L-carnitine Infusion Research Articles

Evaluation of the effect of nicotine and O-acetyl-L-carnitine on testosterone-induced spatial learning impairment in Morris water maze and assessment of protein markers

The hippocampus has an essential role in learning and memory and is a target for androgen actions. Thus, the effect of testosterone and its metabolites on learning and memory has attracted researchers' attention.The present study aimed to identify the effects of four-day bilateral intra-hippocampal infusion of nicotine and o-Acetyl L-carnitine alone and in combination on testosterone enanthate (TE)-induced spatial learning deficits using Morris water maze (MWM). The expression of CREB, pCREB and BDNF proteins was quantified using western blots.We observed that bilateral intra-hippocampal infusion of TE significantly impaired spatial learning and a significant decrease in CREB, pCREB and BDNF protein markers compared to a control group that did not receive TE. In addition, administration of O-acetyl L-carnitine and/or nicotine reversed TE-induced spatial learning impairment in behavioural and molecular assessments.Thus, our findings suggest that administration of TE in the hippocampus of adult male rats impairs memory function, possibly via down-regulation of cAMP/PKA-CREB-BDNF signaling pathway.

L-carnitine infusion does not alleviate lipid-induced insulin resistance and metabolic inflexibility.

BackgroundLow carnitine status may underlie the development of insulin resistance and metabolic inflexibility. Intravenous lipid infusion elevates plasma free fatty acid (FFA) concentration and is a model for simulating insulin resistance and metabolic inflexibility in healthy, insulin sensitive volunteers. Here, we hypothesized that co-infusion of L-carnitine may alleviate lipid-induced insulin resistance and metabolic inflexibility.MethodsIn a randomized crossover trial, eight young healthy volunteers underwent hyperinsulinemic-euglycemic clamps (40mU/m2/min) with simultaneous infusion of saline (CON), Intralipid (20%, 90mL/h) (LIPID), or Intralipid (20%, 90mL/h) combined with L-carnitine infusion (28mg/kg) (LIPID+CAR). Ten volunteers were randomized for the intervention arms (CON, LIPID and LIPID+CAR), but two dropped-out during the study. Therefore, eight volunteers participated in all three intervention arms and were included for analysis.ResultsL-carnitine infusion elevated plasma free carnitine availability and resulted in a more pronounced increase in plasma acetylcarnitine, short-, medium-, and long-chain acylcarnitines compared to lipid infusion, however no differences in skeletal muscle free carnitine or acetylcarnitine were found. Peripheral insulin sensitivity and metabolic flexibility were blunted upon lipid infusion compared to CON but L-carnitine infusion did not alleviate this.ConclusionAcute L-carnitine infusion could not alleviated lipid-induced insulin resistance and metabolic inflexibility and did not alter skeletal muscle carnitine availability. Possibly, lipid-induced insulin resistance may also have affected carnitine uptake and may have blunted the insulin-induced carnitine storage in muscle. Future studies are needed to investigate this.

Valproic acid poisoning: is L-carnitine infusion useful to alter pharmacokinetics or improve outcome?

Objectives: Valproic acid (VPA) poisoning causes life-threatening neurological, cardiovascular and metabolic disorders. L-carnitine is used to reverse toxicity without clinical evidence of effectiveness. We aimed to investigate the effects of L-carnitine treatment on VPA pharmacokinetics and its contribution to the patient prognosis.

