Metabolic Tolerance Research Articles

Bacterial persistence and bet hedging in Sinorhizobium meliloti

We recently described a novel bet-hedging mechanism in which the bacterium Sinorhizobium meliloti responds to starvation by forming two discrete cell types via cell division. The old-pole daughter cell retains most of the resource, polyhydroxybutyrate (PHB) and is capable of surviving long-term starvation, while the low-PHB, new-pole daughter cell is capable of quickly resuming growth when starvation ends. Here we present additional data showing that the high-PHB, old-pole cells are similar to bacterial persisters, characterized by metabolic dormancy and antibiotic tolerance. Using two independent methods, we generated clonal populations of S. meliloti that varied in the frequency of the high- and low-PHB phenotypes, and then challenged these populations with ampicillin. Populations containing more high-PHB cells were significantly more antibiotic-tolerant. In a separate experiment, we used GFP fluorescence as a marker of overall metabolic activity. After 24 hours of starvation, new-pole cells were 64% brighter than their old-pole sister cells, demonstrating that the divergence in metabolic rate is rapid.

Treatment with growth hormone, somatostatin, and insulin in combination with hypocaloric parenteral nutrition in gastrointestinal cancer patients after surgery

Objective The metabolic response to gastrointestinal cancer in patients undergoing surgery is associated with hypermetabolism and insulin resistance. The potential use of synergetic anabolic hormones in conjunction with hypocaloric parenteral nutrition (HPN) has become a significant area of investigation. The presented study was performed to determine the clinical efficiency and safety of hormone therapy combined with HPN in patients with gastrointestinal cancer. Methods One hundred patients with a Nutrition Risk Screening score of 3 or 4 undergoing surgery for gastrointestinal cancer were randomized into two groups. The patients in the control group received standard total parenteral nutrition and systemic insulin. The patients in the study group received HPN and systemic insulin in addition to pretreatment with recombinant human growth hormone and octreotide. Clinical efficiency and safety were evaluated by the measurement of hormones and protein metabolites, immune function, clinical outcome, and adverse events. Follow-ups were performed to determine the influence on prognosis. Results Treatment with recombinant human growth hormone, octreotide, and insulin in combination with HPN significantly increased protein synthesis, immune function, and metabolic tolerance, decreased infectious complications, and shortened postoperative hospital stays, but did not increase the risk of tumor development and recurrence in the study group compared with the control group. Conclusion The proper short-term perioperative administration of growth hormone, somatostatin, and insulin in combination with HPN can overcome the postoperative stress response through the increase of protein synthesis to improve immune function in patients with gastrointestinal cancer after surgery.

Normal citratemia and metabolic tolerance of citrate anticoagulation for hemodiafiltration in severe septic shock burn patients

Anticoagulation during renal replacement therapy remains an important challenge for burn patients due to their high risk of bleeding. In this study we compared the efficacy and safety of citrate anticoagulation to heparin anticoagulation for hemodiafiltration (HDF) in severe burn patients, focusing on metabolic tolerance and handling of citrate. Retrospective observational study (January 2000-December 2007) at a university teaching hospital. Among 548 patients admitted with burns, 70 severe burn septic shock patients (median age 57.5 years, interquartile range 42-76 years; median burned surface area 40%, interquartile range 30-60%) who underwent HDF for more than 24 h were included. Of the 70 HDF patients, 31 at high risk of bleeding were treated with citrate and 39 with heparin, with a mortality rate of 70.9 and 71.8%, respectively. In continuous venovenous hemodiafiltration (CVVHDF), the filter survival was higher with citrate, and hemorrhagic complications were lower (0.035 vs. 0.145 episodes/day, respectively). During citrate CVVHDF [median delivered dialysis dose: 578.9 ml kg(-1) day(-1) (461.5-769.2 ml kg(-1) day(-1))] in catecholamine-supported patients (norepinephrine 0.53 μg kg(-1) min(-1)), no metabolic derangements in pH, bicarbonates, Na+, K+, Ca++, and ionized calcium were observed. Systemic citratemia was within the normal range (<0.4 mmol/l) and was associated with a marked citrate removal in the effluent (5 patients, 36-60% of infused amount). In septic shock burn patients, citrate for CVVHDF was efficient and safe, and superior to heparin for hemorrhagic complications and filter survival. Observed metabolic stability was most likely due to a marked loss of citrate in effluent volume and subsequent low total citrate load for the patient.

