Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carnitine and its derivative propionyl-L-carnitine are endogenous cofactors which enhance carbohydrate metabolism and reduce the intracellular buildup of toxic metabolites in ischemic conditions. The carnitines have been, and are being used in a spectrum of diseases including multiple cardiovascular conditions. These include angina, acute myocardial infarction, postmyocardial infarction, congestive heart failure, peripheral vascular disease, dyslipidemia, and diabetes. Most published data on carnitine, propionyl-L-carnitine, and other carnitine congeners are favorable but the clinical trials have been relatively small. In currently used doses, these substances are virtually devoid of significant side effects.
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PMID:Carnitine and its derivatives in cardiovascular disease. 940 79

This study was designed to study the pathogenesis of cardiomyopathy in animals with longstanding (6 months) diabetes mellitus. Male Wistar rats were made diabetic by the injection of streptozotocin (35 mg/kg) intraperitoneal at 6 months of age. Myocardial contractility was evaluated at 1 year of age by an echocardiogram. Blood was collected at that time to measure blood glucose and hemoglobin A1c as an indicator of metabolic control. Serum carnitine was also measured on the same sample to evaluate the availability of this substance so essential for fatty acid metabolism in the myocardium. Myocardial anatomy was evaluated by both light and electron microscopy after the animals had diabetes for 6 months. It was found that the left ventricular volume was greater at the end of systole and diastole. There was the suggestion of left ventricular fractional shortening and calculated reduced ejection fraction indicating decreased contractility consistent with cardiomyopathy. The hearts had no evidence of coronary vascular occlusion, and the serum cholesterol was normal. Myocardial ultrastructure revealed abnormal-appearing mitochondria consistent with carnitine deficiency. Serum and myocardial carnitine levels in the animals with diabetes and reduced myocardial function were low. Carnitine levels and metabolism could be important in the pathogenesis of diabetic cardiomyopathy.
J Diabetes Complications
PMID:Diabetic cardiomyopathy and carnitine deficiency. 1043 72

Carnitine derivatives may have beneficial effects on cardiac and nerve function in patients with diabetes. The aim of this study was to investigate the effect of acetyl-L-carnitine (ALC) on myocardial sympathetic nervous function as measured with 123I-meta-iodobenzyl guanidine (MIBG) and single-photon emission tomography (SPET) in 19 patients with diabetes (placebo group, n = 6; ALC group, n = 13) at the beginning and at the end of a 1-year randomized, placebo-controlled, double-blind trial. The coefficient of variation for the MIBG analysis was 4%. In patients who were given a placebo, global myocardial MIBG uptake deteriorated during the study (MIBG uptake 1-year follow-up/baseline, 0.86 +/- 0.05, mean +/- standard error of mean), whereas in patients treated with ALC, MIBG uptake did not change significantly (1-year follow-up/baseline, 1.07 +/- 0.08; p = 0.03 between the groups). On the basis of these preliminary data, we conclude that long-term treatment with ALC may be of potential value in preventing the progressive loss of myocardial sympathetic nervous function in patients with diabetes. MIBG-SPET is a sensitive and thus valuable method in assessing the development of myocardial sympathetic nervous dysfunction.
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PMID:Long-term effect of acetyl-L-carnitine on myocardial 123I-MIBG uptake in patients with diabetes. 1075 Jun 38

Carnitine is an endogenous cofactor involved in the transport of long-chain fatty acids into the mitochondria where they undergo beta-oxidation. Through another reaction, carnitine produces free coenzyme A and reduces the ratio of acetyl-coenzyme A to coenzyme A, thereby enhancing oxidative use of glucose, augmenting adenosine triphosphate synthesis, and reducing lactate production and acidosis. Because of its regulatory action on the energy flow from the different oxidative sources, especially under ischemic conditions, carnitine has been used in cardiovascular diseases such as coronary heart disease, congestive heart failure, peripheral vascular disease, dyslipidemia, diabetes, and chronic renal diseases with satisfactory results. A flap is also a relatively ischemic tissue and may obtain benefit from carnitine. To investigate this, 30 rats were divided into three groups of 10 animals: a control group and two carnitine-treated groups. Random dorsal skin flaps were elevated on the rats. In the control group, no pharmacologic agents were used. Of the two treated groups, group 1 was treated with 50 mg/kg/day carnitine for 1 week and group 2 was treated with 100 mg/kg/day carnitine for 1 week. The areas of flap necrosis were measured in each group. The median areas of flap necrosis of the groups were 12.55, 9.23, and 4.9 cm2, respectively. There was a statistically significant improvement of flap necrosis in carnitine-treated groups compared with the control group (group 2, p = 0.001; group 3, p = 0.000). Furthermore, there was less necrosis in the high-dose carnitine-treated group than the low-dose carnitine-treated group. As a conclusion, carnitine may have a dose-dependent effect to increase flap survival in random skin flaps.
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PMID:The effect of carnitine on random-pattern flap survival in rats. 1154 53