2417 PEG-Asparaginase (PEG-ASP) Induced Liver Injury: Case Report and Systematic Review of the Literature

INTRODUCTION: Drug induced liver injury (DILI) is the most common cause of acute liver failure (ALF) in the USA. L-asparaginase (L-ASP) and its pegylated form (PEG-ASP) are antineoplastic agents used in acute leukemias. Here we present a case of severe DILI secondary to PEG-ASP and a systematic review of published cases. CASE DESCRIPTION/METHODS: Methods: PubMed search detected 343 abstracts related to ASP, of which 18 were relevant to our case. We used descriptive statistics to compare the published experience with our patient. Case: A 45 yo female with acute lymphoblastic leukemia (ALL) was admitted with a cholestatic liver injury and jaundice 14 days after starting PEG-ASP. She had normal liver enzymes prior to onset of treatment. Tests for viral and autoimmune hepatitis were unremarkable. Diagnostic ultrasound suggested only a fatty liver parenchyma. Liver biopsy revealed severe steatosis and mild cholestasis without fibrosis. Naranjo scale was 6 consistent with probable adverse drug reaction. PEG-ASP was stopped, steroids and L-carnitine infusion were started, however DILI continued to worsen. At their peak Total/direct bilirubin were 21/17 mg/dL, ALP 1,504 U/L, GGT 2,329 U/L and AST/ALT 153/50 U/L. Patient never developed ALF. Liver enzyme panel normalized over the next 8 weeks. Results: In our review of 18 reported cases, most were females (72%), adults (72%), with 32% being adults <50 years. The patterns of liver enzyme abnormality were cholestatic (26%), hepatocellular (21%), or mixed (21%) (unknown in 32%). Median time from starting ASP to DILI was 17 days. When biopsy was performed (11 patients) macrovesicular steatosis was uniformly present. Overall 6 patients died (one died of ALF) and 12 recovered with normalization of liver enzymes over the course of 2-26 weeks. DISCUSSION: Our patient is a classic case of DILI given onset of injury within 2-3 weeks of initiation of treatment, exclusion of alternate etiologies, histopathology showing severe steatosis, and complete normalization of liver enzymes following drug discontinuation. It is important to recognize ASP-DILI as 30% of cases end in ALF or death; nearly all cases will delay important treatment of acute leukemia. L-carnitine was reported as a potential rescue therapy, though its efficacy is uncertain. CONCLUSION: ASP related DILI is marked by severe steatosis and significant liver enzyme abnormalities occurring within weeks of starting treatment and resolving over many weeks after. Prompt recognition and drug discontinuation are imperative.

L-carnitine ameliorated weight loss in fasting therapy: A propensity score-matched study

l-carnitine infusion has been proven to reduce fasting-induced fatigue and hunger in patients with metabolic syndrome in our former study. However, the association between l-carnitine and clinical outcomes of fasting therapy is yet to be investigated. In this study, data from 192 patients who finished fasting therapy from September 2008 to July 2018 were reviewed, among which 142 patients received l-carnitine infusion in fasting regimen. Propensity matching was used to overcome retrospective bias. Patients’ anthropometric measurements and metabolic markers were evaluated. After propensity matching, 40 patients were included in each group. Weight (-4.05 ± 1.65 kg vs -3.25 ± 1.68 kg, P = 0.031) and BMI (-1.51±0.61 kg/m2 vs -1.20 ± 0.62 kg/m2, P = 0.036) decreased in both groups, but significantly more in l-carnitine group, while diastolic blood pressure (-1.67±9.82 mmHg vs -6.21±8.83 mmHg, P = 0.043) and triglycerides (-0.18±0.63 mmol/L vs -1.05±1.70 mmol/L, P = 0.007) decreased significantly more in non-l-carnitine group compared between groups, blood glucose did not differ significantly between groups. l-carnitine can boost the positive effects of fasting therapy on weight loss and maintain the stability of blood pressure.

L-carnitine ameliorated fasting-induced fatigue, hunger, and metabolic abnormalities in patients with metabolic syndrome: a randomized controlled study.