Cerebrospinal fluid HIV-1 virological escape with lymphocytic meningitis under lopinavir/ritonavir monotherapy

Cerebrospinal fluid HIV-1 virological escape with lymphocytic meningitis under lopinavir/ritonavir monotherapy

Association of postprandial and fasting triglycerides with traits of the metabolic syndrome in the Metabolic Intervention Cohort Kiel

Postprandial (pp) lipid metabolism is associated with insulin resistance and type 2 diabetes. In young men, pp triglycerides (TGs) are more strongly associated with traits of metabolic syndrome (MS) than fasting TGs. We established a cohort of middle-aged men selected for traits of MS and pp lipid metabolism to determine if fasting TGs or pp TGs are more closely related to MS. A total of 1558 men were characterized for MS. A total of 755 men underwent an oral metabolic tolerance test consisting of a standardized high-fat meal and an oral glucose tolerance test. Blood samples were drawn in the fasting state and hourly until 9 h to determine pp TGs and free fatty acids. Glucose and insulin were analyzed until 5 h pp. In the overall cohort, 329 subjects (21.1%) had a complete MS based on the Adult Treatment Panel III criteria, and 650 subjects (41.7%) had a complete MS based on the International Diabetes Federation criteria. The association of pp TGs with MS parameters was not stronger than the association of fasting TGs with them. Pp TGs were independently associated with beta-cell function. Pp TGs did not show a higher correlation with MS traits than fasting TGs. This finding is probably due to the high incidence of overweight subjects in this middle-aged cohort.

フッ素を含む不斉中心の構築法

Fluorinated compounds have drawn the attention of medicinal chemists because of their potential metabolic tolerance and modulation of drug efficacy. Thus stereo- and enantioselective construction of fluorinated carbon center is an important issue. In spite of remarkable progress in the last decade, the first effective method of catalytic enantioselective fluorination by nucleophilic fluorine reagent has been reported in this year. In this article, construction of fluorinated chiral center is reviewed being categolized into three classes.

Temporal allocation of metabolic tolerance in the body of beet armyworm in response to three gossypol-cotton cultivars

The nutrient composition and enzyme activities in larvae of the beet armyworm, Spodoptera exigua (Hübner), fed on high, medium or low gossypol cotton cultivars were examined at different time intervals. Significantly lower free fatty acid was observed in larvae fed for 6 h on high gossypol 'M9101' compared to larvae fed on the low (ZMS13) and intermediate (HZ401) gossypol cultivars. Significantly higher trypsin activity was observed in larvae fed on high gossypol 'M9101' for 24 h compared to those fed for 1, 4 and 6 h. Significantly higher catalase and total superoxide dismutase enzyme activities were observed in larvae of S. exigua fed on high gossypol 'M9101' compared with low gossypol cultivars 'ZMS13' and 'HZ401' for 1, 4, 6 and 24 h. However, significantly lower carboxylesterase and acetylcholinesterase enzyme activities were found in larvae fed on high gossypol 'M9101' compared with the other cultivars for 1, 4, 6 and 24 h. The interaction between cotton variety and beet armyworm infestation time significantly affected the carboxylesterase enzyme activity in S. exigua. The characterization of the effects of plant allelochemicals on herbivorous larvae is important for aiding understanding of plant-insect interaction as well as in devising solutions to pest problems by breeding plant resistance, identifying metabolic targets for insecticide development, etc.

