The Dietary Supplement Creatyl-l-Leucine Does Not Bioaccumulate in Muscle,Brain or Plasma and Is Not a Significant Bioavailable Source of Creatine

Creatine is an important energy metabolite that is concentrated in tissues such as the muscles and brain. Creatine is reversibly converted to creatine phosphate through a reaction with ATP or ADP, which is catalyzed by the enzyme creatine kinase. Dietary supplementation with relatively large amounts of creatine monohydrate has been proven as an effective sports supplement that can enhances athletic performance during acute high-energy demand physical activity. Some side effects have been reported with creatine monohydrate supplementation, which have stimulated research into new potential molecules that could be used as supplements to potentially provide bioavailable creatine. Recently, a popular supplement, creatyl-l-leucine, has been proposed as a potential dietary ingredient that may potentially provide bioavailable creatine. This study tests whether creatyl-l-leucine is a bioavailable compound and determines whether it can furnish creatine as a dietary supplement. Rats were deprived of dietary creatine for a period of two weeks and then given one of three treatments: a control AIN-93G creatine-free diet, AIN-93G supplemented with creatine monohydrate or AIN-93G with an equimolar amount of creatyl-l-leucine supplement in the diet for one week. When compared to the control and the creatine monohydrate-supplemented diet, creatyl-l-leucine supplementation resulted in no bioaccumulation of either creatyl-l-leucine or creatine in tissue.     

Citrulline Supplementation Improves Organ Perfusion and Arginine Availability under Conditions with Enhanced Arginase Activity

Enhanced arginase-induced arginine consumption is believed to play a key role in the pathogenesis of sickle cell disease-induced end organ failure. Enhancement of arginine availability with l-arginine supplementation exhibited less consistent results; however, l-citrulline, the precursor of l-arginine, may be a promising alternative. In this study, we determined the effects of l-citrulline compared to l-arginine supplementation on arginine-nitric oxide (NO) metabolism, arginine availability and microcirculation in a murine model with acutely-enhanced arginase activity. The effects were measured in six groups of mice (n = 8 each) injected intraperitoneally with sterile saline or arginase (1000 IE/mouse) with or without being separately injected with l-citrulline or l-arginine 1 h prior to assessment of the microcirculation with side stream dark-field (SDF)-imaging or in vivo NO-production with electron spin resonance (ESR) spectroscopy. Arginase injection caused a decrease in plasma and tissue arginine concentrations. l-arginine and l-citrulline supplementation both enhanced plasma and tissue arginine concentrations in arginase-injected mice. However, only the citrulline supplementation increased NO production and improved microcirculatory flow in arginase-injected mice. In conclusion, the present study provides for the first time in vivo experimental evidence that l-citrulline, and not l-arginine supplementation, improves the end organ microcirculation during conditions with acute arginase-induced arginine deficiency by increasing the NO concentration in tissues.     

Effect of Acute and Chronic Oral l-Carnitine Supplementation on Exercise Performance Based on the Exercise Intensity: A Systematic Review