BackgroundThe present study aimed to determine that whether L-carnitine infusion could ameliorate fasting-induced adverse effects and improve outcomes.MethodIn this 7-day, randomized, single-blind, placebo-controlled, pilot study, 15 metabolic syndrome (MetS) patients (11/4 F/M; age 46.9 ± 9.14 years; body mass index [BMI] 28.2 ± 1.8 kg/m2) were in the L-carnitine group (LC) and 15 (10/5 F/M; age 46.8 ± 10.9 years; BMI 27.1 ± 2.3 kg/m2) were in the control group (CT). All participants underwent a 5-day modified fasting therapy introduced with 2-day moderate calorie restriction. Patients in the LC group received 4 g/day of intravenous L-carnitine, while patients in the CT group were injected with saline. Blood pressure (BP), anthropometric characteristics, markers of liver function, metabolic indices (plasma glucose, lipid profiles, uric acid, free fatty acid and insulin) and hypersensitivity C-reactive protein were measured. Perceived hunger was recorded daily by self-rating visual analogue scales. Fatigue was evaluated by Wessely and Powell scores.ResultsIn contrast to the CT group, total cholesterol, alanine aminotransferase, systolic and diastolic BP did not change significantly in the LC group after prolonged fasting. There were significant differences in weight loss (LC −4.6 ± 0.9 vs. CT −3.2 ± 1.1 kg, P = 0.03), and waist circumference (LC −5.0 ± 2.2 vs. CT −1.7 ± 1.16 cm, P < 0.001), waist hip ratio (LC −0.023 ± 0.017 vs. CT 0.012 ± 0.01, P < 0.001), insulin concentration (LC −9.9 ± 3.58 vs. CT −6.32 ± 3.44 µU/mL, P = 0.046), and γ-glutamyltransferase concentration (LC −7.07 ± 6.82 vs. CT −2.07 ± 4.18, P = 0.024). Perceived hunger scores were significantly increased (P < 0.05) in the CT group during starvation, which was alleviated with L-carnitine administration in the LC group. Physical fatigue (LC −3.2 ± 3.17 vs. CT 1.8 ± 2.04, P < 0.001) and fatigue severity (LC −11.6 ± 8.38 vs. CT 8.18 ± 7.32, P < 0.001) were significantly reduced in the LC group but were aggravated in the CT group.ConclusionIntravenous L-carnitine can ameliorate fasting-induced hunger, fatigue, cholesterol abnormalities and hepatic metabolic changes and facilitate fasting-induced weight loss in MetS patients.Trial registrationChiCTR-TNRC-12002835.

Preliminary Safety and Efficacy of L‐carnitine Infusion for the Treatment of Vasopressor‐Dependent Septic Shock

Sepsis is characterized by metabolic disturbances, and previous data suggest a relative carnitine deficiency may contribute to metabolic dysfunction. Studies regarding safety and patient-centered efficacy of carnitine during septic shock are lacking. This was a double-blind randomized control trial of levocarnitine (L-carnitine) infusion vs normal saline for the treatment of vasopressor-dependent septic shock. Patients meeting consensus definition for septic shock with a cumulative vasopressor index ≥ 3 and sequential organ failure assessment (SOFA) score ≥ 5 enrolled within 16 hours of the recognition of septic shock were eligible. The primary safety outcome was difference in serious adverse events (SAEs) per patient between groups. Efficacy outcomes included proportion of patients demonstrating a decrease in SOFA score of 2 or more points at 24 hours and short- and long-term survival. Of the 31 patients enrolled, 16 were in the L-carnitine and 15 were in the placebo arm. There was no difference in SAEs between placebo and intervention (2.1 vs 1.8 SAEs per patient, P = .44). There was no difference in the proportion of patients achieving a decrease in SOFA score of 2 or more points at 24 hours between placebo and treatment (53% vs 44%, P = .59). Mortality was significantly lower at 28 days in the L-carnitine group (4/16 vs 9/15, P = .048), with a nonsignificant improved survival at 1 year (P = .06). L-carnitine infusion appears safe in vasopressor-dependent septic shock. Preliminary efficacy data suggest potential benefit of L-carnitine treatment, and further testing is indicated.

Feed restriction, but not l-carnitine infusion, alters the liver transcriptome by inhibiting sterol synthesis and mitochondrial oxidative phosphorylation and increasing gluconeogenesis in mid-lactation dairy cows

Abomasal carnitine infusion during acute feed restriction increases hepatic fatty acid oxidation and decreases liver lipid in dairy cows. Eight mid-lactation Holstein cows were used in a replicated 4×4 Latin square design with 14-d periods. A 2×2 factorial arrangement was used to determine the effects of water infusion+ad libitum dry matter intake (DMI), water infusion+restricted DMI (50% of previous 5-d average), l-carnitine infusion (20g/d)+ad libitum DMI, or l-carnitine infusion+restricted DMI. Liver RNA from 7 healthy cows was used for transcriptome profiling using a bovine microarray. An ANOVA with a false discovery rate was used to identify treatment and interaction effects. A substantial transcriptome change was observed only with DMI restriction, resulting in 312 (155 downregulated, 157 upregulated) differentially expressed genes. Quantitative PCR was performed to verify microarray data and measure expression of additional genes not present on the microarray. The quantitative PCR data confirmed the effect of feed restriction but not of l-carnitine treatment. Feed restriction increased expression of GPX3 and of genes associated with gluconeogenesis (PC, PDK4), inflammation (SAA3), and signaling (ADIPOR2). In contrast, feed restriction downregulated BBOX, a key for l-carnitine biosynthesis, and the transcription factor HNF4A. The bioinformatics functional analysis of genes affected by DMI restriction uncovered biosynthesis of cholesterol and energy generation by mitochondrial respiration as the most relevant and inhibited functions. The data also indicated an increase of flux toward gluconeogenesis. We interpreted those results as a likely response of the liver to spare energy and provide glucose for the lactating mammary gland during feed deprivation.