Carnitine acyltransferases have crucial roles in the transport of fatty acids for beta-oxidation. Dysregulation of these enzymes can lead to serious diseases in humans, and they are targets for therapeutic development against diabetes. We report the crystal structures of murine carnitine acetyltransferase (CRAT), alone and in complex with its substrate carnitine or CoA. The structure contains two domains. Surprisingly, these two domains share the same backbone fold, which is also similar to that of chloramphenicol acetyltransferase and dihydrolipoyl transacetylase. The active site is located at the interface between the two domains. Carnitine and CoA are bound in deep channels in the enzyme, on opposite sides of the catalytic His343 residue. The structural information provides a molecular basis for understanding the catalysis by carnitine acyltransferases and for designing their inhibitors. Specifically, our structural information suggests that the substrate carnitine may assist the catalysis by stabilizing the oxyanion in the reaction intermediate.
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PMID:Crystal structure of carnitine acetyltransferase and implications for the catalytic mechanism and fatty acid transport. 1252 98

l-Carnitine and its esters are products of intermediary metabolism of organisms. The distribution pattern or the favored excretion of individual acylcarnitines tells something about metabolic diseases. The determination of the urinary acylcarnitine pattern by flow injection analysis (FIA)-electrospray ionization (ESI)-mass spectrometry (MS) is presented. Groups of healthy probands and patients suffering from diabetes mellitus were investigated due to their significant acylcarnitine profile. The statistical analysis of data sets obtained clearly shows a difference in the acylcarnitine pattern of healthy and sick probands. In comparison to the controls, diabetes mellitus patients excrete more long-chain carnitine esters ranging from dodecanoyl to palmitoylcarnitine. Thus, the urinary acylcarnitine pattern determined by ESI-MS can be a useful tool in the diagnosis and therapy monitoring of diabetes mellitus.
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PMID:The pattern of urinary acylcarnitines determined by electrospray mass spectrometry: a new tool in the diagnosis of diabetes mellitus. 1256 Sep 63

Carnitine is an ammo acid derivative found in high energy demanding tissues (skeletal muscles, myocardium, the liver and the suprarenal glands). It is essential for the intermediary metabolism of fatty acids. Carnitine is indispensable for beta-oxidation of long-chain fatty acids in the mitochondria but also regulates CoA concentration and removal of the produced acyl groups. AcylCoAs act as restraining factor for several enzymes participating in intermediary metabolism. Transformation of AcylCoA into acylcarnitine is an important system for removing the toxic acyl groups. Although primary deficiency is unusual, depletion due to secondary causes, such as a disease or a medication side effect, can occur. Primary carnitine deficiency is caused by a defect in plasma membrane carnitine transporter in muscle and kidneys. Secondary carnitine deficiency is associated with several inborn errors of metabolism and acquired medical or iatrogenic conditions, for example in patients under valproate and zidovuline treatment. In cirrhosis and chronic renal failure, carnitine biosynthesis is impaired or carnitine is lost during hemodialysis. Other chronic conditions like diabetes mellitus, heart failure, Alzheimer disease may cause carnitine deficiency also observed in conditions with increased catabolism as in critical illness. Preterm neonates develop carnitine deficiency due to impaired proximal renal tubule carnitine re-absorption and immature carnitine biosynthesis. Carnitine stabilizes the cellular membrane and raises red blood cell osmotic resistance but has no metabolic influence on lipids in dialysis patients. L-Carnitine has been administered in senile dementia, metabolic nerve diseases, in HIV infection, tuberculosis, myopathies, cardiomyopathies, renal failure anemia and included in baby foods and milk.
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PMID:Carnitine metabolism and deficit--when supplementation is necessary? 1276 64

