Carnitine levels in iron-deficient rat pups

Hypertriglyceridemia and fatty livers have been observed in pups of Fe-deficient rats. Lowered tissue carnitine level is proposed as a mechanism responsible for altered lipid metabolism. Two hydroxylases involved in carnitine synthesis have been shown to require Fe in vitro. To determine if dietary Fe deficiency reduces tissue carnitine levels, two groups of 12 rats were fed 6 ppm Fe (-Fe) or 250 ppm Fe (+Fe) ad libitum from d 1 gestation to d 16 lactation. Feeding -Fe diets to dams resulted in 15% lower hemoglobin levels in pups on d 2 (P less than 0.02) and 50% lower levels on d 16 (P less than 0.001). Total carnitine level (nanomoles/milligram noncollagen protein) and triacylglycerol were assayed in pup tissues on d 2 and 16. While tissue carnitine and triacyglycerol was similar on d 2, d 16 liver carnitine was lower (P less than 0.001), triacylglycerol was eightfold higher in -Fe pups than in controls. Fe deficiency did not alter either carnitine concentration in milk on d 2 or 16 or the concentration of amino acid precursors of carnitine in milk on d 16. Decreased carnitine levels in the -Fe rat pup are contribute to triacylglycerol accumulation in liver.     

Urinary excretion of zinc, copper and iron in the streptozotocin-diabetic rat

The influence of the chemically diabetic condition on urinary excretion of zinc, copper and iron was investigated. Male Sprague-Dawley rats were injected with streptozotocin to induce insulin-dependent diabetes (day 0) and 24-hour urinary collections taken 1, 4, 7, 10 and 14 days later. Onset of the diabetic condition was correlated with a rapid and persistent increase in the amounts of the three trace metals excreted daily in the urine. Diabetic rats excreted 3.4-, 5.0- and 4.9-fold more zinc, copper and iron, respectively, than controls in the urine on day 14. Insulin treatment of diabetic rats significantly reduced the quantities of the micronutrients excreted in urine, suggesting that altered hormonal status was the primary cause of increased urinary losses. Enhanced urinary output of the metals was not associated with reduction in the plasma, liver and kidney contents of zinc, copper and iron. Urinary trace metal excretion was correlated with food ingestion and urinary volume with greater amounts lost during the dark period for control and diabetic animals. The influence of endocrine status on urinary excretion of trace metals is discussed.     

Carnitine in the perinatal period of mammals

Our present day knowledge on the role of carnitine may be summarized as follows: (1) carnitine is essential for fatty acid oxidation and ketone formation, (2) carnitine is essential for heat production in brown adipose tissue of suckling rats (see also 42), (3) the newborn rat and probably man require carnitine in their food since they cannot make it in sufficient amounts. This is probably not the case in the adult, since surgical patients fed intravenously maintain normal plasma levels of carnitine for at least 20 days.     

Carnitine alters binding of aflatoxin to DNA and proteins in rat hepatocytes and cell-free systems.

The objective of this study was to determine effects of L-carnitine on aflatoxin B(1) (AFB(1))-DNA adduct formation in isolated rat hepatocytes, its dose response, specificity and mode of action. All experiments were conducted in either freshly isolated rat hepatocytes or cell-free systems. There was negative linear correlation between the dosage of carnitine and formation of [(3)H]AFB(1)-DNA adducts in the hepatocytes; however, the partitioning of AFB(1) into cellular compartments was not affected by carnitine. The attenuating effect of carnitine on AFB(1)-DNA adduct formation was also present in a cell-free system, but there was lack of specificity because acetylcarnitine and gamma-aminobutyric acid (GABA) were equally effective. Carnitine appears to interfere with bioactivation of AFB(1) and binding of AFB(1)-epoxide to DNA. On the contrary, carnitine enhanced the binding of AFB(1) and its epoxide to microsomal proteins, plasma proteins and bovine serum albumin. These results indicate that carnitine diverts AFB(1)-epoxide away from DNA by promoting binding to proteins. We conclude that modulation of AFB(1) binding to proteins and DNA by carnitine alters the carcinogenic and hepatotoxic potential of AFB(1) and poses concerns about the human AFB(1)-exposure data based on the AFB(1)-albumin adduct concentrations as a biomarker.     