Vegetarians have a reduced skeletal muscle carnitine transport capacity

Ninety-five percent of the body carnitine pool resides in skeletal muscle where it plays a vital role in fuel metabolism. However, vegetarians obtain negligible amounts of carnitine from their diet. We tested the hypothesis that muscle carnitine uptake is elevated in vegetarians compared with that in nonvegetarians to maintain a normal tissue carnitine content. Forty-one young (aged ≈22 y) vegetarian and nonvegetarian volunteers participated in 2 studies. The first study consisted of a 5-h intravenous infusion of l-carnitine while circulating insulin was maintained at a physiologically high concentration (≈170 mU/L; to stimulate muscle carnitine uptake) or at a fasting concentration (≈6 mU/L). The second study consisted of oral ingestion of 3 g l-carnitine. Basal plasma total carnitine (TC) concentration, 24-h urinary TC excretion, muscle TC content, and muscle carnitine transporter [organic cation transporter 2 (OCTN2)] messenger RNA and protein expressions were 16% (P < 0.01), 58% (P < 0.01), 17% (P < 0.05), 33% (P < 0.05), and 37% (P = 0.09) lower, respectively, in vegetarian volunteers. However, although nonvegetarians showed a 15% increase (P < 0.05) in muscle TC during l-carnitine infusion with hyperinsulinemia, l-carnitine infusion in the presence or absence of hyperinsulinemia had no effect on muscle TC content in vegetarians. Nevertheless, 24-h urinary TC excretion was 55% less in vegetarians after l-carnitine ingestion. Vegetarians have a lower muscle TC and reduced capacity to transport carnitine into muscle than do nonvegetarians, possibly because of reduced muscle OCTN2 content. Thus, the greater whole-body carnitine retention observed after a single dose of l-carnitine in vegetarians was not attributable to increased muscle carnitine storage.

Chronic oral ingestion of l‐carnitine and carbohydrate increases muscle carnitine content and alters muscle fuel metabolism during exercise in humans

We have previously shown that insulin increases muscle total carnitine (TC) content during acute i.v. l-carnitine infusion. Here we determined the effects of chronic l-carnitine and carbohydrate (CHO; to elevate serum insulin) ingestion on muscle TC content and exercise metabolism and performance in humans. On three visits, each separated by 12 weeks, 14 healthy male volunteers (age 25.9 ± 2.1 years, BMI 23.0 ± 0.8 kg m−2) performed an exercise test comprising 30 min cycling at 50% , 30 min at 80% , then a 30 min work output performance trial. Muscle biopsies were obtained at rest and after exercise at 50% and 80% on each occasion. Following visit one, volunteers ingested either 80 g of CHO (Control) or 2 g of l-carnitine-l-tartrate and 80 g of CHO (Carnitine) twice daily for 24 weeks in a randomised, double blind manner. All significant effects reported occurred after 24 weeks. Muscle TC increased from basal by 21% in Carnitine (P < 0.05), and was unchanged in Control. At 50% , the Carnitine group utilised 55% less muscle glycogen compared to Control (P < 0.05) and 31% less pyruvate dehydrogenase complex (PDC) activation compared to before supplementation (P < 0.05). Conversely, at 80% , muscle PDC activation was 38% higher (P < 0.05), acetylcarnitine content showed a trend to be 16% greater (P < 0.10), muscle lactate content was 44% lower (P < 0.05) and the muscle PCr/ATP ratio was better maintained (P < 0.05) in Carnitine compared to Control. The Carnitine group increased work output 11% from baseline in the performance trial, while Control showed no change. This is the first demonstration that human muscle TC can be increased by dietary means and results in muscle glycogen sparing during low intensity exercise (consistent with an increase in lipid utilisation) and a better matching of glycolytic, PDC and mitochondrial flux during high intensity exercise, thereby reducing muscle anaerobic ATP production. Furthermore, these changes were associated with an improvement in exercise performance.

