 31 °C and 22 °C, respectively, p < .001). There was no significant effect of environmental temperature on insulin, growth hormone or pancreatic polypeptide concentrations (all p > .17). The cortisol response to the glucose load was reduced 30, 60, 90 and 120 minutes postload at 31 °C compared with 22 °C (p = .001). The interleukin-6 concentration was also lower in the session at 31 °C (p = .043). Conclusion: We conclude that the effects of environmental temperature on the glucoregulatory hormones and biomarkers reported in this study do not explain the exaggerated increase in blood glucose after a glucose load taken in a warm environmental temperature. Precis statement: This work demonstrates in healthy men and women that the ingestion of glucose elicits an exaggerated increase in blood glucose when the environmental temperature is warm.

Impaired glucose tolerance after brief heat exposure: a randomized crossover study in healthy young men.

A high demand on thermoregulatory processes may challenge homoeostasis, particularly regarding glucose regulation. This has been understudied, although it might concern millions of humans. The objective of this project was to examine the isolated and combined effects of experimental short-term mild heat exposure and metabolic level on glucoregulation. Two experimental randomized crossover studies were conducted. Ten healthy young men participated in study A, which comprises four sessions in a fasting state at two metabolic levels [rest and exercise at 60% of maximal oxygen uptake (O2) for 40 min] in two environmental temperatures (warm: 31°C and control: 22°C). Each session ended with an ad libitum meal, resulting in similar energy intake across sessions. In study B, 12 healthy young men underwent two 3 h oral glucose tolerance tests (OGTTs) in warm and control environmental temperatures. Venous blood was sampled at several time points. In study A, repeated measure ANOVAs revealed higher postprandial serum glucose and insulin levels with heat exposure. Glycaemia following the OGTT was higher in the warm temperature compared with control. The kinetics of the serum glucose response to the glucose load was also affected by the environmental temperature (temperature-by-time interaction, P=0.030), with differences between the warm and control conditions observed up to 90 min after the glucose load (all P<0.033). These studies provide evidence that heat exposure alters short-term glucoregulation. The implication of this environmental factor in the physiopathology of Type 2 diabetes has yet to be investigated.

Citrulline enhances myofibrillar constituents expression of skeletal muscle and induces a switch in muscle energy metabolism in malnourished aged rats.

Citrulline (Cit) actions on muscle metabolism remain unclear. Those latter were investigated using a proteomic approach on Tibialis muscles from male Sprague-Dawley rats. At 23 months of age, rats were either fed ad libitum (AL group) or subjected to dietary restriction for 12 weeks. At the end of the restriction period, one group of rats was euthanized (R group) and two groups were refed for one week with a standard diet supplemented with nonessential amino acids group or Cit (CIT group). Results of the proteomic approach were validated using targeted Western blot analysis and assessment of gene expression of the related genes. Maximal activities of the key enzymes involved in mitochondrial functioning were also determined. Cit supplementation results in a significant increase in the protein expression of the main myofibrillar constituents and of a few enzymes involved in glycogenolysis and glycolysis (CIT vs. AL and R, p < 0.05). Conversely, the expression of oxidative enzymes from Krebs cycle and mitochondrial respiratory chain was significantly decreased (CIT vs. AL, p < 0.05). However, maximal activities of key enzymes of mitochondrial metabolism were not significantly affected, except for complex 1 which presented an increased activity (CIT vs. AL and R, p < 0.05). In conclusion, Cit supplementation increases expression of the main myofibrillar proteins and seems to induce a switch in muscle energy metabolism, from aerobia toward anaerobia.

Leucine and citrulline modulate muscle function in malnourished aged rats.