l-Carnitine (l-C) and any of its forms (glycine-propionyl l-Carnitine (GPL-C) or l-Carnitine l-tartrate (l-CLT)) has been frequently recommended as a supplement to improve sports performance due to, among others, its role in fat metabolism and in maintaining the mitochondrial acetyl-CoA/CoA ratio. The main aim of the present systematic review was to determine the effects of oral l-C supplementation on moderate- (50–79% V˙O_{2 max}) and high-intensity (≥80% V˙O_{2 max}) exercise performance and to show the effective doses and ideal timing of its intake. A structured search was performed according to the PRISMA^® statement and the PICOS guidelines in the Web of Science (WOS) and Scopus databases, including selected data obtained up to 24 October 2021. The search included studies where l-C or glycine-propionyl l-Carnitine (GPL-C) supplementation was compared with a placebo in an identical situation and tested its effects on high and/or low–moderate performance. The trials that used the supplementation of l-C together with additional supplements were eliminated. There were no applied filters on physical fitness level, race, or age of the participants. The methodological quality of studies was evaluated by the McMaster Critical Review Form. Of the 220 articles obtained, 11 were finally included in this systematic review. Six studies used l-C, while three studies used l-CLT, and two others combined the molecule propionyl l-Carnitine (PL-C) with GPL-C. Five studies analyzed chronic supplementation (4–24 weeks) and six studies used an acute administration (<7 days). The administration doses in this chronic supplementation varied from 1 to 3 g/day; in acute supplementation, oral l-C supplementation doses ranged from 3 to 4 g. On the one hand, the effects of oral l-C supplementation on high-intensity exercise performance variables were analyzed in nine studies. Four of them measured the effects of chronic supplementation (lower rating of perceived exertion (RPE) after 30 min at 80% V˙O_{2 max} on cycle ergometer and higher work capacity in “all-out” tests, peak power in a Wingate test, and the number of repetitions and volume lifted in leg press exercises), and five studies analyzed the effects of acute supplementation (lower RPE after graded exercise test on the treadmill until exhaustion and higher peak and average power in the Wingate cycle ergometer test). On the other hand, the effects of l-C supplementation on moderate exercise performance variables were observed in six studies. Out of those, three measured the effect of an acute supplementation, and three described the effect of a chronic supplementation, but no significant improvements on performance were found. In summary, l-C supplementation with 3 to 4 g ingested between 60 and 90 min before testing or 2 to 2.72 g/day for 9 to 24 weeks improved high-intensity exercise performance. However, chronic or acute l-C or GPL-C supplementation did not present improvements on moderate exercise performance.     

Effects of Levocarnitine on Brachial-Ankle Pulse Wave Velocity in Hemodialysis Patients: A Randomized Controlled Trial

Background and Aims: Atherosclerotic cardiovascular disease is the most common cause of mortality in patients with end-stage kidney disease. Chronic kidney disease patients often exhibit a deficiency in l-carnitine due to loss during hemodialysis (HD). We studied the effects of l-carnitine supplementation on brachial-ankle pulse wave velocity (baPWV), a marker of atherosclerosis, in HD patients. Methods: This was a prospective, open-label, randomized, parallel controlled, multi-center trial testing the anti-atherosclerotic efficacy of oral l-carnitine administration (20 mg/kg/day). HD patients (n = 176, mean age, 67.2 ± 10.3 years old; mean duration of HD, 54 ± 51 months) with plasma free l-carnitine deficiency (<40 μmol/L) were randomly assigned to the oral l-carnitine group (n = 88) or control group (n = 88) and monitored during 12 months of treatment. Results: There were no significant differences in baseline clinical variables between the l-carnitine and control groups. l-carnitine supplementation for 12 months significantly increased total, free, and acyl carnitine levels, and reduced the acyl/free carnitine ratio. The baPWV value decreased from 2085 ± 478 cm/s at baseline to 1972 ± 440 cm/s after six months (p < 0.05) to 1933 ± 363 cm/s after 12 months (p < 0.001) of l-carnitine administration, while no significant changes in baPWV were observed in the control group. Baseline baPWV was the only factor significantly correlated with the decrease in baPWV. Conclusions: l-carnitine supplementation significantly reduced baPWV in HD patients. l-carnitine may be a novel therapeutic strategy for preventing the progression of atherosclerotic cardiovascular disease.     

The Functional DNA Methylation Signatures Relevant to Altered Immune Response of Neonatal T Cells with l-Arginine Supplementation

l-Arginine is an important nutrient in the infant diet that significantly regulates the maturation of the immune system in neonates, including the maturation of CD4⁺ T cells. The biological activities of CD4⁺ T cells differ substantially between neonates and adults, and these differences may be governed by epigenetic processes. Investigating these differences and the causative processes may help understand neonatal and developmental immunity. In this study, we compared the functional DNA methylation profiles in CD4⁺ T cells of neonates and adults, focusing on the role of l-arginine supplementation. Umbilical cord blood and adult CD4⁺ T cells were cultured with/without l-arginine treatment. By comparing DNA methylation in samples without l-arginine treatment, we found that CD4⁺ T cells of neonatal cord blood generally showed higher DNA methylation than those of adults (average CpG methylation percentage 0.6305 for neonate and 0.6254 for adult, t-test p-value < 0.0001), suggesting gene silencing in neonates. By examining DNA methylation patterns of CpG dinucleotides induced by l-arginine treatment, we found that more CpG dinucleotides were hypomethylated and more genes appeared to be activated in neonatal T-cells as compared with adult. Genes activated by l-arginine stimulation of cord blood samples were more enriched regarding immune-related pathways. CpG dinucleotides at IL-13 promoter regions were hypomethylated after l-arginine stimulation. Hypomethylated CpG dinucleotides corresponded to higher IL-13 gene expression and cytokine production. Thus, DNA methylation partially accounts for the mechanism underlying differential immune function in neonates. Modulatory effects of l-arginine on DNA methylation are gene-specific. Nutritional intervention is a potential strategy to modulate immune function of neonates.     