Photosynthesis, photochemistry and antioxidative defence in response to two drought severities and with re‐watering in Allocasuarina luehmannii

Gas exchange, chlorophyll fluorescence and water potentials, together with ascorbate and glutathione concentrations, were studied during moderate and severe drought stress and in response to re-watering in Allocasuarina luehmannii seedlings. Moderate drought stress (MS) decreased stomatal conductance (g(s)) and net CO(2) assimilation rates (A) to approximately 40% and approximately 60% of control values, respectively, and caused decreases in internal CO(2) concentration (C(i)) and maximum light use efficiency of light-acclimated photosystem II (PSII) centres (Fv'/Fm'). Severe drought stress (SS) decreased g(s) and A to approximately 5% and approximately 15% of the control values, respectively, and caused increases in C(i) and PSII excitation pressure (1 - qP), as well as decreases in water potentials, effective quantum yield of PSII (PhiPSII), maximum efficiency of PSII (Fv/Fm) and Fv'/Fm'. Ascorbate and glutathione concentrations remained unaffected by drought treatments, but ascorbate became more oxidised under severe stress. MS seedlings recovered within 1 day (C(i), Fv'/Fm') to 1 week (A, g(s)) of re-watering. In comparison, SS seedlings had longer-lasting after-stress effects, with recovery of many variables (g(s), water potentials, Fv/Fm, PhiPSII, Fv'/Fm') taking between 1 and 3 weeks from re-watering. We found no indication that interaction with antioxidants played a significant role in recovery. In conclusion, A. luehmannii seedlings appear to function normally under moderate drought, but do not seem to have particular metabolic tolerance mechanisms to endure severe drought, which may have implications for its persistence under climate change at the drier margins of its distribution.

Increase of propofol requirement after repeated administration for experimental anaesthesia

Increase of propofol requirement after repeated administration for experimental anaesthesia

Intra-cornu ammonis 1 administration of the human immunodeficiency virus-1 protein trans-activator of transcription exacerbates the ethanol withdrawal syndrome in rodents and activates N-methyl- d-aspartate glutamate receptors to produce persisting spatial learning deficits

Human immunodeficiency virus-1 (HIV-1) infection may produce neurological deficits, such as cognitive decline, that may be worsened by concurrent ethanol (EtOH) abuse. Among the many biochemical cascades likely mediating HIV-1-associated neuronal injury is enhancement of N-methyl- d-aspartate (NMDA) receptor function and progression to excitotoxicity, an effect that may be directly or indirectly related to accumulation in brain of the HIV-1 trans-activator of transcription (Tat) factor. The present studies were designed to examine the hypothesis that binge-like EtOH pre-exposure would enhance effects of Tat on NMDA receptor function. These studies employed a modified in vivo binge EtOH exposure regimen designed to produce peak blood EtOH levels (BEL) of <200 mg/dl in adult male rats and were designed to examine effects of intra-hippocampal injection of Tat (0.5 μl/500 pM/2 min) on EtOH withdrawal-related behavior, spatial learning, and histological measures. Unilateral cannulae were implanted into the cornu ammonis 1 (CA1) pyramidal cell layer of animals prior to beginning a 4-day binge EtOH regimen. EtOH was administered via intragastric intubation (∼3.0–5.0 g/kg) with dose determined by behavioral ratings of intoxication daily for 4 days (at 08:00, 16:00, and 24:00 h). EtOH withdrawal behaviors were monitored 12 h after the last administration of EtOH. Morris water maze learning was assessed during the following 4 days, at which times brains were harvested for autoradiographic measurement of NMDA receptor density and neuroinflammation. Maximal BELs of 187.69 mg/dl were observed 60 min after EtOH administration on day 2 of the regimen. In contrast, peak BELs of approximately 100 mg/dl were observed 60 min after EtOH administration on day 4 of the regimen, suggesting development of metabolic tolerance. Significant behavioral abnormalities were observed in EtOH withdrawn animals, including tremor and seizures. Intra-CA1 region injection of Tat significantly potentiated EtOH withdrawal behavioral abnormalities, an effect that was reduced by MK-801 pre-exposure. While EtOH withdrawn animals showed learning similar to control animals, EtOH withdrawn animals that received intra-CA1 Tat injection demonstrated persisting deficits in spatial learning on days 3 and 4 of training, effects that were markedly reduced by administration of the competitive NMDA receptor antagonist MK-801 30 min prior to Tat injection. No changes in [ 3H]MK-801 binding were observed. Binding density of [ 3H]PK11195, a ligand for peripheral benzodiazepine receptors expressed on activated microglia, was elevated proximal to cannula tracks in all animals, but was not altered by EtOH or Tat exposure. These findings suggest that EtOH abuse and/or dependence in HIV-positive individuals may promote HIV-1-associated cognitive deficits by altering NMDA receptor function in the absence of microglial activation or neuroinflammation.