Protein energy malnutrition in the elderly causes preferential loss of muscle mass which is associated with poor functional states. Leucine and citrulline are able to stimulate muscle protein synthesis in aged rats but no study has been undertaken to evaluate their effect on muscle function. Sprague-Dawley male rats aged 23 months were used in the experiment. Part of them were subjected to a dietary restriction for 12 weeks and then assigned to four groups: a group was euthanized (restricted group), and the others were refed for 1 week with either a leucine-, a citrulline-supplemented diet, or a standard diet. The other rats were fed ad libitum. Muscle mass and motor activity significantly increased during the refeeding with either leucine or citrulline (respectively, +51 and +37% for muscle mass, P < 0.05). The improvement of muscle mass and of motor activity induced by leucine and citrulline was highly associated with that of maximal tetanic isometric force (r = 0.769, P < 0.0001; r = 0.389, P < 0.05, respectively) but only leucine improved maximal tetanic isometric force (+101%, P < 0.05). In conclusion, this is the first study to demonstrate the ability of two amino acids (leucine and citrulline) to modulate muscle function.

Intrusive experiences in posttraumatic stress disorder: Treatment response induces changes in the directed functional connectivity of the anterior insula.

BACKGROUND: One of the core features of posttraumatic stress disorder (PTSD) is re-experiencing trauma. The anterior insula (AI) has been proposed to play a crucial role in these intrusive experiences. However, the dynamic function of the AI in re-experiencing trauma and its putative modulation by effective therapy need to be specified. METHODS: Thirty PTSD patients were enrolled and exposed to traumatic memory reactivation therapy. Resting-state functional magnetic resonance imaging (fMRI) scans were acquired before and after treatment. To explore AI-directed influences over the rest of the brain, we referred to a mixed model using pre-/posttreatment Granger causality analysis seeded on the AI as a within-subject factor and treatment response as a between-subject factor. To further identify correlates of re-experiencing trauma, we investigated how intrusive severity affected (i) causality maps and (ii) the spatial stability of other intrinsic brain networks. RESULTS: We observed changes in AI-directed functional connectivity patterns in PTSD patients. Many within- and between-network causal paths were found to be less influenced by the AI after effective therapy. Insular influences were found to be positively correlated with re-experiencing symptoms, while they were linked with a stronger default mode network (DMN) and more unstable central executive network (CEN) connectivity. CONCLUSION: We showed that directed changes in AI signaling to the DMN and CEN at rest may underlie the degree of re-experiencing symptoms in PTSD. A positive response to treatment further induced changes in network-to-network anticorrelated patterns. Such findings may guide targeted neuromodulation strategies in PTSD patients not suitably improved by conventional treatment.

Oscillococcinum® for upper respiratory tract infections and exacerbations in COPD: an observational, prospective study (OXITUNIS).

BACKGROUND: Upper respiratory tract infections (URTIs) are a major cause of exacerbations in patients with chronic obstructive pulmonary disease (COPD). We assessed the effectiveness of Oscillococcinum® in the protection from URTIs in patients with COPD who had been vaccinated against influenza infection over the 2018-2019 winter season. METHODS: Patients (n=106; mean ± standard deviation age: 66.0 ± 10.3 years; 89.6% men) were randomized into two groups: group V received influenza vaccination only and group OV received influenza vaccination plus Oscillococcinum® (one oral dose per week from inclusion in the study until the end of follow-up, with a maximum of 6 months follow-up over the winter season). The primary endpoint was the incidence rate of URTIs (number of URTIs/1000 patient-treatment exposure days) during follow-up compared between the two groups. RESULTS: There was no significant difference in any of the demographic characteristics, baseline COPD, or clinical data between the two treatment groups (OV and V). The URTI incidence rate was significantly higher in group V than in group OV (2.9 versus 1.2 episodes/1000 treatment days, difference OV-V = -1.7; p=0.0312). There was a significant delay in occurrence of an URTI episode in the OV group versus the V group (mean ± standard error: 48.7 ± 3.0 versus 67.0 ± 2.8 days, respectively; p=0.0158). Limitations to this study include its small population size and the self-recording by patients of the number and duration of URTIs and exacerbations. CONCLUSION: Oscillococcinum may decrease the incidence rate and delay the appearance of URTIs in patients with COPD.

Impact of 3-week citrulline supplementation on postprandial protein metabolism in malnourished older patients: The Ciproage randomized controlled trial.

