Role of carnitine in promoting the effect of antidiabetic biguanides on hepatic ketogenesis.

Effects of biguanides on carnitine content of rat and guinea pig liver and on capacity of rat liver slices for ketogenesis were studied. In acute experiments, fed. 24-hour and 48-hour fasted male rats were given a single dose ofbuformin and the carnitine and acetylearnitine level in the tissues were determined 1 or 3 hr afterwards. The same was performed on fed guinea pigs. In all the 1-hr groups we found an increase ranging from 30 to 50 per cent in hepatic carnitine level. In chronic experiments rats were treated with buformin or metformin for 6 days. The carnitine content, carnitine acetyltransferase and carnitine palmitoyltransferase activities were determined. The respective carnitine levels in the buformin- and metformin-treated groups were 4 times and 2.5 times the control value expressed on a per gram basis. In addition, carnitine acetyltransferase activity, given as mU/mg mitochondrial protein, increased 2-fold in the buformin-treated group. The increase in carnitine content strongly suggests that liver has enhanced capacity for oxidation of fatty acids and consequently for production of ketone bodies. The latter has been verified in the chronic experiments by the following observations: (1) The buformin administration increased the total ketone body content of the freeze-clamped liver specimens to 210 per cent of the control value. The calculated mitochondrial NAD⁺/NADH ratio was reduced from 10.6 to 5.96 in the same specimens. (2) the liver slices from treated animals formed 30–40 per cent more ketone bodies than those from control ones during the 30-min and 60-min incubations. (3) The ketone body associated radioactivity deriving from Na-[1¹⁴-C] palmitate accounted for 90.5 per cent of water soluble radioactivity in slices from treated animals, whereas it accounted for 66.8 per cent in slices from control ones.     

Pharmacokinetics of IV and oral acetyl-L-carnitine in a multiple dose regimen in patients with senile dementia of Alzheimer type

Summary Acetyl-L-carnitine (ALC), a physiological component of the L-carnitine family, has been proposed for treating Alzheimer's disease in pharmacological doses. As this condition requires prolonged therapy, its kinetics has been examined after a multiple dose regimen, involving different routes of administration, in 11 patients suffering from Senile Dementia of Alzheimer Type.The study design comprised a 3-day basal observation period, sham treatment with repeated blood sampling; treatment with 30 mg·kg^–1 i.v. given twice for 10 days (plasma kinetics was studied on the 7th day), and 50 days of 2.0 g/day p.o. given in three daily doses. Total acid soluble L-carnitine, L-carnitine and acetyl-L-carnitine in plasma and CSF were evaluated using an enantioselective radioenzyme assay. Short chain L-carnitine esters were calculated as the difference between total and free-L-carnitine.The plasma concentrations of individual components of the L-carnitine family did not change during the three days of the basal period, nor were they affected during the sham therapy period.Following the i.v. bolus injections, the plasma concentrations showed a biphasic curve, with average t_1/2 of 0.073 h and 1.73 h, respectively.At the end of oral treatment, plasma acetyl-L-carnitine and L-carnitine short chain esters were significantly higher than during the run-in phase.The CSF concentrations paralleled those in plasma, suggesting that ALC easily crosses the blood-brain barrier.It is concluded that i.v. and oral administration of multiple doses of ALC can increase its plasma and CSF concentration in patients suffering from Alzheimer's disease.     

Morbid Obesity,Gastric Plication and a Severe Neurological Deficit

ABSTRACT. SomerH, BergstrÖm L, Mustajoki P, Rovamo L. (Department of Neurology, Third Department of Internal Medicine and Children's Hospital, University of Helsinki, Helsinki, Finland.) Morbid obesity, gastric plication and a severe neurological deficit. A 39-year-old man had protracted vomiting after gastric plication for morbid obesity. Within three months he lost 53 kg in weight and developed neuromuscular weakness, especially in the lower extremities. Clinical and laboratory studies suggested both radicular and peripheral neuropathy. One year later the condition was only marginally improved: he took only few steps unsupported. The apparent etiology is malnutrition but the primary cause remained unknown.     