Ameliorating Hypertension and Insulin Resistance in Subjects at Increased Cardiovascular Risk

Insulin resistance, a key component of the metabolic syndrome, is a risk factor for diabetes mellitus and cardiovascular disease. Acetyl-L-carnitine infusion acutely ameliorated insulin sensitivity in type 2 diabetics with insulin resistance. In this sequential off-on-off pilot study, we prospectively evaluated the effects of 24-week oral acetyl-L-carnitine (1 g twice daily) therapy on the glucose disposal rate (GDR), assessed by hyperinsulinemic euglycemic clamps, and components of the metabolic syndrome in nondiabetic subjects at increased cardiovascular risk a priori segregated into 2 groups with GDR < or =7.9 (n=16) or >7.9 (n=16) mg/kg per minute, respectively. Baseline GDR and systolic blood pressure were negatively correlated (n=32; P=0.001; r=-0.545), and patients with GDR < or =7.9 mg/kg per minute had higher systolic/diastolic blood pressure than those with higher GDR. Acetyl-L-carnitine increased GDR from 4.89+/-1.47 to 6.72+/-3.12 mg/kg per minute (P=0.003, Bonferroni-adjusted) and improved glucose tolerance in patients with GDR < or =7.9 mg/kg per minute, whereas it had no effects in those with higher GDRs. Changes in GDR were significantly different between groups (P=0.017, ANCOVA). Systolic blood pressure decreased from 144.0+/-13.6 to 135.1+/-8.4 mm Hg and from 130.8+/-12.4 to 123.8+/-10.8 mm Hg in the lower and higher GDR groups, respectively (P<0.05 for both; P<0.001 overall) and progressively recovered toward baseline over 8 weeks posttreatment. Total and high molecular weight adiponectin levels followed specular trends. Diastolic blood pressure significantly decreased only in those with higher GDRs. Treatment was well tolerated in all of the patients. Acetyl-L-carnitine safely ameliorated arterial hypertension, insulin resistance, impaired glucose tolerance, and hypoadiponectinemia in subjects at increased cardiovascular risk. Whether these effects may translate into long-term cardioprotection is worth investigating.

Effect of l-Carnitine Infusion and Feed Restriction on Carnitine Status in Lactating Holstein Cows

Previously we determined that abomasal infusion of l-carnitine increased in vitro hepatic fatty acid oxidation, decreased liver lipid accumulation, and supported higher fat-corrected milk yield in feed-restricted lactating cows. The objectives of this study were to examine the effects of supplemental l-carni-tine and amount of feed intake on free carnitine and carnitine ester concentrations in liver, muscle, milk, and plasma of lactating dairy cows. Eight lactating Holstein cows (132±36 d in milk) were used in a replicated 4×4 Latin square design with 14-d periods to test factorial combinations of water or l-carnitine infusion (20g/d; d 5 to 14) and ad libitum or restricted (50% of previous 5-d intake; d 10 to 14) dry matter intake. Plasma was obtained 3 times daily on d 4, 8, and 12; milk samples were collected on d 8, 9, 13, and 14. Liver and muscle were biopsied on d 14 of each period. Free carnitine, short-chain acylcarnitine, and long-chain acylcarnitine concentrations were determined using a radioenzymatic assay coupled with ion exchange chromatography. Abomasal l-carnitine infusion increased total carnitine in plasma on d 8 and d 12. All liver carnitine fractions were increased by carnitine infusion. Feed restriction elevated concentrations of free carnitine, long-chain acylcarnitine, and total carnitine in liver tissue from carnitine-infused cows but not in those infused with water. In muscle, acid-soluble carnitine, long-chain acylcarnitine, and total carnitine concentrations were increased by carnitine infusion and feed restriction without significant interaction. Feed restriction increased free carnitine concentrations in muscle from water-infused cows but not in carnitine-infused cows. Carnitine infusion increased the concentration of each milk carnitine fraction as well as milk carnitine output on d 8 to 9. On d 13 to 14, all carnitine fractions except short-chain acylcarnitine were increased in milk from water-infused, feed-restricted cows, whereas all fractions were increased in carnitine-infused, feed-restricted cows. Carnitine infusion increased total carnitine in plasma, liver, muscle, and milk during feed restriction, whereas feed restriction alone increased carnitine concentrations in muscle and milk but not in liver. Liver carnitine concentrations might limit hepatic fatty acid oxidation capacity in dairy cows during the periparturient period; therefore, supplemental l-carnitine might decrease liver lipid accumulation in periparturient cows.