Mamao Pomace Extract Alleviates Hypertension and Oxidative Stress in Nitric Oxide Deficient Rats

Reactive oxygen species (ROS)-induced oxidative stress plays a major role in pathogenesis of hypertension. Antidesma thwaitesianum (local name: Mamao) is a tropical plant distributed in the tropical/subtropical areas of the world, including Thailand. Mamao pomace (MP), a by-product generated from Mamao fruits, contains large amounts of antioxidant polyphenolic compounds. The aim of this study was to investigate the antihypertensive and antioxidative effects of MP using hypertensive rats. For this purpose, male Sprague-Dawley rats were given N^ω-nitro-l-arginine methyl ester (l-NAME), an inhibitor of endothelial nitric oxide synthase (eNOS), in drinking water (50 mg/kg) for three weeks. MP extract was orally administered daily at doses of 100 and 300 mg/kg. l-NAME administration induced marked increase in blood pressure, peripheral vascular resistance, and oxidative stress. MP treatment significantly prevented the increase in blood pressure, hindlimb blood flow and hindlimb vascular resistance of l-NAME treated hypertensive rats (p < 0.05). The antihypertensive effect of MP treatment was associated with suppression of superoxide production from carotid strips and also with an increase in eNOS protein expression and nitric oxide bioavailability. The present results provide evidence for the antihypertensive effect of MP and suggest that MP might be useful as a dietary supplement against hypertension.     

l-Glutamine and Whole Protein Restore First-Phase Insulin Response and Increase Glucagon-Like Peptide-1 in Type 2 Diabetes Patients

l-glutamine triggers glucagon-like peptide-1 (GLP-1) release from L cells in vitro and when ingested pre-meal, decreases postprandial glycaemia and increases circulating insulin and GLP-1 in type 2 diabetes (T2D) patients. We aimed to evaluate the effect of oral l-glutamine, compared with whole protein low in glutamine, on insulin response in well-controlled T2D patients. In a randomized study with a crossover design, T2D patients (n = 10, 6 men) aged 65.1 ± 5.8, with glycosylated hemoglobin (HbA1c) 6.6% ± 0.7% (48 ± 8 mmol/mol), received oral l-glutamine (25 g), protein (25 g) or water, followed by an intravenous glucose bolus (0.3 g/kg) and hyperglycemic glucose clamp for 2 h. Blood was frequently collected for analyses of glucose, serum insulin and plasma total and active GLP-1 and area under the curve of glucose, insulin, total and active GLP-1 excursions calculated. Treatments were tested 1–2 weeks apart. Both l-glutamine and protein increased first-phase insulin response (p ≤ 0.02). Protein (p = 0.05), but not l-glutamine (p = 0.2), increased second-phase insulin response. Total GLP-1 was increased by both l-glutamine and protein (p ≤ 0.02). We conclude that oral l-glutamine and whole protein are similarly effective in restoring first-phase insulin response in T2D patients. Larger studies are required to further investigate the utility of similar approaches in improving insulin response in diabetes.     