Individual variation in macronutrient regulation measured by proton magnetic resonance spectroscopy of human plasma

Proton nuclear magnetic resonance ((1)H-NMR) spectroscopy of plasma provides a global metabolic profiling method that shows promise for clinical diagnostics. However, cross-sectional studies are complicated by a lack of understanding of intraindividual variation, and this limits experimental design and interpretation of data. The present study determined the diurnal variation detected by (1)H NMR spectroscopy of human plasma. Data reduction methods revealed three time-of-day metabolic patterns, which were associated with morning, afternoon, and night. Major discriminatory regions for these time-of-day patterns included the various kinds of lipid signals (-CH(2)- and -CH(2)OCOR), and the region between 3 and 4 ppm heavily overlapped with amino acids that had alpha-CH and alpha-CH(2). The phasing and duration of time-of-day patterns were variable among individuals, apparently because of individual difference in food processing/digestion and absorption and clearance of macronutrient energy sources (fat, protein, carbohydrate). The times of day that were most consistent among individuals, and therefore most useful for cross-sectional studies, were fasting morning (0830-0930), postprandial afternoon (1430-1630), and nighttime samples (0430-0530). Importantly, the integrated picture of metabolism provided by (1)H-NMR spectroscopy of plasma suggests that this approach is suitable to study complex regulatory processes, including eating patterns/eating disorders, upper gastrointestinal functions (gastric emptying, pancreatic, biliary functions), and absorption/clearance of macronutrients. Hence, (1)H-NMR spectroscopy of plasma could provide a global metabolic tolerance test to assess complex processes involved in disease, including eating disorders and the range of physiological processes causing dysregulation of energy homeostasis.

Metabolic Syndrome and Impaired Glucose Tolerance Combination Predict Angiographically Critical Coronary Disease in Patients with Abnormal Stress Echo

Metabolic Syndrome and Impaired Glucose Tolerance Combination Predict Angiographically Critical Coronary Disease in Patients with Abnormal Stress Echo

Medium‐chain fatty acids ameliorate insulin resistance caused by high‐fat diets in rats

High dietary intake of saturated fat impairs insulin sensitivity and lipid metabolism. The influence of fatty acid chain length, however, is not yet fully understood, but evidence exists for different effects of saturated long-chain (LC) versus saturated medium-chain (MC) fatty acids (FA). To investigate the effects of the FA chain length, male Wistar rats were fed high-fat diets containing triacylglycerols composed of either MC- or LCFA for 4 weeks; rats fed maintenance diet served as a control. The animals underwent euglycemic hyperinsulinemic clamping or oral metabolic tolerance testing respectively; enzyme activities of mitochondrial (EC2.3.1.21 carnitine palmitoyl transferase) and peroxisomal (EC1.3.3.6 acyl-CoA oxidase) FA oxidation were measured in liver and muscle. LCFA consumption resulted in higher fasted serum insulin and glucose concentrations compared to controls, while MCFA-fed animals did not differ from controls. Insulin sensitivity was reduced by 30% in the LCFA group while the MCFA group did not differ from controls. Feeding MCFA resulted in the controls' lowered fasted and post-prandial triacylglycerol concentration compared to LCFA, while triacylglycerol concentrations in muscle were higher in both high-fat groups compared to controls. No diet-induced changes were found in acyl-CoA oxidase (ACO) activity (liver and muscle), while LCFA feeding significantly raised carnitine palmitoyltransferase activity. The chain length of saturated fatty acids in isocaloric diets affects insulin sensitivity, lipid metabolism and mitochondrial fatty acid oxidation without influencing body weight. While dietary LCFA clearly impair insulin sensitivity and lipid metabolism, MCFA seem to protect from lipotoxicity and subsequent insulin resistance without caloric restriction.