Carnitine acyltransferases catalyze the exchange of acyl groups between coenzyme A (CoA) and carnitine. They have important roles in many cellular processes, especially the oxidation of long-chain fatty acids, and are attractive targets for drug discovery against diabetes and obesity. These enzymes are classified based on their substrate selectivity for short-chain, medium-chain, or long-chain fatty acids. Structural information on carnitine acetyltransferase suggests that residues Met-564 and Phe-565 may be important determinants of substrate selectivity with the side chain of Met-564 located in the putative binding pocket for acyl groups. Both residues are replaced by glycine in carnitine palmitoyltransferases. To assess the functional relevance of this structural observation, we have replaced these two residues with small amino acids by mutagenesis, characterized the substrate preference of the mutants, and determined the crystal structures of two of these mutants. Kinetic studies confirm that the M564G or M564A mutation is sufficient to increase the activity of the enzyme toward medium-chain substrates with hexanoyl-CoA being the preferred substrate for the M564G mutant. The crystal structures of the M564G mutant, both alone and in complex with carnitine, reveal a deep binding pocket that can accommodate the larger acyl group. We have determined the crystal structure of the F565A mutant in a ternary complex with both the carnitine and CoA substrates at a 1.8-A resolution. The F565A mutation has minor effects on the structure or the substrate preference of the enzyme.
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PMID:Structural and biochemical studies of the substrate selectivity of carnitine acetyltransferase. 1515 26

Carnitine is essential for the lipid and carbohydrate metabolism, and proper metabolic control in type 1 diabetes has potential impact on long-term complications. The plasma total, free, and acylcarnitine levels in 47 children and adolescents with type 1 diabetes were determined by a radioisotopic assay and compared to the values of a series of anthropometric measurements and metabolic parameters, including blood glycosylated hemoglobin Alc, serum cholesterol and triglycerides, and urine microalbumin levels. Plasma values for total, free, and acylcarnitine were 30.1+/-7.26, 20.0+/-4.50, and 10.2+/-6.47 micromol/l, respectively. Acyl/free carnitine ratio was 0.544+/-0.369. Individuals with type 1 diabetes had significantly lower total and free carnitine levels and significantly higher acyl/free carnitine ratios than controls (P<.001). Plasma total and free carnitine levels were inversely correlated to the duration of diabetes (P=.036 and P=.071, respectively). No statistical relationship was documented between carnitine levels and the remaining anthropometric and metabolic variables. In conclusion, total and free carnitine levels are decreased in children and adolescents with type 1 diabetes. This reduction is time related and may have potential interactions with the long-term complications of type 1 diabetes. Larger studies are required for final conclusions to be drawn on the precise role of carnitine and the possible benefit, if any, of carnitine supplementation in diabetic patients.
J Diabetes Complications
PMID:Carnitine deficiency in children and adolescents with type 1 diabetes. 1533

Carnitine status in humans is reported to vary according to body composition, gender, and diet. Plasma carnitine concentration positively correlates with the dietary intake of carnitine. The content of carnitine in foodstuff is based on old and inadequate methodology. Nevertheless, dietary carnitine is important. The molecular biology of the enzymes of carnitine biosynthesis has recently been accomplished. Carnitine biosynthesis requires pathways in different tissues and is an efficient system. Overall biosynthesis is determined by the availability of trimethyllysine from tissue proteins. Carnitine deficiency resulting from a defect in biosynthesis has yet to be reported. The role of carnitine in long-chain fatty acid oxidation is well defined. Recent evidence supports a role for the voltage-dependent anion channel in the transport of acyl-CoAs through the mitochondrial outer membrane. The mitochondrial outer membrane carnitine palmitoyltransferase-I in liver can be phosphorylated and when phosphorylated the sensitivity to malonyl-CoA is greatly decreased. This may explain the change in sensitivity of liver carnitine palmitoyltransferase-I observed during fasting and diabetes. Recently reported data clarify the role of carnitine and the carnitine transport system in the interplay between peroxisomes and mitochondrial fatty acid oxidation. Lastly, the buffering of the acyl-CoA/CoA coupled by carnitine reflects intracellular metabolism. This mass action effect underlies the use of carnitine as a therapeutic agent. In summary, these new observations help to further our understanding of the molecular aspects of carnitine in medicine.
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PMID:Carnitine: a nutritional, biosynthetic, and functional perspective. 1536 36


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