Deficiency in the Essential Amino Acids l-Isoleucine,l-Leucine and l-Histidine and Clinical Measures as Predictors of Moderate Depression in Elderly Women: A Discriminant Analysis Study

Increases in depression are common in some elderly women. Elderly women often show moderate depressive symptoms, while others display minimal depressive symptoms. These discrepancies have produced contradictory and inconclusive outcomes, which have not been explained entirely by deficits in neurotransmitter precursors. Deficiency in some amino acids have been implicated in major depression, but its role in non-clinical elderly women is not well known. An analysis of essential amino acids, depression and the use of discriminant analysis can help to clarify the variation in depressive symptoms exhibited by some elderly women. The aim was to investigate the relationship of essential amino acids with affective, cognitive and comorbidity measures in elderly women without major depression nor severe mood disorders or psychosis, specifically thirty-six with moderate depressive symptoms and seventy-one with minimal depressive symptoms. The plasma concentrations of nineteen amino acids, Beck Depression Inventory (BDI) scores, Geriatric Depression Scale (GDS) scores, global cognitive scores and comorbidities were submitted to stepwise discriminant analysis to identify predictor variables. Seven predictors arose as important for belong to the group based on amino acid concentrations, with the moderate depressive symptoms group characterized by higher BDI, GDS and cognitive scores; fewer comorbidities; and lower levels of l-histidine, l-isoleucine and l-leucine. These findings suggest that elderly women classified as having moderate depressive symptoms displayed a deficiency in essential amino acids involved in metabolism, protein synthesis, inflammation and neurotransmission.     

Synergistic Antihypertensive Effect of Carthamus tinctorius L. Extract and Captopril in l-NAME-Induced Hypertensive Rats via Restoration of eNOS and AT1R Expression

This study examined the effect of Carthamus tinctorius (CT) extract plus captopril treatment on blood pressure, vascular function, nitric oxide (NO) bioavailability, oxidative stress and renin-angiotensin system (RAS) in N^ω-Nitro-l-arginine methyl ester (l-NAME)-induced hypertension. Rats were treated with l-NAME (40 mg/kg/day) for five weeks and given CT extract (75 or 150 or 300 or 500 mg/kg/day): captopril (5 mg/kg/day) or CT extract (300 mg/kg/day) plus captopril (5 mg/kg/day) for two consecutive weeks. CT extract reduced blood pressure dose-dependently, and the most effective dose was 300 mg/kg/day. l-NAME-induced hypertensive rats showed abnormalities including high blood pressure, high vascular resistance, impairment of acetylcholine-induced vasorelaxation in isolated aortic rings and mesenteric vascular beds, increased vascular superoxide production and plasma malondialdehyde levels, downregulation of eNOS, low level of plasma nitric oxide metabolites, upregulation of angiotensin II type 1 receptor and increased plasma angiotensin II. These abnormalities were alleviated by treatment with either CT extract or captopril. Combination treatment of CT extract and captopril normalized all the abnormalities found in hypertensive rats except endothelial dysfunction. These data indicate that there are synergistic antihypertensive effects of CT extract and captopril. These effects are likely mediated by their anti-oxidative properties and their inhibition of RAS.     

<Emphasis Type="SmallCaps">l</Emphasis>-Arginine supplementation prevents allodynia and hyperalgesia in painful diabetic neuropathic rats by normalizing plasma nitric oxide concentration and increasing plasma agmatine concentration

Purpose

Neuropathic pain is a common diabetic complication. It is characterized by symptoms of spontaneous and stimulus-evoked pain including hyperalgesia and allodynia. l-Arginine is a common precursor of many metabolites of biological interest, in particular, nitric oxide (NO), ornithine, and hence polyamines. In central nervous system, NO, glutamate, and polyamines share an N-methyl-d-aspartate (NMDA) receptor-mediated effect. We hypothesized that a variation in arginine metabolism caused by diabetes may contribute to development and maintenance of neuropathic pain and to the worsening of clinical and biological signs of diabetes.

Methods

We examined whether oral l-arginine supplementation (2.58 ± 0.13 g/l in drinking water for 3 weeks) could improve the development of neuropathic pain and the clinical, biological, and metabolic complications of diabetes in streptozocin (STZ)-induced diabetic (D) rats.

Results

STZ administration induced classical symptoms of type 1 diabetes. Diabetic rats also displayed mechanical hypersensitivity, tactile, and thermal allodynia. Plasma citrulline and NO levels were increased in diabetic hyperalgesic/allodynic rats. l-Arginine supplementation failed to reduce hyperglycaemia, polyphagia, and weight loss. Moreover, it abolished hyperalgesia and allodynia by normalizing NO plasma concentration and increasing plasma agmatine concentration.