Decrease of serum carnitine levels in patients with or without gastrointestinal cancer cachexia

AIM: To evaluate the levels of serum carnitine in patients with cancer in digestive organs and to compare them with other cancers in order to provide new insights into the mechanisms of cachexia. METHODS: Fifthy-flve cachectic patients with or without gastrointestinal cancer were enrolled in the present study. They underwent routine laboratory investigations, including examination of the levels of various forms of carnitine present in serum (i.e., long-chain acylcarnitine, short-chain acylcarnitine, free carnitine, and total carnitine). These values were compared with those found in 60 cancer patients in good nutritional status as well as with those of 30 healthy control subjects. RESULTS: When the cachectic patients with gastrointestinal cancer were compared with the cachectic patients without gastrointestinal cancer, the difference was -6.8μmol/L in free carnitine (P < 0.005), 0.04μmol/ L in long chain acylcarnitine (P < 0.05), 8.7μmol/L in total carnitine (P < 0.001). In the cachectic patients with or without gastrointestinal cancer, the difference was 12.2μmol/L in free carnitine (P < 0.001), 4.60μmol/L in short chain acylcarnitine (P < 0.001), and 0.60μmol/L in long-chain acylcarnitine (P < 0.005) and 17.4μmol/L in total carnitine (P < 0.001). In the cachectic patients with gastrointestinal cancer and the healthy control subjects, the difference was 15.5μmol/L in free carnitine (P < 0.001), 5.2μmol/L in short-chain acylcarnitine (P < 0.001), 1.0 umol/L in long chain acylcarnitine (P < 0.001), and 21.8 umol/L in total carnitine (P < 0.001). CONCLUSION: Low serum levels of carnitine in terminal neoplastic patients are decreased greatly due to the decreased dietary intake and impaired endogenous synthesis of this substance. These low serum carnitine levels also contribute to the progression of cachexia in cancer patients.     

Competition between acetate and oleate for the formation of malonyl-CoA and mitochondrial acetyl-CoA in the perfused rat heart

We previously showed that, in the perfused rat heart, the capacity of n-fatty acids to generate mitochondrial acetyl-CoA decreases as their chain length increases. In the present study, we investigated whether the oxidation of a long-chain fatty acid, oleate, is inhibited by short-chain fatty acids, acetate or propionate (which do and do not generate mitochondrial acetyl-CoA, respectively). We perfused rat hearts with buffer containing 4 mM glucose, 0.2 mM pyruvate, 1 mM lactate, and various concentrations of either (i) [U-(13)C]acetate, (ii) [U-(13)C]acetate plus [1-(13)C]oleate, or (iii) unlabeled propionate plus [1-(13)C]oleate. Using mass isotopomer analysis, we determined the contributions of the labeled substrates to the acetyl moiety of citrate (a probe of mitochondrial acetyl-CoA) and to malonyl-CoA. We found that acetate, even at low concentration, markedly inhibits the oxidation of [1-(13)C]oleate in the heart, without change in malonyl-CoA concentration. We also found that propionate, at a concentration higher than 1 mM, decreases (i) the contribution of [1-(13)C]oleate to mitochondrial acetyl-CoA and (ii) malonyl-CoA concentration. The inhibition by acetate or propionate of acetyl-CoA production from oleate probably results from a competition for mitochondrial CoA between the CoA-utilizing enzymes.     

Decline of life’s energy theory of ageing 1. Revitalisation of energy metabolism and ageing mitochondria

This article discusses the decline in mitochondrial energy production capability that occurs as animals age. Correlation is made between age-related mitochondrial functionality decline, lower growth hormone (GH) secretion and declining mitochondrial component levels and the chronic wasting conditions that arise as a consequence. During the past few years a number of patents have been issued that have utilised compositions containing the nutraceuticals carnitine, acetyl carnitine and their derivatives to therapeutically treat problems of energy metabolism. The administration of carnitine derivatives will improve the quality of living during the period of life when the body’s energy declines. The significance of the patented therapeutic use of carnitine derivatives to re-establish mitochondrial functionality and its relationship to the ageing process are reviewed.     

Autopsy case of the neonatal form of carnitine palmitoyltransferase-II deficiency triggered by a novel disease-causing mutation del1737C

Carnitine palmitoyltransferase-II (CPT-II) deficiency is an autosomal recessive disease involving mitochondrial long-chain fatty acid oxidation that results in a distinct clinical phenotype. Reported herein is an autopsy case of the neonatal form of CPT-II deficiency in a 2-day-old Japanese boy who died due to a severe hepatocardiomuscular disease with an extremely early onset. Autopsy examination indicated massive pulmonary atelectasis with intra-alveolar hemorrhage, and the patient had marked cardiomegaly and hepatomegaly, both of which demonstrated the presence of abundant intracytoplasmic steatosis. Three years after the autopsy examination, CPT-II deficiency was suggested by acylcarnitine analysis of dried-blood on filter paper from the patient's younger sister at the age of 1. The younger sister also died due to sudden onset of cardiopulmonary arrest; a remarkable increase of long-chain (C16–18) acylcarnitines was detected on tandem mass spectrometry (TMS). Decreased CPT-II expression was detected in the liver, heart and kidney of the patient. Furthermore, del1737C, a novel mutation of the CPT-II gene, was detected as well as a known GA transition at codon 174. Eventually, laboratory and autopsy findings led to diagnosis of the neonatal form of CPT-II deficiency. TMS can be expected to be widely used to detect metabolic disorders in neonates.     