Metabolic Effects of Abomasal l-Carnitine Infusion and Feed Restriction in Lactating Holstein Cows

l-Carnitine is required for mitochondrial fatty acid oxidation, but the effects of carnitine supplementation on nutrient metabolism during dry matter intake depression have not been determined in dairy cows. Studies in other species have revealed responses to l-carnitine that may be of specific benefit to dairy cows during the periparturient period. Eight lactating Holstein cows (132±36 d in milk) were used in a replicated 4×4 Latin square experiment with 14-d periods. Treatments were factorial combinations of abomasal infusion of either water or l-carnitine (20g/d; d 5 to 14) and either ad libitum or restricted intake (50% of previous 5-d dry matter intake; d 10 to 14) of a balanced lactation diet. Liver and muscle biopsies were obtained on d 14 of each period. Feed restriction induced negative balances of energy and metabolizable protein. In feed-restricted cows, carnitine infusion increased 3.5% fat-corrected milk yield compared with those infused with water. Total carnitine concentration in liver was increased in feed-restricted cows infused with carnitine but not in feed-restricted cows infused with water. Carnitine infusion stimulated in vitro oxidation of [1-14C] palmitate to acid-soluble products and decreased the proportion of [1-14C] palmitate that was converted to esterified products by liver slices. Feed-restricted cows infused with carnitine had lower liver total lipid concentration and tended to have decreased triglyceride accumulation compared with feed-restricted cows infused with water. Plasma nonesterified fatty acid concentration was not altered by carnitine infusion but was increased by feed restriction; serum β-hydroxybutyric acid was increased by carnitine infusion in feed-restricted cows. In cows fed for ad libitum intake, carnitine infusion affected β-hydroxybutyric acid, insulin, and urea N in serum, liver glycogen concentration, and in vitro alanine oxidation by liver slices, suggesting that hepatic and peripheral nutrient metabolism was influenced. l-Carnitine infusion effectively decreased liver lipid accumulation during feed restriction as a result of greater capacity for hepatic fatty acid oxidation. Further research examining dietary supplementation of l-carnitine during the periparturient period is warranted.

A threshold exists for the stimulatory effect of insulin on plasmal-carnitine clearance in humans

Maintaining hyperinsulinemia ( approximately 160 mU/l) during steady-state hypercarnitinemia ( approximately 550 mumol/l) increases skeletal muscle total carnitine (TC) content by approximately 15% within 5 h. The aim of the present study was to further examine the relationship between serum insulin concentration and skeletal muscle carnitine accumulation by attempting to identify the serum insulin concentration at which this stimulatory effect of insulin on carnitine retention becomes apparent. On four randomized experimental visits, eight healthy men (body mass index 23.8 +/- 0.9 kg/m(2)) underwent a 6-h euglycemic insulin clamp of 5, 30, 55, or 105 mU x m(-2) x min(-1) accompanied by a 5-h iv infusion of l-carnitine (15 mg/kg bolus followed by 10 mg x kg(-1) x h(-1)). The clamps produced steady-state serum insulin concentrations of 10.1 +/- 0.5, 48.8 +/- 1.0, 88.9 +/- 2.8, and 173.9 +/- 6.5 mU/l, respectively. During l-carnitine infusion, plasma TC concentration remained above 450 mumol/l during all four visits. However, there was a significant treatment effect of insulin (P < 0.001), such that by the end of infusion the plasma TC concentration in the 55- and 105-mU clamps was lower than that seen in the 5- (P < 0.05 and P < 0.01, respectively) and 30-mU (P < 0.01) clamps. The findings demonstrate that only high circulating serum insulin concentrations (> or =90 mU/l) are capable of stimulating skeletal muscle carnitine accumulation. This is of relevance to athletes, and the treatment of obesity and type 2 diabetes, where increasing skeletal muscle carnitine content may be used as tool to modify skeletal muscle energy metabolism.