Conclusions

l-Arginine supplementation prevented the development of mechanical hyperalgesia, tactile, and thermal allodynia in painful diabetic neuropathy with concomitant reduction of NO and increased agmatine production, offering new therapeutic opportunities for the management of diabetic neuropathic pain.

     

Effects of l-Arginine Plus Vitamin C Supplementation on Physical Performance,Endothelial Function,and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial

Long COVID, a condition characterized by symptom and/or sign persistence following an acute COVID-19 episode, is associated with reduced physical performance and endothelial dysfunction. Supplementation of l-arginine may improve endothelial and muscle function by stimulating nitric oxide synthesis. A single-blind randomized, placebo-controlled trial was conducted in adults aged between 20 and 60 years with persistent fatigue attending a post-acute COVID-19 outpatient clinic. Participants were randomized 1:1 to receive twice-daily orally either a combination of 1.66 g l-arginine plus 500 mg liposomal vitamin C or a placebo for 28 days. The primary outcome was the distance walked on the 6 min walk test. Secondary outcomes were handgrip strength, flow-mediated dilation, and fatigue persistence. Fifty participants were randomized to receive either l-arginine plus vitamin C or a placebo. Forty-six participants (median (interquartile range) age 51 (14), 30 [65%] women), 23 per group, received the intervention to which they were allocated and completed the study. At 28 days, l-arginine plus vitamin C increased the 6 min walk distance (+30 (40.5) m; placebo: +0 (75) m, p = 0.001) and induced a greater improvement in handgrip strength (+3.4 (7.5) kg) compared with the placebo (+1 (6.6) kg, p = 0.03). The flow-mediated dilation was greater in the active group than in the placebo (14.3% (7.3) vs. 9.4% (5.8), p = 0.03). At 28 days, fatigue was reported by two participants in the active group (8.7%) and 21 in the placebo group (80.1%; p < 0.0001). l-arginine plus vitamin C supplementation improved walking performance, muscle strength, endothelial function, and fatigue in adults with long COVID. This supplement may, therefore, be considered to restore physical performance and relieve persistent symptoms in this patient population.     

Orally administered l-ornithine elevates brain l-ornithine levels and has an anxiolytic-like effect in mice

Abstract

Intracerebroventricular injection of l-ornithine has demonstrated sedative and hypnotic effects in neonatal chicks exposed to acute stressful conditions. However, whether orally administered l-ornithine can reduce acute mental stress remains to be defined. To clarify the nutritional importance of l-ornithine in controlling the stress response, in Experiment 1 we first investigated whether orally administered l-ornithine can be transported into the brain of mice. Mice were orally administered l-ornithine (3 mmol/water 10 ml/kg, per os). l-Ornithine levels were significantly elevated in the cerebral cortex and hippocampus at 30 and 60 minutes post-administration. In Experiment 2, the effect of orally administered l-ornithine (0, 0.1875, 0.75 and 3 mmol/water 10 ml/kg, per os) on anxiety-like behavior in mice exposed to the elevated plus-maze test was examined at 30 minutes post-administration. There was a significant increase in the percentage of time spent and entries in the open arms in the group receiving 0.75 mmol of l-ornithine compared to the control group. Furthermore, locomotion activity in a novel environment was not significantly changed between the control group and 0.75 mmol of l-ornithine group in Experiment 3. Therefore, it appears that orally administrated l-ornithine is bioavailable to the rodent brain and reduces anxiety-like behavior as demonstrated by the elevated plus-maze test.     

Long-term dietary l-arginine supplementation increases endothelial nitric oxide synthase and vasoactive intestinal peptide immunoexpression in rat small intestine

Background and aims

Nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) are important intestinal neurotransmitters that coexist in the gut enteric nervous system and play an important role in intestinal physiology (e.g., absorption, motility, fluid secretion and smooth muscle relaxation). It is also known that cold exposure alters several aspects of gastrointestinal physiology and induces hyperphagia to meet increased metabolic demands, but there are no data regarding NO and VIP involvement in intestinal response during acclimation to cold. The objective of this study was to determine the influence of long-term l-arginine supplementation on the expression of the three isoforms of nitric oxide synthase (NOS) and VIP in small intestine of rats acclimated to room temperature or cold.