Carnitine Metabolism In Man

Recent developments in assay methodology for carnitine and acylcamitine have made advances in our understanding of carnitine metabolism in physiological and various pathological conditions possible.     

The Role of Carnitine and Carnitine Supplementation During Exercise in Man and in Individuals with Special Needs

Carnitine is critical for normal skeletal muscle bioenergetics. Carnitine has a dual role as it is required for long-chain fatty acid oxidation, and also shuttles accumulated acyl groups out of the mitochondria. Muscle requires optimization of both of these metabolic processes during peak exercise performance. Theoretically, carnitine availability may become limiting for either fatty acid oxidation or the removal of acyl-CoAs during exercise. Despite the theoretical basis for carnitine supplementation in otherwise healthy persons to improve exercise performance, clinical data have not demonstrated consistent benefits of carnitine administration. Additionally, most of the anticipated metabolic effects of carnitine supplementation have not been observed in healthy persons. The failure to demonstrate clinical efficacy of carnitine may reflect the complex pharmacokinetics and pharmacodynamics of carnitine supplementation, the challenges of clinical trial design for performance endpoints, or the adequacy of endogenous carnitine content to meet even extreme metabolic demands in the healthy state.

In patients with end stage renal disease there is evidence of impaired cellular metabolism, the accumulation of metabolic intermediates and increased carnitine demands to support acylcarnitine production. Years of nutritional changes and dialysis therapy may also lower skeletal muscle carnitine content in these patients. Preliminary data have demonstrated beneficial effects of carnitine supplementation to improve muscle function and exercise capacity in these patients.

Peripheral arterial disease (PAD) is also associated with altered muscle metabolic function and endogenous acylcarnitine accumulation. Therapy with either carnitine or propionylcarnitine has been shown to increase claudication-limited exercise capacity in patients with PAD.

Further clinical research is needed to define the optimal use of carnitine and acylcarnitines as therapeutic modalities to improve exercise performance in disease states, and any potential benefit in healthy individuals.     

Carnitine femoral arterial-venous differences in the stressed critically ill

Femoral arterial and venous carnitine concentrations from critically ill patients were measured in order to determine if the large urinary carnitine excretions seen in these patients was associated with a net loss of carnitine from skeletal muscle. Bloods were drawn two or three times during the 7-day study period. A 24-hr urine sample was obtained on the same day. The arterial-venous difference for free carnitine plus short chain acylcarnitine was -2.8 +/- 0.9 microM (means +/- SEM), and -2.7 +/- 1.0 microM for total carnitine. Both values were significantly less than zero (p less than 0.05). Median urinary free carnitine excretion was 1237 mumol/day while the median acylcarnitine excretion was 544 mumol/day. We conclude that skeletal muscle in these patients is in negative carnitine balance, and is at least one source of the increase in carnitine excretion seen in critically ill patients.     

Carnitine increases glucose disposal in humans

OBJECTIVE: The goal of this work is to assess the effect of L-carnitine on glucose disposal, particularly on insulin sensitivity, in healthy volunteers. METHODS: Fourteen healthy human volunteers were subjected to the intravenous glucose tolerance test (analyzed by means of the minimal model technique), together with indirect calorimetry and measurement of serum free fatty acids, after a bolus of glucose plus carnitine (C) or a bolus of glucose plus saline (P). RESULTS: The minimal model demonstrated a significant increase in glucose disposal from plasma with carnitine: Glucose effectiveness passed from 2.7%/min to 3.8%/min. No significant changes were observed in the Insulin Sensitivity Index or in Insulin/C-Peptide secretion. Calorimetry showed a significant increase in respiratory quotient, resulting from a significant increase in carbohydrate oxidation rate during carnitine administration by an average of 0.0176+/-0.0118 g/min (p=0.015). Energy expenditure was not modified by treatment. A smaller decrease in plasma fatty acid concentrations was noted with carnitine plus glucose than after glucose alone. CONCLUSIONS: From these data it appears that carnitine stimulates glucose disposal and oxidation in the healthy volunteer. Therefore, carnitine might be useful as an adjunct in the therapy of diabetes mellitus.     