Boosted darunavir as a new therapeutic option for treatment-naive HIV-infected patients

HIV infection is one of the major global public health problem. Currently, among the specialists, an estimated 33 million people are infected with HIV worldwide. At present, six main classes of antiretroviral drugs exist, and almost all of them are used in antiretroviral therapy regimen in treatment-experienced as well as treatment-naive patients. Protein inhibitors are selective inhibitors of the cleavage of HIV-encoded gag-pol polyproteins. Darunavir, previously known as TMC-114, is a new, second-generation PI. Darunavir has high potency, genetic barrier and very good clinical and metabolic tolerance. In twice-daily dose darunavir is used as a rescue therapy in treatment-experienced patients. However, after ARTEMIS study, it was recently approved in first-line antiretroviral therapy for treatment-naïve HIV-infected patients.

Raltegravir: first integrase inhibitor for the treatment of HIV infection

Raltegravir is the first of the integrase inhibitors to have been approved for treating HIV-1-infected adult patients who have evidence of viral replication and HIV-resistant strains to multiple antiretroviral agents, in combination with other antiretroviral agents. Raltegravir is an inhibitor of strand transfer of reverse-transcribed viral DNA into the host genome, and is administered orally twice daily without boosting. Clinical and pharmacokinetic studies showed strong virological responses, with as yet unmet antiretroviral potency, as well as excellent metabolic tolerance, and a favorable drug drug interaction profile. Further evaluation of possible indications and strategies are needed in terms of long-term tolerability, resistance, penetration in different anatomical compartments, effect on reservoirs, new antiretroviral combinations, first-line treatment, and switching to and treatment intensifications with raltegravir.

Measuring the Effect of a Study Meal on Portal Concentrations of Glucagon-Like Peptide 1 (GLP-1) in Non Diabetic and Diabetic Patients with Liver Cirrhosis: Transjugular Intrahepatic Portosystemic Stent Shunt (TIPSS) as a New Method for Metabolic Measurements

Diabetes in liver cirrhosis is associated with a blunted insulin response, which might be explained by an impaired release of the incretin hormone glucagon-like peptide 1 (GLP-1) into the portal circulation. To investigate basal and stimulated portal venous and peripheral GLP-1 concentrations in non-diabetic (ND) and diabetic (D) patients with liver cirrhosis undergoing transjugular intrahepatic portosystemic stent shunt (TIPSS) implantation. After elective TIPSS portalvenous and peripheral probes were drawn from 10 ND and 10 D patients with stable liver disease during an oral metabolic test and plasma glucose, immunoreactive GLP-1, insulin and C-peptide were measured. The study meal led to a significant rise in portal GLP-1 levels in ND and D. Basal and stimulated portal GLP-1 concentrations were not significantly different between ND and D. Peripheral GLP-1 did not differ significantly from portal venous levels. Insulin response in ND was more pronounced in the portal blood than in the periphery and was absent in D. TIPSS allows a direct evaluation of hormonal changes in the portal circulation during an oral metabolic tolerance test. A disturbed GLP-1 secretion does not play a role in blunting the insulin response observed in patients with hepatogenous diabetes.