L‐Carnitine and level of feed intake alter hepatic nutrient metabolism and tissue carnitine distribution in lactating dairy cows

Dairy cows are prone to excessive hepatic lipid accumulation around parturition. Carnitine stimulates fatty acid oxidation by bovine liver slices and may prevent or reduce hepatic lipid accumulation. Eight lactating cows were used in a replicated 4 × 4 Latin square design. Treatments were factorial combinations of feed intake (FI) restriction and abomasal carnitine (20 g/d) infusion: water infusion + ad libitum FI (WA), water infusion + restricted FI (WR), carnitine infusion + ad libitum FI (CA), carnitine infusion + restricted FI (CR). Each period of 14 d consisted of infusions on d 5–14, restricted FI imposed on d 10–14, and liver and muscle biopsies obtained on d 14 of each period. Milk was sampled on d 9 and 14. L-carnitine infusion increased the rate and proportion of palmitate oxidation and decreased the proportion of palmitate esterified by liver slices (P < 0.05). Liver triacylglycerol concentration tended to be lower (P < 0.10) in WA, CA, and CR (0.3% wet basis) than in WR (0.9%). Restricted FI reduced propionate conversion to CO2 by liver slices. Alanine conversion to CO2 was higher in CA versus other treatments. Conversion of alanine and propionate to glucose was unaffected by treatment. Liver carnitine was not altered in WR compared with WA, but was elevated in CR versus CA. Muscle carnitine was increased by carnitine infusion and restricted FI without interaction. Carnitine infusion increased milk carnitine content on d 9, while carnitine infusion and restricted FI increased milk carnitine content on d 14. L-Carnitine prevents hepatic lipid accumulation in feed-restricted lactating dairy cows. Supported by Lonza, Inc. (Allendale, NJ).

Insulin stimulates L‐carnitine accumulation in human skeletal muscle

Increasing skeletal muscle carnitine content may alleviate the decline in muscle fat oxidation seen during intense exercise. Studies to date, however, have failed to increase muscle carnitine content, in healthy humans, by dietary or intravenous L-carnitine administration. We hypothesized that insulin could augment Na+-dependent skeletal muscle carnitine transport. On two randomized visits, eight healthy men underwent 5 h of intravenous L-carnitine infusion with serum insulin maintained at fasting (7.4+/-0.4 mIU*l(-1)) or physiologically high (149.2+/-6.9 mIU*l(-1)) concentrations. The combination of hypercarnitinemia (approximately 500 micromol*l(-1)) and hyperinsulinemia increased muscle total carnitine (TC) content from 22.0 +/- 0.9 to 24.7 +/- 1.4 mmol*(kg dm)(-1) (P<0.05) and was associated with a 2.3 +/- 0.3-fold increase in carnitine transporter protein (OCTN2) mRNA expression (P<0.05). Hypercarnitinemia in the presence of a fasting insulin concentration had no effect on either of these parameters. This study demonstrates that insulin can acutely increase muscle TC content in humans during hypercarnitinemia, which is associated with an increase in OCTN2 transcription. These novel findings may be of importance to the regulation of muscle fat oxidation during exercise, particularly in obesity and type 2 diabetes where it is known to be impaired.

Intoxications graves par l'acide valproïque

The incidence of valproic acid (VPA) intoxication has increased by more than 129% since 1995, particularly in the United States. Approximately 50% of the patients express only minor effects, and mortality reaches 2%. Life-threatening poisoning is thus rare, and not systematically related to a very high VPA plasmatic level: some severe forms are due to a metabolic diversion caused by a secondary deficit in carnitine. The structural configuration of VPA is close to that of the fatty acids. VPA may interfere with fatty acids during the transport (related to the carnitine), the intra-mitochondrial metabolism (β-oxidation) and the elimination steps (related to the carnitine). It can result in a metabolic diversion with the development of a hyperammoniemia, a hyperlactatemia and a coma. Infusion of l-carnitine, together with supportive treatment, could be helpful for the correction of the metabolic disorders. The effectiveness of l-carnitine was shown at the experimental level and several clinical cases suggested its usefulness, but a prospective and randomized study remains to be carried out.