Methods

Animals (six per group) acclimated to room temperature (22 ± 1 °C) and cold (4 ± 1 °C), respectively, were treated with 2.25 % l-arginine, a substrate for NOSs, or with 0.01 % N ^ω-nitro-l-arginine methyl ester, an inhibitor of NOSs, for 45 days. The topographical distribution of VIP and NOSs expression in small intestine was studied by immunohistochemistry, and ImageJ software was used for semiquantitative densitometric analysis of their immunoexpression.

Results

Long-term dietary l-arginine supplementation increases VIP and NOSs immunoexpression at room temperature while at cold increases the endothelial NOS, inducible NOS and VIP but decrease neuronal NOS in rat small intestine.

Conclusion

Our results demonstrate that long-term dietary l-arginine supplementation modulates NOSs and VIP immunoexpression in rat small intestine with respect to ambient temperature, pointing out the eNOS as a predominant NOS isoform with an immunoexpression pattern similar to VIP.     

d-Allulose Inhibits Ghrelin-Responsive,Glucose-Sensitive and Neuropeptide Y Neurons in the Arcuate Nucleus and Central Injection Suppresses Appetite-Associated Food Intake in Mice

d-allulose, a rare sugar, has sweetness with few calories. d-allulose regulates feeding and glycemia, and ameliorates hyperphagia, obesity and diabetes. All these functions involve the central nervous system. However, central mechanisms underlying these effects of d-allulose remain unknown. We recently reported that d-allulose activates the anorexigenic neurons in the hypothalamic arcuate nucleus (ARC), the neurons that respond to glucagon-like peptide-1 and that express proopiomelanocortin. However, its action on the orexigenic neurons remains unknown. This study investigated the effects of d-allulose on the ARC neurons implicated in hunger, by measuring cytosolic Ca²⁺ concentration ([Ca²⁺]_i) in single neurons. d-allulose depressed the increases in [Ca²⁺]_i induced by ghrelin and by low glucose in ARC neurons and inhibited spontaneous oscillatory [Ca²⁺]_i increases in neuropeptide Y (NPY) neurons. d-allulose inhibited 10 of 35 (28%) ghrelin-responsive, 18 of 60 (30%) glucose-sensitive and 3 of 8 (37.5%) NPY neurons in ARC. Intracerebroventricular injection of d-allulose inhibited food intake at 20:00 and 22:00, the early dark phase when hunger is promoted. These results indicate that d-allulose suppresses hunger-associated feeding and inhibits hunger-promoting neurons in ARC. These central actions of d-allulose represent the potential of d-allulose to inhibit the hyperphagia with excessive appetite, thereby counteracting obesity and diabetes.     

Differential effects of physical exercise and l-arginine on cortical spreading depression in developing rats

Abstract

Objective

We investigated the effect of early-in-life administration of l-arginine, combined with physical exercise, on cortical spreading depression (CSD) in young and adult rats.

Methods

l-arginine (300 mg/kg/day, n = 40) or distilled water (vehicle, n = 40) was given to the rats during postnatal days 7–35 by gavage. Physical exercise (treadmill) was carried out during postnatal days 15–35 in half of the animals in each gavage condition described above. The other half (non-exercised) was used for comparison. When the animals reached 35–45 days (young groups) or 90–120 days of age (adult) CSD was recorded on two cortical points during 4 hours and CSD propagation velocity was calculated.

Results

l-arginine-treated + exercised rats had increased body weight, but not brain weight, in adult age compared to l-arginine + non-exercised ones (P < 0.05). In both young and adult animals, l-arginine increased, whereas exercise decreased the CSD propagation velocity. Analysis of variance revealed a significant interaction between gavage treatment and age (P < 0.001), and also between gavage treatment and exercise (P = 0.004), but not between age and exercise. An additional control group of young rats, treated with 300 mg/kg of l-histidine, presented CSD velocities comparable to the corresponding water-treated controls, suggesting that the CSD acceleration seen in the l-arginine group was an l-arginine-specific effect, rather than an effect due to a non-specific amino acid imbalance.

Discussion

l-arginine and exercise affect CSD differentially (l-arginine accelerated, while exercise decelerated CSD), and both effects did interact. Probably, they depend on developmental plasticity changes associated with the treatments.     