BACKGROUND: Citrulline (CIT), is not extracted by the splanchnic area, can stimulate muscle protein synthesis and could potentially find clinical applications in conditions involving low amino acid (AA) intake, such as in malnourished older subjects. OBJECTIVE: Our purpose was to research the effects of CIT supplementation on protein metabolism in particular on non-oxidative leucine disposal (NOLD, primary endpoint), and splanchnic extraction of amino acids in malnourished older patients. DESIGN: This prospective randomized multicenter study determined whole-body and liver protein synthesis, splanchnic protein metabolism and appendicular skeletal muscle mass (ASMM) in 24 malnourished older patients [80-92 years; 18 women and 6 men] in inpatient rehabilitation units. All received an oral dose of 10 g of CIT or an equimolar mixture of six non-essential amino acids (NEAAs), as isonitrogenous placebo, for 3 weeks. RESULTS: NOLD and albumin fractional synthesis rates were not different between the NEAA and CIT groups. Splanchnic extraction of dietary amino acid tended to decrease (p = 0.09) in the CIT group (45.2%) compared with the NEAA group (60.3%). Total differences in AA and NEAA area under the curves between fed-state and postabsorptive-state were significantly higher in the CIT than in the NEAA group. There were no significant differences for body mass index, fat mass (FM), lean mass (LM) or ASMM in the whole population except for a tendential decrease in FM for the citrulline group (p = 0.089). Compared with Day 1, lean mass and ASMM significantly increased (respectively p = 0.016 and p = 0.018) at Day 20 in CIT-treated women (mean respective increase of 1.7 kg and 1.1 kg), and fat mass significantly decreased (p = 0.001) at Day 20 in CIT-group women (mean decrease of 1.3 kg). CONCLUSIONS: Our results demonstrate that CIT supplementation has no effect on whole-body protein synthesis or liver protein synthesis in malnourished older subjects. However, CIT supplementation was associated with a higher systemic AA availability. In the subgroup of women, CIT supplementation increased LM and ASMM, and decreased FM.

Ambient temperature-related exaggerated post-prandial insulin response in a young athlete: a case report and implications for climate change.

The objective is to present the case of a 21-yr-old athlete observed with non-physiological immediate postprandial insulin response (1162 pmol/l; normal glucose excursion: 6.6 mmol/l), in a warm environment. No suspicion or evidence of any underlying pathology was found in this well-trained Afro-Caribbean male runner. He never reported any hypoglycemic episode. When performing the same protocol performed in a cooler environment (21.0°C vs 30.3°C), only physiological responses were observed. We conclude that 1) youth, leanness and regular exercise training are not absolutely protective against glucose metabolism impairment in apparently healthy subjects; 2) ambient temperature should be regarded as a potential source of glucose metabolism impairment.

Influence of Hot and Cold Environments on the Regulation of Energy Balance Following a Single Exercise Session: A Mini-Review.

Understanding the regulation of human food intake in response to an acute exercise session is of importance for interventions with athletes and soldiers, as well as overweight individuals. However, the influence of hot and cold environments on this crucial function for the regulation of body mass and motor performance has not been summarized. The purpose of this review was to exhaustively search the literature on the effect of ambient temperature during an exercise session on the subsequent subjective feeling of appetite, energy intake (EI) and its regulation. In the absence of stress due to environmental temperature, exercise-induced energy expenditure is not compensated by EI during an ad libitum meal following the session, probably due to decreased acylated ghrelin and increased peptide tyrosine tyrosine (PYY), glucagon-like peptide 1 (GLP-1), and pancreatic polypeptide (PP) levels. No systematic analysis has been yet made for major alterations of relative EI in cold and hot environments. However, observed eating behaviors are altered (proportion of solid/liquid food, carbohydrate/fat) and physiological regulation appears also to be altered. Anorexigenic signals, particularly PYY, appear to further increase in hot environments than in those that are thermoneutral. Ghrelin and leptin may be involved in the observed increase in EI after exercise in the cold, in parallel with increased energy expenditure. The potential influence of ambient thermal environment on eating behaviors after an exercise session should not be neglected.

Effect of heat exposure and exercise on food intake regulation: A randomized crossover study in young healthy men.