Carnitine as an essential nutrient

Carnitine performs a critically important role in energy metabolism and is synthesized in the healthy adult predominantly in the liver and kidney. The typical well balanced American diet contains significant amounts of carnitine as well as the essential amino acids and micronutrients needed for carnitine biosynthesis. Thus carnitine is an infrequent problem in the healthy, well nourished adult population in the United States. However, carnitine can be a conditionally essential nutrient for several different types of individuals. Preterm infants require carnitine for life-sustaining metabolic processes but have a carnitine biosynthetic capability that is not fully developed. There is an increasing number of documented problems with carnitine metabolism in preterm infants not receiving an exogenous source of carnitine indicating that endogenous biosynthesis of carnitine is not adequate to meet the infant's need. Children with different forms of organic aciduria appear to have a greatly increased need for carnitine to function in the excretion of the accumulating organic acids. This need exceeds their dietary carnitine intake and carnitine biosynthetic capability. Renal patients treated with chronic hemodialysis appear to lose carnitine via the hemodialysis treatment, and this loss cannot be repleted simply by endogenous biosynthesis and dietary intake. Treatment with drugs such as valproic acid and metabolic stresses such as trauma, sepsis, organ failure, etc, can also result in a requirement for exogenous carnitine. Accurate assessment of the carnitine status of patients at risk for carnitine deficiency is fundamental to the identification of those patients who require carnitine as the result of altered metabolism.     

Carnitine nutriture of dialysis patients

Hemodialysis patients often experience muscle weakness, cardiac arrhythmias, and hypertriglyceridemia, along with other conditions that may lead to atherosclerosis and coronary heart disease. A contributing factor in the etiology of the symptoms may be carnitine deficiency. Patients undergoing renal dialysis treatment are at risk for developing a carnitine deficiency. The small carnitine molecule can be easily lost into the dialysate. A diseased kidney may lead to a decrease in the endogenous supply of carnitine since the kidney is a major site of carnitine biosynthesis. The diet of dialysis patients may be limiting in preformed carnitine as well as in the precursors and micronutrients required for carnitine biosynthesis. Both oral and intravenous supplementation of L-carnitine have been shown to alleviate muscle weakness, reduce the incidence and severity of arrhythmias, and decrease plasma triglyceride levels, along with alleviating other complications noted in dialysis patients. Health care professionals must be aware of the possible benefits of providing carnitine supplementation for renal dialysis patients.     

Antihyperglycemic effect of umbelliferone in streptozotocin-diabetic rats

The present study was designed to investigate the antihyperglycemic effect of Umbelliferone (UMB) in normal and streptozotocin (STZ)-diabetic rats. Diabetes was induced in adult male albino rats of the Wistar strain, weighing 180-200 g, by administration of STZ (40 mg/kg of body weight) intraperitoneally. Diabetic rats showed an increase in levels of blood glucose and glycosylated hemoglobin (HbA(1c)) and activities of gluconeogenic enzymes such as glucose-6-phosphatase and fructose-1,6-bisphosphatase, and a decrease in levels of plasma insulin, hemoglobin (Hb), and liver glycogen and activities of glucokinase and glucose-6-phosphate dehydrogenase. Intraperitoneal administration of UMB (10, 20, and 30 mg/kg of body weight) and glibenclamide (600 micro g/kg of body weight) in 10% dimethyl sulfoxide dissolved in water, for 45 days, produced significantly decreased levels of blood glucose and HbA(1c) and activities of glucose-6-phosphatase and fructose-1,6-bisphosphatase, while elevating levels of plasma insulin, Hb, and liver glycogen and activities of glucokinase and glucose-6-phosphate dehydrogenase to near normal levels in STZ-diabetic rats when compared with normal control rats. Normal rats treated with UMB (30 mg/kg of body weight) also showed a significant effect on glycemic control. Thus, our results show that UMB at 30 mg/kg of body weight possesses a promising antihyperglycemic effect that is comparable with glibenclamide.     

An Enzymatic Function of Carnitine

With palmitale (but not shorter chain fatty acids) the addition of carnitine to rat liver homogenates increases the formation of ketone bodies but has no influence on carbon dioxide production.