Low Exposure to Asbestos

In a previous survey of shipyard pipe coverers and controls, clinical criteria were used to define pulmonary asbestosis. This second survey focused on physiologic abnormalities.

Pipe coverers had significantly reduced vital capacities (FVC) as well as single breath (DlSB) and exercise steady stale (DlSS-Ex) diffusing capacities. Resting steady state diffusing capacity (DlSS-R), fraction carbon monoxide removed (Fco), and the diffusing constant (K) differed from selected normals but not from all controls. Airways resistance, specific conductance, minute ventilation, arterial carbon dioxide pressure (Pco ₂) and dead space were not significantly abnormal. Obstructive disease was equally common in both groups. All workers with clinical “asbestosls” also had severely reduced Dl and Fco.

The significance of isolated reduction of Dlrequires further study. However, In a third survey three years later, Dl in exposed workers had deteriorated more rapidly than FVC; some with initially isolated reduction of Dl had developed other signs of disease.     

Decreased diabetes risk over 9 year after 18-month oral <Emphasis Type="SmallCaps">l</Emphasis>-arginine treatment in middle-aged subjects with impaired glucose tolerance and metabolic syndrome (extension evaluation of <Emphasis Type="SmallCaps">l</Emphasis>-arginine study)

Purpose

This study aimed to determine whether l-arginine supplementation lasting for 18 months maintained long-lasting effects on diabetes incidence, insulin secretion and sensitivity, oxidative stress, and endothelial function during 108 months among subjects at high risk of developing type 2 diabetes.

Methods

One hundred and forty-four middle-aged subjects with impaired glucose tolerance and metabolic syndrome were randomized in 2006 to an l-arginine supplementation (6.4 g orally/day) or placebo therapy lasting 18 months. This period was followed by a 90-month follow-up. The primary outcome was a diagnosis of diabetes during the 108 month study period. Secondary outcomes included changes in insulin secretion (proinsulin/c-peptide ratio), insulin sensitivity (IGI/HOMA-IR), oxidative stress (AOPPs), and vascular function. After the 18 month participation, subjects that were still free of diabetes and willing to continue their participation (104 subjects) were further followed until diabetes diagnosis, with a time span of about 9 years from baseline.

Results

Although results derived from the 18 month of the intervention study demonstrated no differences in the probability of becoming diabetics, at the end of the study, the cumulative incidence of diabetes was of 40.6% in the l-arginine group and of 57.4% in the placebo group. The adjusted HR for diabetes (l-arginine vs. placebo) was 0.66; 95% CI 0.48, 0.91; p < 0.02). Proinsulin/c-peptide ratio (p < 0.001), IGI/HOMA-IR (p < 0.01), and AOPP (p < 0.05) levels were ameliorated in l-arginine compared to placebo.

Conclusions

These results may suggest that the administration of l-arginine could delay the development of T2DM for a long period. This effect could be mediated, in some extent, by l-arginine-induced reduction in oxidative stress.

     

The impact of chronic imipramine treatment on amino acid concentrations in the hippocampus of mice

Abstract

The relationship between antidepressants and monoamine concentrations in the brain has been well investigated, but few studies have investigated the relationship between antidepressants and amino acid concentrations in the brain. The purpose of the present study was therefore to investigate the effect of the chronic antidepressant imipramine on amino acid and monoamine concentrations in the mouse brain and plasma. Chronic imipramine treatment decreased the concentration of 5-hydroxyindoleaceticacid/5-hydroxytryptamine in the cerebral cortex and increased that of norepinephrine (NE) in the hippocampus. Since these changes were conspicuous effects of the antidepressant, we concluded that imipramine acts on the central nervous system. No change in amino acid concentrations in plasma was induced by chronic imipramine treatment, but several changes were confirmed in the cerebral cortex, the hypothalamus and the hippocampus. Chronic imipramine treatment caused increases in l-methionine, l-tyrosine, and l-lysine in the cerebral cortex, and an increase in l-aspartate in the hypothalamus. Contrary to this, the concentrations of l-aspartate, l-serine, l-asparagine, glycine, l-glutamine, gamma-aminobutyric acid, l-threonine, l-arginine, l-proline, l-valine, and l-methionine in the hippocampus were decreased by chronic imipramine treatment. The present results demonstrate that the metabolism of several amino acids in the brain, but not of those in plasma, was altered by chronic imipramine treatment. The findings in the present study may help to further elucidate the relationship between amino acids and the effects and side effects of antidepressants.     