Prevention of Postischemic Spinal Cord Injury by Means of Regional Infusion of Adenosine and l-carnitine Dissolved in Normothermic Saline

Spinal cord ischemia still remains an unsolved problem in modern aortic surgery. In this study, we investigated the effectiveness of combined agents such as adenosine and L-carnitine infused to the isolated segment of abdominal aorta in a rabbit model. Twenty-eight rabbits divided into four groups underwent 40 min of isolated infrarenal aortic occlusion. Group I animals received no medication. Group II received an infusion of 100 mg/kg L-carnitine in normothermic saline over the first 10 min of ischemia. Group III received 50 mg adenosine, and group IV received a combination of the two agents in the same fashion. Spinal cord function was evaluated at 24 and 72 hr after operation on the basis of Tarlov scale and similar results were obtained. After a second evaluation, spinal cords were harvested for histological examination. Group I animals were all paraplegics. Spinal cord function was partially intact in two of the group II animals with Tarlov scores of 5 in two and 4 in two whereas one of the rabbits could not hop with a score of 3, and the remaining two could not sit with scores of 1 and 0. The spinal cord function of group III animals was intact with Tarlov scores of 5 in three, 4 in two, and 3 and 1 in remaining ones. In the group IV animals, it was fully intact with Tarlov scores of 5. Histological examination in group I revealed marked enlargement of the vacuoles of glial cells in the white matter of spinal cord. Glial cells were deteriorated in some locations in group II whereas they were mostly protected in the third group. In group IV, histological examination revealed no evidence of spinal cord injury. In conclusion, combined infusion of adenosine and L-carnitine provided better protection against postischemic spinal cord injury than individual infusion of these agents.

Acetyl- l-carnitine infusion increases glucose disposal in type 2 diabetic patients

Little information is available in the literature on the effect of L-carnitine to improve glucose disposal in healthy control subjects and type 2 diabetic patients. No data are reported on the pharmacological properties of acetyl-L-carnitine (ALC) in type 2 diabetes mellitus. The present study evaluates glucose uptake and oxidation rates with either ALC or placebo administration in 18 type 2 diabetic patients. On different days, each patient received both a primed-constant infusion of ALC (5 mg/kg body weight [BW] priming bolus and either 0.025, 0.1, or 1.0 mg/kg BW/min constant infusion) and a comparable placebo formulation. During the infusion period, continuous indirect calorimetric monitoring and a euglycemic-hyperinsulinemic clamp (EHC) study were performed. The total end-clamp glucose tissue uptake (M value) was significantly increased by the administration of ALC (from 3.8 to 5.2 mg/kg/min, P = .006), and the dose dependence of this effect reached borderline statistical significance (P = .037). The increase in the M/I ratio was also highly significant after ALC administration (from 3.9 to 5.8 x 10(-2) mg/kg/min/(microUI/mL, P < .001), while no statistically significant effect was attributable to the different dosages. The increase in the M value was related to increased glucose storage (highly significant effect of ALC) rather than increased glucose oxidation (no statistical significance). In conclusion, the effect of ALC on glucose disposal has no relationship to the amount administered. This could be due to an effect of ALC on the enzymes involved in both the glycolytic and gluconeogenetic pathways, and a possible reversibility of glycogen synthase inhibition in diabetic subjects.

Entry of [(1,2-13C2)acetyl]-L-carnitine in liver tricarboxylic acid cycle and lipogenesis: a study by 13C NMR spectroscopy in conscious, freely moving rats.

The biochemical pathways involved in acetyl-L-carnitine utilization were investigated in conscious, freely moving rats by 13C NMR spectroscopy. Following 4-h [(1,2-13C2)acetyl]-L-carnitine infusion in fasted animals, the free carnitine levels in serum were increased, and an efflux of unlabelled acetyl-L-carnitine from tissues was observed. [(1,2-13C2)Acetyl]-L-carnitine was found to enter biosynthetic pathways in liver, and the acetyl moiety was incorporated into both cholesterol and 3-hydroxybutyrate carbon skeleton. In accord with the entry of [(1,2-13C2)acetyl]-L-carnitine in the mitochondrial acetylCoA pool associated with tricarboxylic acid cycle, the 13C label was also found in liver glutamate, glutamine, and glutathione. The analysis of the 13C-labelling pattern in 3-hydroxybutyrate and cholesterol carbon skeleton provided evidence that the acetyl-L-carnitine-derived acetylCoA pool used for ketone bodies synthesis in mitochondria was homogeneous, whereas cholesterol was synthesized from two different acetylCoA pools located in the extra- and intramitochondrial compartment, respectively. Furthermore, cholesterol molecules were shown to be preferentially synthesized by the metabolic route involving the direct channelling of CoA-activated mitochondria-derived ketone bodies into 3-hydroxy-3-methylglutarylCoA pathway, prior to equilibration of their acyl groups with extramitochondrial acetylCoA pool via acetoacetylCoA thiolase.