Allelic and phenotypic heterogeneity in 49 Italian patients with the muscle form of CPT-II deficiency

As genotype-phenotype correlations require the study of large patient populations, we investigated 49 Italian patients (33 unreported) with the muscle form of carnitine-palmitoyl-transferase-II (CPT-II) deficiency and CPT2 gene mutations. CPT enzyme activity below 25% of controls would lead to the development of muscle symptoms, and CPT activity below 15% would cause a relatively severe phenotype of the muscle form. Of the 15 different mutations found, 6 are novel (40%). A functional significance of mutations could be derived only for the two homozygous missense mutations found: both the p.S113L and the p.R631C (recurring in four unrelated patients from a genetic isolate) alleles caused a severe CPT enzyme defect (15% and 7%, respectively) and a relatively severe clinical phenotype of the muscle form. We identified three genotypes (homozygous p.R631C, homozygous p.S113L, and heterozygous null mutations) usually associated with a relatively severe and often life-threatening condition, which should be considered both in the clinical management of newly diagnosed patients (to prevent symptoms) and in their possible inclusion in therapeutic trials. We confirmed the existence of symptomatic heterozygous patient(s), through a family study, providing an important issue when offering genetic counseling and suggesting the crucial role of polymorphisms or environmental factors in determining the phenotype.     

The efficacy of combined l-carnitine and l-acetyl carnitine in men with idiopathic oligoasthenoteratozoospermia: A systematic review and meta-analysis

The purpose of our analysis is to identify the effect of l -carnitine (LC) and l -acetyl carnitine (LAC) on the semen parameters of men with idiopathic oligoasthenoteratozoospermia (iOAT). We performed a comprehensive search to ascertain all the trials about LC and LAC in the treatment of iOAT and compared the results, including percentage of total sperm motility, sperm concentration, percentage of forward sperm motility, semen volume, percentage of atypical forms, total motile spermatozoa, forward motile spermatozoa and the number of pregnancies between the two groups that treated with LC + LAC or placebo respectively. Seven randomised controlled trials (RCTs) involving 693 patients were included in our analysis. We found that patients who treated with LC and LAC had significantly increased the percentage of forward sperm motility (MD 6.98; 95% CI 1.06–12.90; p = .02), total motile spermatozoa (MD 16.45; 95% CI 8.10–24.79; p = .0001), forward motile spermatozoa (MD 13.01; 95% CI 11.08–14.94; p < .00001) and the number of pregnancies (OR 3.76; 95% CI 1.66–8.50; p = .002). However, no significant differences were found in other semen indicators between the two groups. LC and LAC can significantly increase part of the semen parameters. The combination therapy of LC and LAC is effective in the men with iOAT.     

原发性肉碱缺乏症的筛查、诊断、治疗及基因型研究

目的 分析新生儿及母源性原发性肉碱缺乏症(PCD)临床筛查、诊断、治疗及基因型,为PCD的临床诊治提供依据。方法 采用串联质谱法(MS/MS)对2009年1月1日—2018年12月31日在浙江省医疗机构出生后3 d的新生儿足跟血进行多种遗传代谢病筛查。游离肉碱(C0)低于本实验室切值的可疑患儿及其母亲同时召回确诊。结果 共筛查3 040 815例新生儿,血C0低于正常参考值(切值＜10μmol/L)者4 459例,确诊PCD 患儿121例(其中男55例,女66例);发病率为1/25 131。对确诊后随访资料完整的111例患儿分析显示:初筛C0值为(5.94±2.01)μmol/L、召回复查C0值为(5.70±1.99)μmol/L,差异无统计学意义(t=1.05,P>0.05)。左卡尼汀初始剂量为40～200mg/(kg·d),维持剂量时C0的水平为(24.94±10.26)μmol/L,显著高于治疗前C0水平(t=20.728,P<0.001)。母源性PCD 64例,发病率为1/47 513,C0平均为(3.31±1.79)μmol/L。111例PCD患儿共检出SLC22A5基因上42种变异,其中以c.1400C>G (p.S467C) 突变最为常见,约占33.33%(74/222);其次为c.51C>G(p.F17L)占14.73 %。93.75%的母源性PCD患者母亲进行基因检测(60/64),c.1400C>G (p.S467C) 突变约占35.83%(43/120)。除2例患儿不明原因死亡外,其他PCD患儿生长发育正常。结论 PCD可通过新生儿疾病筛查早期发现,但需排除母源性肉碱缺乏症。基因检测可明确诊断,SLC22A5 c.1400C>G (p.S467C) 变异是浙江省PCD患者最常见的突变类型。左卡尼汀治疗有效,但需要长期规范治疗与随访。