The anticonvulsant profile of rufinamide (CGP 33101) in rodent seizure models

To evaluate the anticonvulsant profile and behavioral toxicity of rufinamide in animal seizure models compared to the established antiepileptic drugs (AEDs): phenytoin, phenobarbital, valproate, and ethosuximide, or vehicle. In acute studies of anticonvulsant efficacy, the AEDs were administered via oral (CF1 mice and Sprague-Dawley rats) and intraperitoneal (CF1 mice) routes. The AEDs were assessed for their ability to inhibit seizures induced by maximal electroshock (MES) or subcutaneous pentylenetetrazol, and ability to block seizures induced by subcutaneous strychnine, bicuculline, or picrotoxin. Tolerance of oral rufinamide was assessed in rats following 5-day (versus single-dose) treatment with oral rufinamide using the dose equivalent necessary to achieve a 50% decrease in seizure frequency (ED(50)). Metabolic tolerance was also evaluated using an in vitro liver microsomal assay. Oral rufinamide suppressed pentylenetetrazol-induced seizures in mice (ED(50) 45.8 mg/kg) but not rats, and was active against MES-induced tonic seizures in mice (ED(50) 23.9 mg/kg) and rats (ED(50) 6.1 mg/kg). Intraperitoneal rufinamide suppressed pentylenetetrazol-, bicuculline-, and picrotoxin-induced clonus in mice (ED(50) 54.0, 50.5, and 76.3 mg/kg, respectively). Rufinamide was partially effective in the mouse strychnine test. The behavioral toxicity of rufinamide was similar to or better than established AEDs tested in this study. In general, the protective index of rufinamide was greater than that of the other AEDs. The efficacy and behavioral toxicity profiles in these animal models suggest that rufinamide may be effective in the treatment of generalized and partial seizures.

Ethanol exposure during late gestation and nursing in the rat: Effects upon maternal care, ethanol metabolism and infantile milk intake

Ethanol experiences, during late gestation as well as during nursing, modify the behavioral dynamics of the dam/pup dyad, and leads to heightened ethanol intake in the offspring. This study focuses on: a) behavioral and metabolic changes in intoxicated dams with previous exposure to ethanol during pregnancy and b) infantile consumption of milk when the dam is either under the effects of ethanol or sober. Pregnant rats received water, 1.0 or 2.0 g/kg ethanol, and were administered with water or ethanol during the postpartum period. Intoxication during nursing disrupted the capability of the dam to retrieve the pups and to adopt a crouching posture. These disruptions were attenuated when dams had exposure to ethanol during pregnancy. Ethanol experiences during gestation did not affect pharmacokinetic processes during nursing, whereas progressive postpartum ethanol experience resulted in metabolic tolerance. Pups suckling from intoxicated dams, with previous ethanol experiences, ingested more milk than did infants suckling from ethanol-intoxicated dams without such experience. Ethanol gestational experience results in subsequent resistance to the drug's disruptions in maternal care. Consequently, better maternal care by an intoxicated dam with ethanol experience during gestation facilitates access of pups to milk which could be contaminated with ethanol.

Role of glutamine supplementation in critically ill patients

To update the documentation concerning the clinical use of glutamine supplementation in critically ill patients. Outcome, patient safety and future plans are examined. In terms of outcome studies, the last 2 years have added little to our knowledge. A number of multi-centre studies are under way, however, which can be expected to give better evidence for the use of glutamine in the near future. In terms of patient safety, several new studies have demonstrated metabolic tolerance, vascular tolerance, losses in conjunction with continuous renal replacement therapy and the relation to intracerebral glutamate in head trauma. Glutamine losses in continuous renal replacement therapy are not negligible, and are actually a further argument for exogenous glutamine supplementation. Losses of supplemented glutamine into the dialysate are not a problem. The use of intravenous glutamine supplementation in critically ill patients on total parenteral nutrition is currently the standard of care. The use of exogenous glutamine supplementation in critically ill patients on enteral nutrition is still not supported by sufficient evidence. The use of plasma glutamine concentration as an indicator for glutamine deficiency and a possible indicator for supplementation is suggested.

Quality of Amino Acid Solutions for Preterm Infants

To the Editor. — With great interest, we read the article by Clark et al1 published in the December 2007 issue of Pediatrics. The authors concluded that higher doses of amino acid supplementation did not improve neonatal growth, and might even be unfavorable in terms of metabolic tolerance (increased blood amino acid and urea nitrogen levels). However, we have some comments. Blood chemistry results, including amino acid concentrations, are reported for postnatal days 1, 7, and 28. Regrettably, no such information is provided for day 4, which shows a peak amino acid intake in the “high-dose group” and the largest difference in amino acid intake between groups. We also learn that, for most infants, the parenteral nutrition had been gradually replaced by enteral nutrition. Except for a single value on day 7, however, no …