d-Allulose Improves Endurance and Recovery from Exhaustion in Male C57BL/6J Mice

d-Allulose, a rare sugar, improves glucose metabolism and has been proposed as a candidate calorie restriction mimetic. This study aimed to investigate the effects of d-allulose on aerobic performance and recovery from exhaustion and compared them with the effects of exercise training. Male C57BL/6J mice were subjected to exercise and allowed to run freely on a wheel. Aerobic performance was evaluated using a treadmill. Glucose metabolism was analyzed by an intraperitoneal glucose tolerance test (ipGTT). Skeletal muscle intracellular signaling was analyzed by Western blotting. Four weeks of daily oral administration of 3% d-allulose increased running distance and shortened recovery time as assessed by an endurance test. d-Allulose administration also increased the maximal aerobic speed (MAS), which was observed following treatment for >3 or 7 days. The improved performance was associated with lower blood lactate levels and increased liver glycogen levels. Although d-allulose did not change the overall glucose levels as determined by ipGTT, it decreased plasma insulin levels, indicating enhanced insulin sensitivity. Finally, d-allulose enhanced the phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase and the expression of peroxisome proliferator-activated receptor γ coactivator 1α. Our results indicate that d-allulose administration enhances endurance ability, reduces fatigue, and improves insulin sensitivity similarly to exercise training. d-Allulose administration may be a potential treatment option to alleviate obesity and enhance aerobic exercise performance.     

Effects of l-arginine supplementation on blood flow, oxidative stress status and exercise responses in young adults with uncomplicated type I diabetes

Background and aims

Vascular disease is the principal cause of death and disability in patients with diabetes, and endothelial dysfunction seems to be the major cause in its pathogenesis. Since l-arginine levels are diminished in conditions such as type 1 and type 2 diabetes, in this work we aimed to verify the effects of l-arginine supplementation (7 g/day) over the endothelial function and oxidative stress markers in young male adults with uncomplicated type 1 diabetes. We also investigated the influences of l-arginine administration on vascular/oxidative stress responses to an acute bout of exercise.

Methods

Ten young adult male subjects with uncomplicated type 1 diabetes and twenty matched controls volunteered for this study. We analysed the influence of l-arginine supplementation (7 g/day during 1 week) over lower limb blood flow (using a venous occlusion plethysmography technique), oxidative stress marker (TBARS, Carbonyls), anti-oxidant parameters (uric acid and TRAP) and total tNOx in rest conditions and after a single bout of submaximal exercise (VO₂ at 10 % below the second ventilatory threshold). Data described as mean ± standard error (SE). Alpha level was P < 0.05.

Results

Glycaemic control parameters were altered in type 1 diabetic subjects, such as HbA1c (5.5 ± 0.03 vs. 8.3 ± 0.4 %) and fasted glycaemia (94.8 ± 1.4 vs. 183 ± 19 mg/dL). Oxidative stress/damage markers (carbonyls and TBARS) were increased in the diabetic group, while uric acid was decreased. Rest lower limb blood flow was lower in type 1 diabetic subjects than in healthy controls (3.53 ± 0.35 vs. 2.66 ± 0.3 ml 100 ml^?¹ min^?¹). l-Arginine supplementation completely recovered basal blood flow to normal levels in type 1 diabetics’ subjects (2.66 ± 0.3 to 4.74 ± 0.86 ml 100 ml^?¹ min^?¹) but did not interfere in any parameter of redox state or exercise.

Conclusion

Our findings highlight the importance of l-arginine for the improvement of vascular function in subjects with diabetes, indicating that l-arginine supplementation could be an essential tool for the treatment for the disease complications, at least in non-complicated diabetes. However, based on our data, it is not possible to draw conclusions regarding the mechanisms by which l-arginine therapy is inducing improvements on cardiovascular function, but this important issue requires further investigations.