OBJECTIVE: The effect of physical activity on food intake regulation may be moderated by environmental temperature. The aim of the study was to determine the single and combined effects of metabolic activity and temperature on energy intake and its hormonal regulation. METHODS: A randomized crossover study was conducted in the laboratory. Ten healthy and physically active young Afro-Caribbean men participated in four experimental sessions (rest at 22°C and 31°C and cycling at 60% of their maximal oxygen uptake at 22°C and 31°C, all for 40 min). Each test period was followed by a 30-min recovery period and then an ad libitum meal. The main outcome measures were energy balance, subjective appetite, and plasma pancreatic polypeptide (PP), cholecystokinin (CCK) and ghrelin concentrations. RESULTS: Relative energy intake was significantly decreased whereas plasma PP was increased in the exercise conditions (p=0.004 and p=0.002, respectively). Postprandial levels of CCK were elevated only in the rest conditions. Exposure to heat induced a decrease in plasma ghrelin (p=0.031). CONCLUSIONS: Exercise induced a short-term energy deficit. However, modifications in the hormonal regulation of food intake in response to short-term heat or heat and exercise exposure seem to be minor and did not induce changes in energy intake. This trial was registered at clinicaltrials.gov as NCT02157233.

Two SUR1-specific histidine residues mandatory for zinc-induced activation of the rat KATP channel.

Zinc at micromolar concentrations hyperpolarizes rat pancreatic beta-cells and brain nerve terminals by activating ATP-sensitive potassium channels (KATP). The molecular determinants of this effect were analyzed using insulinoma cell lines and cells transfected with either wild type or mutated KATP subunits. Zinc activated KATP in cells co-expressing rat Kir6.2 and SUR1 subunits, as in insulinoma cell lines. In contrast, zinc exerted an inhibitory action on SUR2A-containing cells. Therefore, SUR1 expression is required for the activating action of zinc, which also depended on extracellular pH and was blocked by diethyl pyrocarbonate, suggesting histidine involvement. The five SUR1-specific extracellular histidine residues were submitted to site-directed mutagenesis. Of them, two histidines (His-326 and His-332) were found to be critical for the activation of KATP by zinc, as confirmed by the double mutation H326A/H332A. In conclusion, zinc activates KATP by binding itself to extracellular His-326 and His-332 of the SUR1 subunit. Thereby zinc could exert a negative control on cell excitability and secretion process of pancreatic beta-and alpha-cells. In fact, we have recently shown that such a mechanism occurs in hippocampal mossy fibers, a brain region characterized, like the pancreas, by an important accumulation of zinc and a high density of SUR1-containing KATP.

Pore loop-mutated rat KIR6.1 and KIR6.2 suppress KATP current in rat cardiomyocytes.

Cardiomyocytes express mRNA for all major subunits of ATP-sensitive potassium (K(ATP)) channels: KIR6.1, KIR6.2, SUR1A, SUR2A, and SUR2B. It has remained controversial as to whether KIR6.1 may associate with KIR6.2 to form the tetrameric pore of K(ATP) channels in cardiomyocytes. To explore this possibility, cultured rat cardiomyocytes were examined for an inhibition of K(ATP) current by overexpression of pore loop-mutated (inactive) KIR6.x. Bicistronic plasmids were constructed encoding loop-mutated (AFA or SFG for GFG) rat KIR6.x followed by EGFP. In ventricular myocytes, the overexpression of KIR6.1SFG-pIRES(2)-EGFP or KIR6.2AFA-pIRES(2)-EGFP DNA caused, after 72 h, a major decrease of K(ATP) current density of 85.8% and 82.7%, respectively (P < 0.01), relative to EGFP controls (59 +/- 9 pA/pF). In atrial myocytes, overexpression of these pore-mutated KIR6.x by 6.0-fold and 10.6-fold, as assessed by quantitative immunohistochemistry, caused a decrease of K(ATP) current density of 73.7% and 58.5%, respectively (P < 0.01). Expression of wild-type rat KIR6.2 increased the ventricular and atrial K(ATP) current density by 58.3% and 42.9%, respectively (P < 0.01), relative to corresponding EGFP controls, indicating a reserve of SUR to accommodate increased KIR6.x trafficking to the sarcolemma. The results favor the view that KIR6.1 may associate with KIR6.2 to form heterotetrameric pores of native K(ATP) channels in cardiomyocytes.